1 a Clinical Approach to Inherited Metabolic Diseases

Home , Argininemia, Citrullinemia, Costeff syndrome, Fanconi syndrome, Fumarase deficiency, GLUT1 deficiency

1 A Clinical Approach to Inherited Metabolic Diseases

Jean-Marie Saudubray, Isabelle Desguerre, Frédéric Sedel, Christiane Charpentier

Introduction – 5 1.1 Classification of Inborn Errors of Metabolism – 5 1.1.1 Pathophysiology – 5 1.1.2 Clinical Presentation – 6 1.2 A cute Symptoms in the Neonatal Period and Early Infancy (<1 Year) – 6 1.2.1 Clinical Presentation – 6 1.2.2 Metabolic Derangements and Diagnostic Tests – 10 1.3 L ater Onset Acute and Recurrent Attacks (Late Infancy and Beyond) – 11 1.3.1 Clinical Presentation – 11 1.3.2 Metabolic Derangements and Diagnostic Tests – 19 1.4 Chronic and Progressive General Symptoms/Signs – 24 1.4.1 Gastrointestina l Symptoms – 24 1.4.2 Muscle Symptoms – 26 1.4.3 Neurological Symptoms – 26 1.4.4 Specific Associated Neurological Abnormalities – 33 1.5 Specific Organ Symptoms – 39 1.5.1 Cardiology – 39 1.5.2 Dermatology – 39 1.5.3 Dysmorphism – 41 1.5.4 Endocrinology – 41 1.5.5 Gastroenterology – 42 1.5.6 Hematology – 42 1.5.7 Hepatology – 43 1.5.8 Immune System – 44 1.5.9 Myology – 44 1.5.10 Nephrology – 45 1.5.11 Neurology – 45 1.5.12 Ophthalmology – 45 1.5.13 Osteology – 46 1.5.14 Pneumology – 46 1.5.15 Psychiatry – 47 1.5.16 Rheumatology – 47 1.5.17 Stomatology – 47 1.5.18 Vascular Symptoms – 47 References – 47

5 1 1.1 · Classification of Inborn Errors of Metabolism

1.1 Classification of Inborn Errors Introduction of Metabolism Inborn errors of metabolism (IEM) are individually rare, but collectively numerous. The recent application of 1.1.1 Pathophysiology tandem mass spectrometry (tandem MS) to newborn screening and prenatal diagnosis has enabled pre- From a pathophysiological perspective, metabolic disorders symptomatic diagnosis for some IEM. However, for can be divided into the following three diagnostically useful most, neonatal screening tests are either too slow, groups. expensive or unreliable and, as a consequence, a simple method of clinical screening is mandatory before initi- Group 1: Disorders which give rise to intoxication. This ating sophisticated biochemical investigations. The group includes inborn errors of intermediary metabolism clinical diagnosis of IEM relies upon a limited number that lead to an acute or progressive intoxication from the of principles: accumulation of toxic compounds proximal to the meta- 4 To consider IEM in parallel with other more com- bolic block. In this group are the inborn errors of amino mon conditions; for example, sepsis or anoxic- acid catabolism (phenylketonuria, maple syrup urine dis- ischemic encephalopathy in neonates, and intoxi- ease, homocystinuria, tyrosinemia etc.), most organic aci- cation, encephalitis and brain tumors in older durias (methylmalonic, propionic, isovaleric etc.), con- patients. genital urea cycle defects, sugar intolerances (galactosemia, 4 To be aware of symptoms that persist and remain hereditary fructose intolerance), metal intoxication (Wilson, unexplained after the initial treatment and the Menkes, hemochromatosis), and porphyrias. All the con- usual investigations have been performed. ditions in this group share clinical similarities: they do not 4 To suspect that any neonatal death may possibly interfere with the embryo-fetal development and they be due to an IEM, particularly those that have been present with a symptom-free interval and clinical signs of attributed to sepsis. »intoxication«, which may be acute (vomiting, coma, liver 4 To carefully review all autopsy findings. failure, thromboembolic complications etc.) or chronic 4 Not to confuse a symptom (such as peripheral (failure to thrive, developmental delay, ectopia lentis, car- neuropathy, retinitis pigmentosa, cardiomyopathy, diomyopathy etc.). Circumstances that can provoke acute etc.) or a syndrome (such as Reye syndrome, Leigh metabolic attacks include catabolism, fever, intercurrent syndrome, sudden infant death, etc.) with etiology. illness and food intake. Clinical expression is often both late 4 To remember that an IEM can present at any age, in onset and intermittent. The diagnosis is straightforward from fetal life to old age. and most commonly relies on plasma and urine amino acid, 4 To know that although most genetic metabolic organic acid and acylcarnitine chromatography. Most errors are hereditary and transmitted as recessive of these disorders are treatable and require the emergency disorders, the majority of individual cases appear removal of the toxin by special diets, extra-corporeal proce- sporadic because of the small size of sibships in dures, or »cleansing« drugs (carnitine, sodium benzoate, developed countries. penicillamine, etc.). 4 To initially consider inborn errors which are amena- Although the pathophysiology is somewhat different ble to treatment (mainly those that cause intoxica- the inborn errors of neurotransmitter synthesis and cata- tion). bolism (monoamines, GABA and glycine) and the inborn 4 In the acute, emergency situation, to undertake errors of amino acid synthesis (serine, glutamine, and only those few investigations that are able to diag- proline/ornithine) can also be included in this group since nose treatable IEM. they share many characteristics: they are inborn errors of 4 To obtain help from specialized centers. intermediary metabolism, their diagnosis relies on plasma, urine, and CSF investigations (amino acid, organic acid Based mainly upon personal experience over 40 years, analyses etc.), and some are amenable to treatment even this chapter gives an overview of clinical clues to when the disorder starts in utero, for example 3-phos- the diagnosis of inborn errors of metabolism in phoglycerate dehydrogenase deficiency [1]. pediatrics and adulthood. In the following pages, inborn errors amenable to treatment are printed in Group 2: Disorders involving energy metabolism. These bold. consists of inborn errors of intermediary metabolism with symptoms due at least partly to a deficiency in energy pro- Do not miss a treatable disorder duction or utilization within liver, myocardium, muscle, First take care of the patient (emergency treatment) brain or other tissues. This group can be divided into mito- and then the family (genetic counselling) chondrial and cytoplasmic energy defects. Mitochondrial defects are the most severe and are generally untreatable. 6 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

They encompass the congenital lactic acidemias (defects of often present as emergencies and are treatable, the clinical I pyruvate transporter, pyruvate carboxylase, pyruvate dehy- presentations, the metabolic abnormalities and the labora- drogenase, and the Krebs cycle), mitochondrial respiratory tory tests required for a tentative diagnosis, are described in chain disorders and the fatty acid oxidation and ketone detail. Chronic progressive generalised symptoms and signs body defects. Only the latter are partly treatable. Cytoplas- which raise suspicion of an IEM are listed in tables that mic energy defects are generally less severe. They include take into account system and organ involvement, leading disorders of glycolysis, glycogen metabolism and gluconeo- symptoms and other signs, and age of onset. Specific organ genesis, hyperinsulinism (all treatable disorders), the more presentations are listed in alphabetical order. For each recently described disorders of creatine metabolism (partly presentation, the diagnostic possibilities listed encompass treatable), and the new inborn errors of the pentose phos- not only inborn errors of metabolism, but also diverse phate pathway (untreatable). Common symptoms in this inherited syndromes which mimic and are possibly related group include hypoglycemia, hyperlactatemia, hepatome- to inborn errors, and a number of non-inherited disorders galy, severe generalized hypotonia, myopathy, cardio- which should be considered in the differential diagnosis. myopathy, failure to thrive, cardiac failure, circulatory col- All treatable disorders are printed in bold. lapse, sudden unexpected death in infancy, and brain involvement. Some of the mitochondrial disorders and pentose phosphate pathway defects can interfere with the 1.2 Acute Symptoms in the Neonatal embryo-fetal development and give rise to dysmorphism, Period and Early Infancy (<1 Year) dysplasia and malformations [2]. Diagnosis is difficult and relies on function tests, enzymatic analyses requiring biop- 1.2.1 Clinical Presentation sies or cell culture, and on molecular analyses. The neonate has a limited repertoire of responses to severe Group 3: Disorders involving complex molecules. This illness [2–4]. IEM may present with non-specific symptoms group involves cellular organelles and includes diseases that such as respiratory distress, hypotonia, poor sucking reflex, disturb the synthesis or the catabolism of complex mole- vomiting, diarrhea, dehydration, lethargy, seizures; prob- cules. Symptoms are permanent, progressive, independent lems which can easily be attributed to infection or some of intercurrent events and unrelated to food intake. All other common cause. Where a previously affected sibling lysosomal storage disorders, peroxisomal disorders, dis- has died, this may have been falsely attributed to sepsis, orders of intracellular trafficking and processing such as heart failure, or intraventricular hemorrhage, and it is im- alpha-1-antitrypsin, congenital disorders of glycosylation portant to critically review clinical records and autopsy (CDG), and inborn errors of cholesterol synthesis belong to reports when they are available. this group. Almost none are treatable acutely; however In group 1 disorders (IEM that give rise to intoxication), enzyme replacement therapy is now available for several an extremely suggestive clinical picture is that of a baby, lysosomal disorders. born at full-term after a normal pregnancy and delivery, who, after an initial entirely symptom-free period, relent- lessly deteriorates for no apparent reason and does not 1.1.2 Clinical Presentation respond to symptomatic therapy. The interval between birth and clinical symptoms may range from hours to Besides newborn screening in the general population (as for weeks, depending on the nature of the metabolic block and phenylketonuria) or in at-risk families, there are four groups the environment. Investigations, routinely performed in of clinical circumstances in which physicians are faced with sick neonates, including a chest X-ray, CSF examination, the possibility of a metabolic disorder: bacteriologic studies, and cerebral ultrasound, yield normal 4 Early symptoms in the antenatal and neonatal period results. This unexpected and »mysterious« deterioration 4 Later-onset acute and recurrent attacks of symptoms after a normal initial period is the most important indica- such as coma, ataxia, vomiting, and acidosis tion for this group of IEM. Careful re-evaluation of the 4 Chronic and progressive generalised symptoms which child’s condition is then warranted. In this context signs can be mainly gastrointestinal (chronic vomiting, failure previously interpreted as non-specific manifestations of to thrive), muscular or neurological (developmental neonatal hypoxia, infection, or other common diagnoses delay, neurological deterioration) take on a new significance. In energy deficiencies (group 2 4 Specific and permanent organ presentations suggestive disorders), clinical presentation is often less evocative of an inborn error of metabolism, such as cardiomyo- and displays variable severity. A clinical algorithm for pathy, hepatomegaly, lens dislocation etc. screening for treatable IEM in neonates is presented in . Table 1.1. These four categories of clinical conditions are presented A careful reappraisal of the child is warranted for the in the following sections. For the first two categories, which following: 7 1 1.2 · Acute Symptoms in the Neonatal Period and Early Infancy (<1 year)

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Neurological Deterioration (Coma, Lethargy) responsive to hyperketotic diet, and biotin responsive bio- I Most inborn errors that result in intoxication or energy de- tinidase deficiency can also present in the first months of ficiency are brought to a doctor’s attention because of neu- life as an epileptic encephalopathy. rological deterioration. With intoxication, the initial symp- Many other non treatable inherited disorders can pre- tom-free interval varies in duration depending on the con- sent in the neonatal period with severe epilepsy: non dition. Typically, the first reported sign is poor sucking and ketotic hyperglycinemia (NKH), D-2-hydroxyglutaric aci- feeding, after which the child sinks into an unexplained duria, and mitochondrial glutamate transporter defect (all coma despite supportive measures. At a more advanced three presenting with myoclonic epilepsy and a burst-sup- state, neurovegetative problems with respiratory abnormal- pression EEG pattern), peroxisomal biogenesis defects, res- ities, hiccups, apneas, bradycardia, and hypothermia can piratory chain disorders, sulfite oxidase deficiency and appear. In the comatose state, characteristic changes in Menkes d isease. In all these conditions, epilepsy is severe, muscle tone and involuntary movements appear. In maple with an early onset, and can present with spasms, myo- syrup urine disease (MSUD) generalized hypertonic epi- clonus, partial or generalized tonic/clonic crises. sodes with opisthotonus are frequent, and boxing or pedal- ling movements as well as slow limb elevations, spontane- Hypotonia ously or upon stimulation, are observed. Conversely, most Severe hypotonia is a common symptom in sick neonates. non metabolic causes of coma are associated with hypo tonia, It is generally observed in non metabolic inherited diseases so that the presence of »normal« peripheral muscle tone in (mainly in severe fetal neuromuscular disorders). Only a a comatose child reflects a relative hypertonia. Another few inborn errors of metabolism present with isolated hypo- neurological pattern observed in organic acidurias is axial tonia in the neonatal period and only very few are treatable. hypotonia and limb hypertonia with large amplitude trem- Discounting disorders in which hypotonia is part of a cons- ors and myoclonic jerks which are often mistaken for con- tellation of abnormalities, including, for example, major vulsions. An abnormal urine and body odor is present in bone changes, dysmorphism, malformations, or visceral some diseases in which volatile metabolites accumulate; symptoms, the most severe metabolic hypotonias are ob- the most important examples are the maple syrup odor of served in hereditary hyperlactatemia, respiratory chain dis- MSUD and the sweaty feet odor of isovaleric acidemia orders, urea cycle defects, NKH, sulfite oxidase (SO) defi- (IVA) and type II glutaric acidemia. If any of the preceding ciency, peroxisomal disorders, and trifunctional enzyme signs or symptoms are present, metabolic disorders should deficiency. Central hypotonia is associated with lethargy, be given a high diagnostic priority. coma, seizures, and neurological symptoms in NKH, SO In energy deficiencies, the clinical presentation is less deficiency, and peroxisomal disorders, and with the charac- evocative and displays a more variable severity. In many teristic metabolic changes in congenital lactic acidosis and conditions, there is no symptom-free interval. The most urea cycle disorders (hyperammonemia). Severe forms of frequent findings are a severe generalized hypotonia, rap- Pompe disease (alpha-glucosidase deficiency) can initially idly progressive neurological deterioration, and possible mimic respiratory chain disorders or trifunctional enzyme dysmorphism, or malformations. However, in contrast to deficiency when generalized hypotonia is associated with the intoxication group, lethargy and coma are rarely initial cardiomyopathy. However, Pompe disease does not strictly signs. Hyperlactatemia with or without metabolic acidosis start in the neonatal period. Finally, one of the most frequent is very frequent. Cardiac and hepatic involvement are com- causes of neonatal hypotonia is Prader-Willi syndrome, monly associated (7 below). where central hypotonia is apparently an isolated symptom Only a few lysosomal storage disorders present in the at birth which can mimick the hypotonia cystinuria syn- neonatal period with neurological deterioration. By con- drome [4a]. trast, most peroxisomal biogenesis defects present at birth The three neurological presentations are summarized with dysmorphism and severe neurological dysfunction. in . Table 1.2.

Seizures Hepatic Presentation and Hydrops Fetalis Five treatable disorders can present in the neonatal period Three main clinical groups of hepatic symptoms can be predominantly with intractable seizures: pyridoxine res- identified: ponsive seizures, pyridox(am)ine-5'-phosphate oxidase 4 Hepatomegaly with hypoglycemia and seizures suggest deficiency, folinic acid responsive seizures, 3-phospho- glycogenosis type I or III, gluconeogenesis defects, or glycerate dehydrogenase deficiency responsive to serine severe hyperinsulinism. supplementation and persistent hyperinsulinemic hypo- 4 Liver failure (jaundice, coagulopathy, hepatocellular glycemia. necrosis with elevated transaminases, and hypoglycemia Biotin responsive holocarboxylase synthetase defi- with ascites and edema) suggests hereditary fructose ciency can also rarely present predominantly with neonatal intolerance (now very rare since infant formulas are seizures. GLUT1 deficiency (brain glucose transporter), fructose free), galactosemia, tyrosinemia type I (after 9 1 1.2 · Acute Symptoms in the Neonatal Period and Early Infancy (<1 year)

. Table 1.2. Neurological presentation

Predominant Main clinical findings Biological abnormalities Most likely diagnoses clinical symptom (disorder or enzyme deficiency)

Neurological Lethargy, coma, hiccups Ketosis, acidosis MSUD (odor) deterioration Poor sucking, hypothermia Hyperlactatemia MMA, PA, IVA (odor) (mostly metabolic Hypotonia, hypertonia Leuconeutropenia MCD and treatable) Abnormal movements Thrombopenia Urea cycle defects Large amplitude tremor Hyperammonemia GA type II (odor) Myoclonic jerks Characteristic changes »Burst suppression« of AAC or OAC Abnormal odor

Seizures Isolated Metabolic ketoacidosis MCD (sometimes Generalized Organic acid profile metabolic, None Pyridoxine responsive seizures sometimes None Folinic acid responsive seizures treatable) Hypocalcemia Congenital magnesium malabsorption Hypomagnesemia Severe hypoglycemia PHHI

Generalized Low serine 3PGD Hypsarythmia (plasma/CSF) Severe microcephaly

Severe hypotonia Low HVA, 5HIAA in CSF, PNPO (pyridoxal phosphate responsive Myoclonic jerks Vanillactic (urine) seizures) Burst suppression EEG Hyperglycinemia NKH None Glutamate transporter S-sulfocysteine (AAC) Sulfite oxidase

Facial dysmorphism VLCFA, phytanic/acid Peroxisomal defects Malformations plasmalogens Severe hypotonia Glycosylated transferrin CDG Sterols in plasma Cholesterol biosynthesis defects

Severe hypotonia Isolated None Prader Willi syndrome (rarely metabolic) Hypotonia cystinuria [4a]

Not treatable Fetal distress None Severe fetal neuromuscular diseases Hydramnios Steinert Arthrogryposis Myasthenia Respiratory failure Congenital myopathy Sensitivo-motor neuropathy

Predominant dysmorphism VLCFA, phytanic acid Peroxisomal defects Malformations plasmalogens Sterols in plasma Cholesterol defects Tubulopathy Lowe syndrome Glycosylated transferrin CDG Aberrant protein O-glycosylation Polymalformative syndromes with muscular dystrophy (Walker Warburg, muscle-eye- brain, etc.) Chromosome analyses Chromosomal abnormalities

Cataract Hyperlactatemia Lowe syndrome Tubulopathy Enzyme/DNA analyses Respiratory chain

Cardiomyopathy Vacuolated lymphocytes Pompe disease Macroglossia Hyperlactatemia Respiratory chain Acylcarnitines Trifunctional enzyme

AAC, amino acid chromatography; CDG, congenital disorders of glycosylation; GA, glutaric aciduria; HVA, homovanillic acid; IVA, isovaleric acidemia; MCD, multiple carboxylase deficiency; MMA, methylmalonic aciduria; MSUD, maple syrup urine disease; NKH, non ketotic hyperglycinemia; OAC, organic acid chromatography; PA, propionic acidemia; PHHI, primary hyperinsulinemic hypoglycemia of infancy; PNPO, pyridox(am)ine-5’-phosphate oxidase; VLCFA, very long chain fatty acids; 3PGD, 3-phosphoglycerate dehydrogenase; 5HIAA, 5-hydroxyindoleaceatic acid; bold face, treatable disorders. 10 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

3 weeks), neonatal hemochromatosis, respiratory chain 1.2.2 Metabolic Derangements and I disorders, and transaldolase deficiency, a disorder of Diagnostic Tests the pentose phosphate pathway which can present with hydrops fetalis. Another disorder described in 15 new- Initial Approach and Protocol for Investigation borns from Finland displays severe fetal growth re- As soon as there is clinical suspicion of an IEM, general tardation, lactic acidosis, failure to thrive, hyperamino- supportive measures and laboratory investigations should aciduria, very high serum ferritin, hemosiderosis of be undertaken concurrently (. Table 1.3). Abnormal urine the liver and early death (GRACILE syndrome). The odors can be detected on a drying filter paper or by opening etiology of this syndrome has been recently identified a container of urine which has been closed at room tem- [5, 6]. perature for a few minutes. Although serum ketone bodies 4 Cholestatic jaundice with failure to thrive is a predomi- reach 0.5–1 mmol/l in early neonatal life, acetonuria, if ob- nant finding in alpha-1-antitrypsin deficiency, Byler served in a newborn, is always abnormal and an important disease, inborn errors of bile acid metabolism, per- sign of a metabolic disease. The dinitrophenylhydrazine oxisomal disorders, Niemann-Pick type C disease, CDG (DNPH) test screens for the presence of alpha-keto acids and citrin deficiency [7, 8]. as occur in MSUD. However, it has now largely been aban- With the exception of long-chain 3-hydroxyacyl- doned because of its poor specificity and because amino CoA dehydrogenase (LCHAD) deficiency which can acid chromatography has become much more readily avail- present early in infancy (but not strictly in the neonatal able. Hypocalcemia and elevated or reduced blood glucose period) as cholestatic jaundice, liver failure and hepatic are frequently present in metabolic diseases and the physi- fibrosis, hepatic presentations of inherited fatty acid cian should be wary of attributing marked neurological oxidation disorders and urea cycle defects consist of dysfunction purely to these findings. acute steatosis or Reye syndrome with normal bilirubin, The metabolic acidosis of organic acidurias is usually slightly prolonged prothrombin time, and moderate accompanied by an elevated anion gap. Urine pH should be elevation of transaminases rather than true liver failure. below 5; otherwise, renal acidosis is a consideration. A nor- One must emphasize that there are frequent difficul- mal blood pH does not exclude hyperlactatemia, as neutral- ties in investigating patients with severe hepatic ity is usually maintained until serum levels reach 5 mmol/l failure. At an advanced state, many non specific abnor- and more. Ammonia and lactic acid should be determined malities secondary to liver damage can be present. systematically in newborns at risk. An elevated ammonia Mellituria (galactosuria, glycosuria, fructosuria), hy- level in itself can induce respiratory alkalosis; hyper- perammonemia, hyperlactatemia, hypoglycemia after ammonemia with ketoacidosis suggests an underlying or- a short fast, hypertyrosinemia (>200 µmol/l), and hy per- ganic acidemia (OA), but an isolated hyperammonemia can methioninemia (sometimes higher than 500 µmol/l) occur. Elevated lactic acid levels in the absence of infec- are encountere d in all cases of advanced hepatocellular tion or tissue hypoxia are a significant finding. Moderate disease. elevations (3–6 mmol/l) are often observed in organic acidemias and in the hyperammonaemias; levels greater Cardiac Presentation than 10 mmol/l are frequent in hypoxia. In most anoxic Some metabolic disorders can present predominantly with lactic acidoses, ketosis is absent. Whenever it is possible, cardiac disease. Cardiac failure and a dilated hypertrophic the measurement of lactate (L), pyruvate (P), 3-hydroxy- cardiomyopathy, most often associated with hypotonia, butyrate (3OHB), and acetoacetate (AcAc) on a plasma muscle weakness, and failure to thrive, suggests fatty acid sample immediately deproteinized at the bedside, allows an oxidation disorders, respiratory chain disorders or Pompe assessment of the cytoplasmic and mitochondrial redox disease. Methylglutaconic aciduria is found in Barth syn- states through the measurement of L/P and 3OHB/AcAc drome and ketoglutarate excretion in ketoglutarate dehy- ratios, respectively. PA, MMA and IVA can induce granulo- drogenase deficiency. Several observations suggest that cytopenia and thrombocytopenia, which may be mistaken some respiratory chain disorders are tissue specific and are for sepsis. Transaldolase deficiency and early onset forms of only expressed in the myocardium. CDG type Ia can some- mevalonate kinase deficiency present with severe recurrent times present in infancy with cardiac failure due to pericar- hemolytic anemia. dial effusions, cardiac tamponnade, and cardiomyopathy. The storage of adequate amounts of plasma, urine, Many defects of long-chain fatty acid oxidation can present blood on filter paper, and CSF, is an important element in with cardiomyopathy and/or arrhythmias and conduction reaching a diagnosis. The utilization of these precious defects (auriculoventricular block, bundle branch blocks, samples should be carefully planned after taking advice ventricular tachycardia) which may lead to cardiac arrest from specialists in IEM. [9, 10]. 11 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

Identification of Five Major Types of Metabolic In our experience, types I and II (MSUD, organic aci- Distress durias), type IVa (urea cycle defects and fatty acid oxida- Once the above clinical and laboratory data have been tion disorders), nonketotic hyper glycinemia and respira- collected, specific therapeutic recommendations can be tory chain disorders, encompass more than 80% of the made (7 Chap. 4). This process is completed within 2–4h newborn infants with inborn errors of intermediary me- and often precludes waiting long periods for the results of tabolism. sophisticated diagnostic investigations. On the basis of this evaluation, most patients can be classified into one of five types (. Table 1.4). The experienced clinician will, of course, 1.3 Later Onset Acute have to carefully interpret the metabolic data, particularly and Recurrent Attacks in relation to time of collection and ongoing treatment. At (Late Infancy and Beyond) the same time it is important to collect all the biologic data listed in . Table 1.3. Some very significant symptoms (such 1.3.1 Clinical Presentation as metabolic acidosis and especially ketosis) can be moderate and transient, largely depending on the symptomatic In about 50% of the patients with inborn errors of inter- therapy. Conversely, at an advanced stage, many non- mediary metabolism, disease onset is later. The symptom- specific abnormalities (such as respiratory acidosis, severe free period is often longer than 1 year and may extend into hyperlactatemia, secondary hyperammonemia) can dis- late childhood, adolescence, or even adulthood. Each attack turb the original metabolic profile. This applies particularly can follow a rapid course ending either in spontaneous im- to IEM with a rapid fatal course such as urea cycle dis- provement or unexplained death, despite supportive mea- orders, in which the initial characteristic presentation of sures in the intensive care unit. Between attacks the patient hyperammonemia with respiratory alkalosis shifts rapidly may appear normal. Onset of acute disease may be pre- to a rather non-specific picture of acidosis and hyper- cipitated by an intercurrent event or may occur without lactatemia. overt cause. Excessive protein intake, prolonged fasting,

. Table 1.3. Protocol for emergency investigations

Immediate investigations Storage of samples

Urine Smell (distinctive odor) Urine collection: collect fresh sample and put it in the Look (distinctive color) refrigerator Acetone (Acetest, Ames) Freezing: freeze samples collected before and after treat- Reducing substances (Clinitest, Ames) ment at –20°C, and collect an aliquot 24 h after treatment. Keto acids (DNPH) Do not use them without having expert metabolic advice pH (pHstix Merck) Metabolic investigations: OAC, AAC, orotic acid, porphyrins Sulfitest (Merck) Electrolytes (Na, K), urea, creatinine Uric acid

Blood Blood cell count Plasma (5 ml) heparinized at –20°C Electrolytes (search for anion gap) Blood on filter paper: 2 spots (as »Guthrie« test) Glucose, calcium Whole blood (10-15 ml) collected on EDTA and frozen – Blood gases (pH, pCO2, HCO3, pO2) (for molecular biology studies) Uric acid Major metabolic investigations: total homocysteine, AAC, Prothrombin time acylcarnitines (tandem MS), OAC, porphyrins, neurotrans- Transaminases (and other liver tests) mitters (HPLC, tandem MS) Ammonia Lactate, pyruvate 3-hydroxybutyrate, acetoacetate Free fatty acids

Miscellaneous Lumbar puncture Skin biopsy (fibroblast culture) Chest X-ray CSF (1 ml), frozen (neurotransmitters, AA) Cardiac echography, ECG Postmortem: liver, muscle biopsies (Chap. 3) Cerebral ultrasound, EEG

AA, amino acid; AAC, amino acid chromatography; CSF, cerebrospinal fluid; DNPH, dinitrophenylhydrazine; ECG, electrocardiogram; EDTA, ethylenediaminetetra-acetic acid; EEG, electroencephalogram; MS, mass spectrometry; HPLC, high performance liquid chromatography; OAC, organic acid chromatography. 12 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.4. Classification of inborn errors revealed in the neonatal period and early in infancy

Types Clinical type Acidosis/ Other signs Most usual diagnosis Elective methods Ketosis (disorder or enzyme of investigation deficiency)

I Neurological Acidosis – NH3 N or n + MSUD (distinctive Aminoacid chromatography deterioration, DNPH +++ Lactate N odor) (plasma, urine) »Intoxication« type Acetest –/+ Blood count N Blood spot for tandem MS-MS Slow movements Glucose N Hypertonia Calcium N

II Neurological Acidosis ++ NH3 n +/++ Organic acidurias OAC by GLCMS (urine, plasma) deterioration, Acetest ++ Lactate N or n + MMA, PA, IVA, MCD Carnitine (plasma) »Intoxication« type DNPH –/+ Blood count: Ketolysis defects Carnitine esters by tandem MS Fast movements Ketoacidosis leucopenia, (urine, plasma) Dehydration thrombopenia Blood spot for tandem MS-MS Glucose N or n + Calcium N or p +

Neurological Acidosis ++/+ NH3 n +/++ Fatty acid oxidation Idem above deterioration, Acetest – Lactate n +/++ and ketogenesis Loading test »energy deficiency« DNPH – Blood count N defects GA II, CPT II, Fasting test type, with liver or No ketosis Glucose p +/++ CAT, VLCAD, MCKAT, Fatty acid oxidation studies on cardiac symptoms Calcium N or p + HMGCoA lyase lymphocytes or fibroblasts Hypoketotic hypoglycemia

III Neurological Acidosis +++/+ NH3 N or n + Congenital lactic Plasma redox states ratios (L:P, deter ioration, Acetest ++/– Blood count: ane- acidoses (pyruvate 3OHB:AcAc) »energy deficiency« Lactate +++/+ mia or N carrier, PC, PDH, OAC (urine), AAC (plasma) type, Lactic acidosis Glucose N or + Krebs cycle, Polarographic studies Tachypnea Calcium N respiratory chain) Enzyme assays (muscle, Hypotonia MCD lymphocytes, fibroblasts) Lactic acidosis (may be well tolerated)

IV a) Neurological Acidosis – NH3 n +/+++ Urea cycle defects AAC, OAC (plasma, urine) deter ioration, (alkalosis) Lactate N or n + Triple H syndrome Orotic acid (urine) »intoxication« type, Acetest –/+ Blood count N Fatty acid oxidation Liver or intestine enzyme Moderate hepato- DNPH – Glucose N defects GA II, CPT II, studies (CPS, OTC) cellular disturbances Calcium N VLCAD, LCHAD, CAT Hypotonia, seizures, PA, MMA, IVA coma

b) Neurological Acidosis – NH3 N NKH, SO plus XO AAC (plasma, CSF) deterioration, Acetest – Lactate N or n + 3PGD AAC (plasma, CSF) Seizures DNPH – Blood count N B6-responsive seizures OAC Myoclonic jerks No major Glucose N PNPO, neurotrans- OAC, neurotransmitters Severe hypotonia metabolic mitter defects (plasma, urine, CSF) disturbance Peroxisomal defects VLCFA, phytanic acid in plasma Trifunctional enzyme Acylcarnitine profile, OAC Respiratory chain Lactate (plasma) CDG Glycosylated transferrin (plasma) Cholesterol syn thesis Sterols (plasma) defects 13 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

. Table 1.4 (continued)

Types Clinical type Acidosis/ Other signs Most usual diagnosis Elective methods Ketosis (disorder or enzyme of investigation deficiency)

V a) Recurrent hypo- Acidosis ++/– Lactate n +/++ Glycogenosis type I Fasting test, Loading test glycemia with Acetest +/– NH3 n +/– (acetest –) DNA analyses, enzyme studies hepatomegaly Glycogenosis type III (liver, lymphocytes, fibroblasts) (acetest +) FBPase FAO defects Organic acids, acylcarnitine Intractable hypo- PHHI Insulin plasma levels glycemia

b) Hepatomegaly Acidosis +/– NH3 N or n + HFI DNA analyses, enzyme studies Jaundice Acetest +/– Lactate / +/++ Galactosemia Liver failure Glucose N or p ++ Tyrosinemia type I Succinyl acetone Hepatocellular necrosis Neonatal Iron-ferritin in salivary glands hemochromatosis Respiratory chain Organic acids, enzyme/DNA defects analyses TALDO Polyols (HPLC)

c) Hepatomegaly Acidosis – NH3 N Alpha-1-antitrypsin Protein electrophoresis Cholestatic Jaundice Ketosis – Lactate N Inborn errors of bile Bile acids (plasma, urine, bile by + Failure to thrive Glucose N acid metabolism tandem MS) + Chronic diarrhea Peroxisomal defects VLCFA, phytanic & pipecolic acid + osteoporosis CDG Glycosylated transferrin + rickets Niemann-Pick type C Fibroblasts studies LCHAD OAC, acylcarnitine profile Mevalonic aciduria OAC Cholesterol meta- Plasma sterols bolism Cerebrotendinous Plasma sterols xanthomatosis Citrin AAC (citrulline can be normal)

d) Hepatosplenomegaly Acidosis – NH3 N Congenital erythro- Porphyrins »Storage« signs Acetest – Lactate N or n poietic porphyria (coarse facies, ascites, Ketosis – Glucose N GM1 gangliosidosis Oligosaccharides, sialic acid hydrops fetalis, macro- DNPH – Hepatic signs ISSD (sialidosis type II) Mucopolysaccharides glossia, bone changes, +/++ I-cell disease Enzyme studies (lymphocytes, cherry red spot, Niemann-Pick type IA fibroblasts) vacuolated lympho- MPS VII cytes) Galactosialidosis + Failure to thrive CDG Glycosylated transferrin + Chronic diarrhea Mevalonic aciduria OAC + Hemolytic anemia TALDO Polyols (HPLC)

N, normal (normal values = NH3 < 80 µM; lactate < 1.5 mM; glucose 3.5-5.5 mM); +, slight; +, moderate; ++, marked; +++, significant/mas- sive; n elevated; p decreased; –, absent (acidosis) or negative (acetest, dinitrophenylhydrazine, DNPH). L, lactate; P, pyruvate; 3OHB, 3-hydroxybutyrate; AcAc, acetoacetate; GLCMS, gas liquid chromatography mass spectrometry; HPLC, high performance liquid chromatography; VLCFA, very-long-chain fatty acids. AAC, amino acid chromatography; CAT, carnitine acylcarnitine translocase; CDG, congenital disorders of glycosylation; CPS, carbamyl phosphate synthetase; CPT II, carnitine palmitoyl transferase II; FAO, fatty acid oxidation; FBPase, fructose-1,6-bisphosphatase; GA II, glutaric aciduria type II; HFI, hereditary fructose intolerance; HMG-CoA, 3-OH-3-methylglutaryl coenzyme A; ISSD, infantile sialic acid storage disease; IVA, isovaleric acidemia; LCHAD, 3-OH long-chain acyl CoA dehydrogenase; MCD, multiple carboxylase; MCKAT, medium-chain 3-ketoacylCoA A thiolase; MMA, methylmalonic acidemia; MPS VII, mucopolysaccharidosis type VII; MSUD, maple syrup urine disease; NKH, nonketotic hyperglycinemia; OAC, organic acid chromatography; OTC, ornithine transcarbamylase; PA, propionic acidemia; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PNPO, pyridox(am)ine-5’-phosphate oxidase; SO, sulfite oxidase; TALDO, transaldolase; VLCAD, very-long-chain acyl CoA dehydrogenase; XO, xanthine oxidase; 3PGD, 3-phosphoglycerate de hydrogenase; bold face, treatable disorders. 14 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.5. Diagnostic approach to recurrent attacks of coma and vomiting with lethargy

Clinical Metabolic derangements and other Most frequent diagnosis Differential diagnosis Presentation important signs (disorder or enzyme deficiency)

Metabolic coma Acidosis (metabolic) Ketosis + Respiratory chain defects Diabetes (without focal pH < 7.20 (acetest ++) MCD, PC Intoxication – neurological signs) HCO3 < 10 mmol/l MMA, PA, IVA, GA I, MSUD* Encephalitis pCO2 < 25 mmHg Ketolysis defects Gluconeogenesis defects

Ketosis – PDH, Ketogenesis defects FAO, FBPase, EPEMA

Hyperammonemia Normal glucose Urea cycle defects* Reye syndrome

NH3 > 100 µmol/l Triple H syndrome Encephalitis Respiratory alkalosis LPI Intoxication pH > 7.45 Hypoglycemia FAO (MCAD*) pCO2 < 25 mmHg HMG-CoA lyase

Hypoglycemia Acidosis + Gluconeogenesis defects Drugs and toxins (< 2 mmol/l) MSUD Ketotic hypoglycemia HMG-CoA lyase Adrenal insufficiency FAO GH deficiency Hypopituitarism

Hyperlactatemia Normal glucose PC, MCD, Krebs cycle defects (> 4 mmol/l) Respiratory chain* PDH* (without ketosis) EPEMA syndrome

Hypoglycemia Gluconeogenesis defects (ketosis variable) FAO (moderate hyperlactatemia, no ketosis)

Neurological coma Biological signs are Cerebral edema MSUD, OTC Cerebral tumor (with focal signs, very variable, can be Hemiplegia Migraine seizures, or intra- absent or moderate; Extrapyramidal signs MSUD, OTC, MMA, PA, PGK Encephalitis cranial hypertension) 7 »Metabolic coma« GA I, Wilson disease* Homocystinuria*

Caudate nucleus and BBGD putamen necrosis

Stroke-like UCD, MMA, PA, IVA* Moya Moya syndrome Respiratory chain (MELAS*) Vascular hemiplegia Homocystinurias* Cerebral thrombo- CDG phlebitis Thiamine responsive megalo- Cerebral tumor blastic anemia Fabry disease* (rarely presenting) Acid maltase* (rare)

Abnormal coagulation, Thromboembolic AT III, Protein C,S Hemolytic anemia accidents Homocystinurias* Sickle cell anemia CDG, PGK 15 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

. Table 1.5 (continued)

Clinical Metabolic derangements and other Most frequent diagnosis Differential diagnosis Presentation important signs (disorder or enzyme deficiency)

Hepatic coma Normal bilirubin Steatosis and Fibrosis FAO, UCD Reye syndrome (hepatomegaly Slight elevation of Hepatitis cytolysis or liver trans aminases Intoxication failure) Reye syndrome Hyperlactatemia Liver failure Respiratory chain defects

Hemolytic jaundice Cirrhosis Wilson disease* Chronic hepatic dysfunction

Hypoglycemia Exudative entero- Hepatic fibrosis with pathy enteropathy (CDG Ib)

AT III, antithrombin III; BBGD, biotin-responsive basal ganglia disease; CDG, congenital disorders of glycosylation; EPEMA, encephalopathy, petechiae, ethylmalonic aciduria syndrome; FAO, fatty acid oxidation; FBPase, fructose-1,6-bisphosphatase; GA, glutaric aciduria; GH, growth hormone; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IVA, isovaleric acidemia; LPI, lysinuric protein intolerance; MCAD, medium chain acyl-CoA dehydrogenase; MCD, multiple carboxylase deficiency; MELAS, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes; MMA, methylmalonic acidemia; MSUD, maple syrup urine disease; OTC, ornithine transcarbamylase; PA, propionic acidemia; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PGK, phosphoglycerate kinase; UCD, urea cycle disorders; bold face, treatable disorders; * presenting or predominant feature reported in adults .

prolonged exercise, and all conditions that enhance protein 2. Neurological coma with focal signs, seizures, severe intra- catabolism, may exacerbate such decompensations. The cranial hypertension, strokes or stroke-like episodes diagnostic approach to recurrent attacks of coma, vomiting, Although most recurrent metabolic comas are not ac- ataxia, and psychiatric disturbances, dehydration, Reye and companied by neurological signs other than encephalo- SIDS are presented in . Tables 1.5 to 1.9. Other acute mani- pathy, some patients with organic acidemias and urea festations are listed in Sect. 1.5. cycle defects present with focal neurological signs or cerebral edema. These patients can be mistakenly diag- Coma, Strokes and Attacks of Vomiting nosed as having a cerebrovascular accident or cerebral with Lethargy (. Table 1.5) tumor. In these disorders, stopping the protein intake, Acute encephalopathy is a common problem in patients delivering glucose at high infusion rate and giving (children and adults) with IEM. All types of coma can be »cleansing drugs« (carnitine, sodium benzoate, etc.) indicative of an IEM, including those presenting with focal can be life saving. Another treatable condition is biotin- neurological signs. Neither the age at onset, the accompany- responsive basal ganglia disease which presents in ing clinical signs (hepatic, gastrointestinal, neurological, childhood with a subacute encephalopathic picture of psychiatric etc.), the mode of evolution (improvement, undefined origin including confusion, vomiting, and a sequelae, death), nor the routine laboratory data, allow an vague history of febrile illness [11, 12]. inborn error of metabolism to be ruled out a priori. Two All severe forms of homocystinuria (total homo- categories can be distinguished: cysteine >100 µmol/l) can cause an acute cerebrovas- 1. Metabolic coma without focal neurological signs cular accident from late childhood to adulthood. These The main varieties of metabolic comas may all be ob- include cystathionine-β-synthase deficiency (usually served in these late-onset, acute diseases: coma with B6-responsive in the late onset presentations), the severe predominant metabolic acidosis, coma with predomi- MTHFR defects (folate responsive) and CblC, CblD nant hyperammonemia, coma with predominant hy- defects (hydroxocobalamin responsive). Patients with poglycemia, and combinations of these three major MMA may, after first presenting with metabolic decom- abnormalities. A rather confusing finding in some or- pensation, have acute extrapyramidal and cortico- ganic acidurias and ketolytic defects is ketoacidosis spinal tract involvement as a result of bilateral destruc- with hyperglycemia and glycosuria that mimics dia- tion of the globus pallidus with variable involvement of betic coma. The diagnostic approach to these meta- the internal capsule. Cerebellar hemorrhage has also bolic derangements is developed below (7 Sect. 1.3.2). been observed in IVA, PA, and MMA. 16 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

EPEMA syndrome, the molecular mechanism of anemia may be an important clue indicating a cobalamin I which has been recently identified [13], starts in general or folate disorder. early in infancy and is characterized by the association When coma is associated with hepatic dysfunction, of progressive encephalopathy with mental retardation, Reye syndrome secondary to disorders of fatty acid oxi- pyramidal signs, and bilateral lesions in the striatum, dation or the urea cycle should be considered. Hepatic resembling Leigh syndrome, relapsing petechiae, orthos- coma with liver failure and hyperlactatemia can be the pre- tatic acrocyanosis, and recurrent attacks of metabolic senting sign of respiratory chain disorders. Finally, hepatic decompensation with lactic acidosis without ketosis, coma with cirrhosis, chronic hepatic dysfunction, hemo- during which there is an exacerbation of ethylmalonic lytic jaundice, and various neurological signs (psychiatric, and methylsuccinic excretions. extra pyramidal) is a classic, but underdiagnosed manifesta- Two patients with 3-hydroxyisobutyric aciduria pre- tion of Wilson disease. senting with recurrent episodes of vomiting and ketoacidotic coma have been described [14]. Patients with Recurrent Attacks of Ataxia (. Table 1.6) mitochondrial DNA mutations have presented with Intermittent acute ataxia and disturbed behavior can be cyclical vomiting associated with intermittent lactic the presenting signs of late-onset MSUD and organic aci- acidosis [15, 16]. GA type I frequently presents with an durias, where they are associated with ketoacidosis and encephalopathic episode, mimicking encephalitis, in sometimes with hyperglycemia which can mimic diabetic association with an intercurrent gastrointestinal or viral ketoacidosis. Late onset ornithine transcarbamylase (OTC) infection. Mitochondrial encephalopathy with lactic deficiency and argininosuccinate synthetase (ASS) defi- acidosis and stroke-like episodes (MELAS) syndrome ciency can present with recurrent attacks of ataxia. Acute is another important diagnostic consideration in such ataxia associated with peripheral neuropathy is a frequent late-onset and recurrent comas. Early episodic central presenting sign of pyruvate dehydrogenase (PDH) defi- nervous system problems, possibly associated with liver ciency; moderate hyperlactatemia with a normal L/P ratio insufficiency or cardiac failure, have been the initial supports this diagnosis. Hartnup disease (the molecular findings in some cases of CDG. Wilson disease can mechanism of which has been recently identified) is a clas- rarely present with an acute episode of encephalopathy sical but very rare cause of acute recurrent ataxia. with extrapyramidal signs. In summary, all these disorders should be consid- Acute Psychiatric Symptoms (. Table 1.7) ered in the differential diagnosis of strokes or stroke- Late-onset forms of congenital hyperammonemia, mainly like episodes. Vaguely defined and/or undocumented partial OTC deficiency, can present late in childhood or in diagnoses such as encephalitis, basilar migraine, intoxi- adolescence with psychiatric symptoms. Because hyperam- cation, poisoning, or cerebral thrombophlebitis should monemia and liver dysfunction can be mild even at the time therefore be questioned, particularly when even moder- of acute attacks, these intermittent late-onset forms of urea ate ketoacidosis, hyperlactatemia, or hyperammonemia cycle disorders can easily be misdiagnosed as hysteria, is present. In fact, these apparent initial acute manifes- schizophrenia, or alcohol or drug intoxication. Acute inter- tations are frequently preceded by other premonitory mittent porphyria and hereditary coproporphyria present symptoms, which may be unrecognized or misinter- classically with recurrent attacks of vomiting, abdominal preted. Such symptoms include acute ataxia, persistent pain, neuropathy, and psychiatric symptoms. Finally, pa- anorexia, chronic vomiting, failure to thrive, hypotonia, tients with homocysteine remethylation defects may and progressive developmental delay – all symptoms present with schizophrenia-like, folate-responsive episodes. that are often observed in urea cycle disorders, respira- In view of these possible diagnoses, it is justified to syste- tory chain defects, and organic acidurias. Late onset matically measure ammonia, porphyrins, plasma homo- forms of PDH can present in childhood with recurrent cysteine and copper in every patient presenting with un- attacks of ataxia, sometimes described by the patient as explained acute psychiatric symptoms. Episodes of acute recurrent episodes of pain or muscular weakness (due psychosis also occur in the newly described autosomal to dystonia or to peripheral neuropathy). dominant disorder neuroferritinopathy which is associated with low serum ferritin [17, 18]. Certain features or symptoms are characteristic of particular disorders. For example, macrocephaly is a frequent Dehydration (. Table 1.8) finding in glutaric aciduria type I; unexplained episodes of In pediatrics, dehydration is a common consequence of dehydration may occur in organic acidurias; and hepato- diarrhea caused by a variety of enteral or parenteral acute megaly at the time of coma is an important although in- infections. However, these common infectious diseases consistent finding in fructose-1,6-bisphosphatase defi- can occasionally trigger acute decompensation of an IEM. ciency. Severe hema tologic manifestations and recurrent Moreover, aside from dehydration due to gastrointestinal infections are common in IVA, PA, and MMA. Macrocytic losses, some IEM can present as recurrent attacks of de- 17 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

. Table 1.6. Diagnostic approach to recurrent attacks of ataxia/+ lethargy

Clinical Metabolic derangements Additional symptoms Most frequent Differential diagnosis presentation or other important signs diagnosis (disorder or enzyme deficiency)

Acute ataxia Ketoacidosis Distinctive odor Late onset MSUD Diabetes Characteristic AAC and OAC Neutropenia MMA, PA, IVA profiles Thrombopenia Hyperglycemia

Hyperammonemia Respiratory alkalosis Urea cycle defects Intoxication (sometimes slight elevation) Hepatomegaly OTC, ASA Encephalitis AAC, orotic acid Brain tumor

Hyperlactatemia Normal L/P ratio PDH Migraine (sometimes very moderate No ketosis Cerebellitis (varicella) and only in post-prandial state) Peripheral neuropathy Polymyoclonia Acetazolamide responsive High L/P ratio MCD ataxia Ketosis Respiratory chain Acute exacerbation in chronic Cutaneous signs defects ataxias

AAC (neutral AA in urines) Skin rashes, pellagra, Hartnup disease sun intolerance

AAC, amino acid chromatography; ASA, arginosuccinic aciduria; IVA, isovaleric acidemia; L, lactate; LPI, lysinuric protein intolerance; MCD, multiple carboxylase deficiency; MMA, methymalonic acidemia; MSUD, maple syrup urine disease; OAC, organic acid chromatography; OTC, ornithine transcarbamylase; P, pyruvate; PA, propionic acidemia; PDH, pyruvate dehydrogenase; bold face, treatable disorders.

. Table 1.7. Diagnostic approach to recurrent attacks of psychiatric symptoms

Clinical presentation Metabolic derangements Additional symptoms Most frequent diagnosis Differential or other important findings (disorder or enzyme deficiency) diagnosis

Psychiatric symptoms Hyperammonemia Slight liver dysfunction Urea cycle defects OTC, ASA, (hallucinations, (sometimes moderate) Vomiting arginase) delirium, dizziness, AAC, orotic acid Failure to thrive LPI aggressiveness, anxiety, schizophrenic-like Ketoacidosis AAC, OAC Ataxia, neutropenia Organic acid defects, behaviour, agitation) MSUD Port-wine urine Abdominal pain Acute intermittent porphyria Hysteria Porphyrins in plasma/urine All kinds of neuropathy Hereditary coproporphyria Vomiting

Homocystinuria (total Stroke, seizures Methylene tetrahydrofolate Schizophrenia homocysteine > 100 µM) Myelopathy reductase

AAC (neutral AA in urines) Skin rashes, pellagra Hartnup disease

Low serum ferritin Dystonia, Parkinsonism, Neuroferritinopathy [17,18] Hallervorden- Pallidal necrosis Spatz Low serum copper Wilson disease acanthocytosis

Foam cells in bone Vertical ophthalmoplegia Niemann Pick type C marrow

None Epilepsy, retinitis Ceroid lipofuscinosis pigmentosa

AAC, amino acid chromatography; ASA, arginosuccinic aciduria; MSUD, maple syrup urine disease; LPI, lysinuric protein intolerance; OAC, organic acid chromatography; OTC, ornithine transcarbamylase; bold face, treatable disorders. 18 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.8. Attacks of dehydration

Leading symptoms Other signs Age at onset Diagnosis (disorder or enzyme deficiency)

Severe diarrhea: Severe watery acidic diarrhea Neonatal Glucose galactose malabsorption »gastrointestinal Glycosuria Lactase causes« Hydramnios, no meconium Congenital Congenital chloride diarrhea Severe watery nonacidic diarrhea Metabolic alkalosis Low K+, Cl–

Severe watery diarrhea After weaning or when Sucrase isomaltase sucrose or starch dextrins are added to the diet

Anorexia, failure to thrive 2-4 Weeks or after weaning Acrodermatitis enteropathica Weight loss (before cutaneous lesions and alopecia)

Ketoacidosis: Polyuria Infancy to early childhood Diabetic coma »organic acidurias« Tachypnea MMA, PA, IVA Hyperglycemia 3-Ketothiolase Glycosuria Hydroxyisobutyric aciduria

Failure to thrive, Photophobia Infancy 3-6 months Cystinosis anorexia, Renal Fanconi syndrome poor feeding, polydipsia, Hypernatremia, vomiting Neonatal to first month Nephrogenic diabetes insipidus polyuria: renal Psychomotor retardation (X-linked) tubular dysfunction Spasticity

Hyperchloremia Early in infancy RTA type I (distal) Metabolic acidosis RTA type II (proximal) Alkaline urine pH RTA type IV

Hypoglycemia Early in infancy Fanconi-Bickel syndrome Hepatic glycogenosis (GLUT2 mutation) Fanconi syndrome

Pulmonary infections Infancy to early childhood Cystic fibrosis Chronic diarrhea Salty sweet

Salt-losing Severe hyponatremia End of first week of life Congenital adrenal hyperplasia syndrome: »adrenal Ambiguous genitalia dysfunctions» Unambiguous genitalia End of first week Hypoaldosteronism

Ambiguous genitalia Infancy to early childhood Congenital adrenal hypoplasia Congenital adrenal hyperplasia, late-onset forms

Unambiguous genitalia Hypo & pseudohypoaldosteronism

Hypoketotic hypoglycemia FAO defects (CPT I and II)

CPT, carnitine palmitoyl transferase; FAO, fatty acid oxidation; GLUT, glucose transporter; IVA, isovaleric acidemia; MMA, methylmalonic aciduria; PA, propionic aciduria; RTA, renal tubular acidosis; bold face, treatable disorders.

hydration secondary to polyuria, hyperventilation or ex- Reye Syndrome, Sudden Unexpected Death cessive sweating. The main accompanying findings (severe in Infancy (SUDI) and Near-miss (. Table 1.9) diarrhea, salt wasting, ketoacidosis, failure to thrive, Within the last decade, an increasing number of IEM have Fanconi syndrome) can be used to classify dehydration due been described that produce episodes fitting the criteria to IEM as shown in . Table 1.8. originally used to define Reye syndrome. There is now con- 19 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

True SUDI due to an IEM is, however, a rare event . Table 1.9. Diseases in which Reye syndrome, sudden unex- despite the large number of publications on the topic and pected death in infancy (SUDI), and near-miss have been reported despite the fact that at least 31 metabolic defects are possible Disorder or Enzyme deficiency Incidence of causes. This assertion is not true in the first week of life the syndrome in which unexpected death or near-miss is a priori due to a fatty acid oxidation disorder and the investigation of Disorders of ureagenesis Frequent Partial OTC Frequent which is mandatory. Partial carbamylphosphate synthetase Rare Partial argininosuccinic acid synthetase Rare Lysinuric protein intolerance Rare 1.3.2 Metabolic Derangements Triple H syndrome Very rare and Diagnostic Tests Disorders of mitochondrial fatty acid Frequent in oxidation & ketogenesis neonates Initial Approach, Protocol of Investigation Carnitine transport defect Rare The initial approach to the late-onset acute forms of in- CPT I Rare herited metabolic disorders, as with the approach to acute CPT II Rare Translocase Rare neonatal distress, is based on the proper use of a few screen- VLCAD / LCAD Very rare ing tests. As with neonates, the laboratory data listed in LHCAD, trifunctional protein Rare . Table 1.3 must be collected during the acute attack and MCAD Rare both before and after treatment. Multiple acyl-CoA dehydrogenase Frequent 3-Hydroxymethylglutaryl-CoA lyase Rare Main Metabolic Presentations Unknown (3-ketoacyl-CoA thiolase?) Very rare Metabolic Acidosis (. Fig. 1.1) Organic acidurias Frequent Metabolic acidosis is a very common finding in pediatrics. 3-methylcrotonyl-CoA carboxylase Very rare It can be observed in a large variety of acquired conditions, Glutaric aciduria type I Rare Respiratory chain defects Rare including infections, severe catabolic states, tissue anoxia, Others (MMA, PA, IVA, biotinidase …) Rare severe dehydration, and intoxication, all of which should be ruled out. However, these can also trigger an acute decom- Carbohydrate metabolism Very rare pensation of an unrecognized IEM. The presence or ab- Hereditary fructose intolerance Glycogenosis type I sence of ketonuria associated with metabolic acidosis is the Fructose-1,6-bisphosphatase major clinical clue to the diagnosis. When metabolic acidosis is not associated with ketosis, Metabolic diseases causing Leigh Very rare PDH deficiency, fatty acid oxidation disorders, and some and Leigh-like syndromes (PDH, PC, respiratory chain defects …) disorders of gluconeogenesis should be considered, particularly when there is moderate to severe hyperlactatemia. Peroxisomal defects Very rare All these disorders except PDH deficiency have concomi- CPT, carnitine palmitoyl transferase; IVA, isovaleric acidemia; tant fasting hypoglycemia. Although fructose-1,6-bisphos- LCAD, long chain acyl-CoA dehydrogenase; LCHAD, 3-hydroxy- phatase deficiency is classically considered to give rise to long chain acyl-CoA dehydrogenase; MCAD, medium chain ketoacidosis, some patients have had low concentrations acyl-CoA dehydrogenase; MMA, methylmalonic acidemia; OTC, of ketone bodies during hypoglycemia. When metabolic ornithine transcarbamylase; PA, propionic acidemia; VLCAD, acidosis occurs with a normal anion gap and without hyper- very long chain acyl-CoA dehydrogenase; bold face, treatable disorders. lactatemia or hypoglycemia, the most frequent cause is renal tubular acidosis (RTA) type I or II. Pyroglutamic aciduria also can present early in life with permanent, isolated siderable evidence that many of the disorders responsible metabolic acidosis, which can be mistaken for RTA type II. for Reye syndrome were misdiagnosed in the past because A number of IEM cause a metabolic acidosis with an of inadequate investigations for IEM. Another important associated ketosis. The range of serum ketone body con- reason for this underestimation is the necessity of collecting centration varies with age and nutritional state (7 Chap. 2). blood and urine specimens for metabolic investigations at Insulin-dependent diabetes, inborn errors of branched- an appropriate time in relation to the illness since most dis- chain amino acid metabolism, congenital lactic acidoses orders affecting the mitochondrial pathway, urea cycle and such as multiple carboxylase and PC deficiencies, inherited FAO disorders may produce only intermittent abnormali- defects in enzymes of gluconeogenesis and of glycogen ties. In addition, in contrast to the usual belief, a normal or synthesis (glycogen synthase), and ketolytic defects are non specific urinary organic acid and acylcarnitine pattern, the main groups of metabolic disorders. The glucose level even at the time of an acute attack, does not exclude an in- which can be high, normal, or low is the first parameter to herited FAO disorder. be considered to classify these disorders. 20 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

. Fig. 1.1. Metabolic acidosis. E3, lipoamide oxidoreductase; FBPase, MSUD, maple syrup urine disease; OA, organic aciduria; OATD, oxoacid- fructose-1,6-bisphosphatase; G6Pase, glucose-6-phosphatase; GS, gly- CoA transferase; PA, propionic acidemia; PC, pyruvate carboxylase; cogen synthase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; PDH, pyruvate dehydrogenase; SCAD, short chain acyl-CoA dehydro- IVA, isovaleric acidemia; KGDH, alpha-ketoglutarate dehydrogenase; genase; bold face, treatable disorders MCD, multiple carboxylase deficiency; MMA, methylmalonic aciduria;

In the case of hyperglycemia, the classic diagnosis is questioned when there is a concomitant severe metabolic diabetic ketoacidosis. However, organic acidurias such as acidosis. propionic, methylmalonic, or isovaleric acidemia and ketolytic defects can also be associated with hyperglycemia Ketosis (. Fig. 1.2) and glycosuria, mimicking diabetes. The distinction be- While ketonuria should always be considered abnormal in tween the different disorders is also based on ammonia and neonates, it is a physiological result of catabolism in late in- lactate levels, which are generally increased in organic fancy, childhood, and even adolescence. However as a gen- acidemias and normal or low in ketolytic defects. eral rule, hyperketosis at a level that produces metabolic aci- In the case of hypoglycemia, the first group of disorders dosis is not physiological. Ketosis which is not associated to be considered is the gluconeogenesis defects and the with acidosis, hyperlactatemia, or hypoglycemia, is likely glycogenoses. The main findings suggestive of this group to be a normal physiological reflection of the nutritional state are hepatomegaly and hyperlactatemia, although they are (fasting, catabolism, vomiting, medium-chain triglyceri de- not constant. When there is no significant hepatomegaly, enriched or other ketogenic diets). Of interest are ketolytic late-onset forms of MSUD and organic acidurias and gly- defects (succinyl-CoA transferase and 3-ketothiolase defi- cogen synthase (GS) deficiency should be considered. A ciencies) that can present with persistent moderate keton uria classic differential diagnosis is adrenal insufficiency, which occurring mainly in the fed state at the end of the day. can cause a ketoacidotic attack with hypoglycemia. Significant fasting ketonuria without acidosis is often If the glucose level is normal, congenital lactic aci- observed in glycogenosis type III in childhood (with dosis must be considered in addition to the disorders marked hepatomegaly) and in the very rare GS defect in discussed above. According to this schematic approach infancy (with normal liver size). In both disorders, there to inherited ketoacidotic states, a simplistic diagnosis of is fasting hypoglycemia, and postprandial hyperlactatemia fasting keto acidosis or ketotic hypoglycemia should be and hyperglycemia. 21 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

. Fig. 1.2. Ketosis (7 also Fig. 1.1). MCAD, medium chain acyl co- short-chain acyl-coenzyme A dehydrogenase; SCHAD, hydroxy short- enzyme A dehydrogenase; MCT, medium chain triglycerides; SCAD, chain acyl-coenzyme A dehydrogenase; bold face, treatable disorders

Ketosis without acidosis is observed in ketotic hypo- of lactate-pyruvate metabolism. Nutritional state also in- glycemias of childhood (a frequent condition) and in asso- fluences the levels of lactate and pyruvate. ciation with hypoglycemias due to adrenal insufficiency. Once the organic acidurias, urea cycle defects (mainly Absence of ketonuria in hypoglycemic states, as well as in citrullinemia), and fatty acid oxidation defects that cause fasting and catabolic circumstances induced by vomiting, secondary hyperlactatemia have been excluded as possible anorexia, or intercurrent infections, is an important ob- diagnoses, four types of inherited disorders remain to be servation, suggesting an inherited disorder of fatty considered: disorders of liver glycogen metabolism, dis- acid oxidation or ketogenesis disorder and can also be orders of liver gluconeogenesis, abnormalities of lactate- observ ed in hyperinsulinemic states at any age and in pyruvate oxidation, PDH deficiency, Krebs cycle defects, growth hormone deficiency in infancy. However, short- and deficient activity in one of the components of the res- chain 3-hydroxy acyl-CoA dehydrogenase (SCHAD), SCAD, piratory chain. The diagnosis of hyperlactatemias is largely and MCAD deficiencies can present as recurrent attacks of based upon two metabolic criteria: ketotic hypoglycemia as these enzymes are both sufficiently 4 Time of occurrence of lactic acidosis relative to feeding: in far down the β-oxidation pathway to be able to generate disorders of gluconeogenesis (fructose-1,6-bisphos- some ketones from long chain fatty acids [19]. phatase and glucose-6-phosphatase deficiencies), hyperlactatemia reaches its maximum level (up to 15 mM) Hyperlactatemia (. Table 1.10) when the patient is fasting and hypoglycemic. By con- Lactate and pyruvate are normal metabolites. Their plasma trast, in glycogenosis types III and VI and in glycogen levels reflect the equilibrium between their cytoplasmic pro- synthase deficiency, hyperlactatemia is observed only duction from glycolysis and their mitochondrial consump- in the postprandial period in patients on a carbohy- tion by different tissues. The blood levels of lactate and py- drate-rich diet. Here, hyperlactatemia never exceeds ruvate and the L/P ratio reflect the redox state of the cells. 7 mM. In pyruvate carboxylase deficiency, hyperlac- Blood lactate accumulates in circulatory collapse, in tatemia is present in both the fed and the fasted state, hypoxic insult, and in other conditions involving failure of but tends to decrease with a short fast. In disorders of cellular respiration. These conditions must be excluded be- PDH, alpha-ketoglutarate dehydrogenase, and respira- fore an inborn error of lactate-pyruvate oxidation is sought. tory chain function, maximum lactate levels are ob- Persistent hyperlactatemias can also result from many served in the fed state (although all hyperlactatemias acquired conditions, such as diarrhea, persistent infections exceeding 7 mM appear more or less permanent). In (mainly of the urinary tract), hyperventilation, and hepatic these disorders, there is a real risk of missing a moderate failure. Ketosis is absent in most hyperlactatemias second- (although significant) hyperlactatemia when the level is ary to tissue hypoxia, while it is a nearly constant finding checked only before breakfast after an overnight fast (as in most inborn errors of metabolism (except in PDH defi- it is usual for laboratory determinations). ciency, glycogenosis type I and FAO disorders). On the 4 Determinations of L/P and ketone bodies ratios before and other hand, the level of lactate is not discriminating; some after meals. These ratios indirectly reflect cytoplasmic acquired disorders are associated with very high levels, (L/P) and mitochondrial (3OHB/AcAc) redox poten- whereas it is only moderately raised in some inborn errors tial states. They must be measured in carefully collected 22 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.10. Diagnostic approach to hyperlactatemias

Time of occurence Main clinical signs Redox potential states Diagnosis (disorder or enzyme deficiency)

Only after feeding Hepatomegaly Not diagnostic Glycogenosis type III (or exacerbated after Fasting ketotic hypoglycemia Glycogen synthase feeding) Neurological signs Normal L/P ratio, no ketosis PDH, pyruvate carrier Encephalomyopathy L/P high, PC (high citrulline, low glutamine) 3OHB/AcAc low MCD Postprandial hyperketosis α-KDH (isolated or E3)

L/P high, 3OHB/AcAc high Respiratory chain defects (3-methyl- Postprandial ketosis glutaconic aciduria, Krebs cycle inter- mediates)

L/P high, No ketosis Respiratory chain

Only after fasting Prominent hepatomegaly Not diagnostic Glycogenosis type I (or exacerbated after Hypoglycemia Fructose-1,6-bisphosphatase (ketosis fasting) inconstant)

Moderate or no hepatomegaly Not diagnostic FAO (cardiac, muscle symptoms) Hypoketotic hypoglycemia Fructose-1,6-bisphosphatase

Permanent Moderate hyperlactatemia Not diagnostic Organic acidurias (MMA, PA, IVA) Recurrent attacks of ketoacidosis MAMEL syndrome [27]

Predominant hyperammonemia Not diagnostic Urea cycle defects (in neonates)

Predominant hypoglycemia Not diagnostic Glycogenosis type I Hepatomegaly Fructose-1,6-bisphosphatase

Neurological signs, encephalo- Highly diagnostic Congenital lactic acidemias myopathy, important (7 above »after feeding«) (7 above »after feeding«) hyperlactatemia (>10 mM)

3OHB, 3-hydroxybutyrate; AcAc, acetoacetate; IVA, isovaleric acidemia; KDH, ketoglutarate dehydrogenase; L, lactate; MAMEL, methyl - malonic aciduria, mitochondrial encephalopathy Leigh-like; MMA, methylmalonic acidemia; MCD, multiple carboxylase deficiency; P, pyruvate; PA propionic acidemia; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; bold face, treatable disorders.

blood samples (7 Chap. 2). Three abnormal hyper lac - All other situations, especially when the L/P ratio tatemia/pyruvicemia profiles are nearly pathognomon- is high without hyperketonemia, are compatible with ic of an inborn error of lactate-pyruvate metabolism: respiratory chain disorders, but all acquired anoxic con- When hyperpyruvicemia is associated with a nor- ditions should also be ruled out (7 above). mal or low L/P ratio (<10) without hyperketonemia, PDH deficiency or pyruvate transporter defect are Hypoglycemia (. Table 1.11) highly probable, regardless of the lactate level. Our approach to hypoglycemia is based on four major When the L/P ratio is very high (>30) and is asso- clinical criteria: liver size, characteristic timing of hypo- ciated with postprandial hyperketonemia and with a glycemia (unpredictable, only postprandial or only after normal or low 3OHB/AcAc ratio (<1.5), a diagnosis of fasting), association with lactic acidosis, and association pyruvate carboxylase (PC) deficiency (isolated or secon- with hyperketosis or hypoketosis. Other clinical findings of dary to biotinidase or holocarboxylase synthetase interest are hepatic failure, vascular hypotension, dehydra- deficiency) or alpha-ketoglutarate dehydrogenase defi- tion, short stature, neonatal body size (head circumference, ciency is virtually certain. In PC deficiency, there is a weight & height), and evidence of encephalopathy, myo- very characteristic amino acid profile with hyperam- pathy, or cardiomyopathy. Based on the liver size, hypo- monemia, high citrulline and low glutamine. glycemias can be classified into two major groups: When both L/P and 3OHB/AcAc ratios are elevated 4 Hypoglycemia with permanent hepatomegaly: Hypo- and associated with a significant postprandial hyperglycemia associated with permanent hepatomegaly is ketonemia, respiratory chain disorders should be sus- usually due to an inborn error of metabolism. However, pected. all conditions, both acquired or inherited, that are as- 23 1 1.3 · Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond)

. Table 1.11. Hypoglycemia: general approach

Leading symptoms Other signs Age at onset Diagnosis (disorder or enzyme deficiency) With permanent hepatomegaly Permanent Severe liver failure Neonatal to Galactosemia short-fast Hepatic necrosis early infancy Hereditary fructose intolerance hypoglycemia Tyrosinemia type I Neonatal hemochromatosis Respiratory chain defects Other severe hepatic failure Fibrosis, Postprandial hypoglycemia Neonatal to Hereditary fructose intolerance Cirrhosis (triggered by fructose), Vomiting early infancy Glycerol intolerance Mental retardation Early in Glycogenosis type IV Hypermethioninemia infancy SAH hydrolase Hepatic failure induced by methionine Respiratory chain defects Exudative enteropathy Early in CDG Ib Cholangitis attacks infancy Short fast hypoglycemia Isolated Fasting hypoglycemia and Infancy G6Pase Hepatomegaly Lactic acidosis, Ketosis FBPase Protuberant abdomen Infancy Glycogenosis type III and VI Fasting hypoglycemia and ketosis Postprandial hyperlactatemia Hypotonia Abnormal glycosylated transferrin Infancy CDG Failure to thrive Fanconi-like tubulopathy Infancy Fanconi-Bickel syndrome Chronic diarrhea Postprandial hyperglycemia (GLUT II mutations) Without permanent hepatomegaly With ketoacidosis Recurrent attacks Infancy to Organic acidurias Hyperlactatemia childhood Late-onset MSUD Ketolysis defects Glycerol kinase FBPase SCHAD, MCAD Respiratory chain defects Dehydration, collapse Neonatal to Adrenal insufficiency Hyponatremia childhood (central or peripheral) Acidosis without ketosis Moderate hyperlactatemia Neonatal to HMG-CoA lyase (frequent) Reye syndrome (with muscle/ infancy HMG-CoA synthase (rare) cardiac symptoms) FAO defects (frequent) Reye syndrome (idiopathic) Ketosis without acidosis Fasting hypoglycemia 1–6 years Recurrent ketotic hypoglycaemia Low lactate levels Adrenal insufficiency Small size for age SCHAD, MCAD, Macrocephaly Glycogen synthase Ketolysis defects Without acidosis or ketosis Unpredictable and postprandial Neonatal to Hyperinsulinisms hypoglycemia reactive to glucagon childhood Cortisol deficiency CDG Factitious or induced illness Short stature, short-fast hypoglycemia Infancy GH deficiency & related disorders Long-fast hypoglycemia Neonatal FAO defects (frequent) Reye syndrome to infancy HMG-CoA lyase (rare) Moderate hepatomegaly FBPase (rare) Transient cytolysis HMG-CoA synthase (rare) CDG, congenital disorders of glycosylation; FAO fatty acid oxidation disorders; FBPase, fructose-1,6-bisphosphatase; GH, growth hormone; G6Pase, glucose-6-phosphatase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; MSUD, maple syrup urine disease; A; SAH, S-adenosylhomocysteine hydrolase; bold face, treatable disorders. 24 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

sociated with severe liver failure, can give rise to severe this pattern is rarely asso ciated with inborn errors of I hypoglycemia, which appears after 2-3h of fasting and metabolism. is associated with moderate lactic acidosis and no ketosis. When hepatomegaly is the most prominent Hypoketotic hypoglycemias encompass several groups of feature without liver insufficiency, gluconeogenesis disorders including hyperinsulinemic states, growth defects (glucose-6-phosphatase deficiency, fructose- hormone deficiency, inborn errors of fatty acid oxidation, 1,6-bisphosphatase deficiency) and glycogenosis type and ketogenesis defects (7 »Ketosis« above). III, are the most likely diagnoses. Disorders presenting with hepatic fibrosis and cirrhosis, such as hereditary Hyperammonemia tyrosinemia type I, also can give rise to hypoglycemia. The diagnostic approach to hyperammonemia is developed The late-onset form of hereditary fructose intolerance in 7 Chap. 20. rarely, if ever, presents with isolated postprandial hypoglycemic attacks. S-adenosylhomocysteine hydrolase deficiency presents with fasting hypoglycemia and 1.4 Chronic and Progressive General hepatocellular insufficiency, often triggered by high Symptoms/Signs protein or methionine ingestion, and is associated with hepatic fibrosis, mental retardation, and marked hyper- As already stated, many acute presentations of inherited methioninemia. Respiratory chain disorders can present disorders that are apparently of delayed onset are preceded with hepatic failure and hypoglycemia. CDG type Ib by insidious premonitory symptoms and which may have (phosphomannose isomerase deficiency) with hepatic been ignored or misinterpreted. These signs fall schemati- fibrosis and exudative enteropathy can cause hypo- cally into three categories according to whether there is glycemia early in infancy [20, 21]. gastrointestinal, muscle or neurological involvement. 4 Hypoglycemia without permanent hepatomegaly: It is important to determine the timing of hypoglycemia and to look for metabolic acidosis and ketosis when the 1.4.1 Gastrointestinal Symptoms patient is hypoglycemic. Most episodes of hypoglycemia, due to IEM that are not accompanied by perma- Gastrointestinal findings (GI) (anorexia, failure to thrive, nent hepatomegaly, appear after at least 8h of fasting. osteoporosis, chronic vomiting) occur in a wide variety of This is particularly true for inherited fatty acid oxida- inborn errors of metabolism. Unfortunately, their cause tion disorders except in the neonatal period. Con- often remains unrecognized, thus delaying the correct versely, unpredictable postprandial or hypoglycaemia diagnosis. Persistent anorexia, feeding difficulties, chronic occurring after a very short fast (2–6h) is mostly due to vomiting, failure to thrive, frequent infections, osteo- hyperinsulinism and growth hormone deficiency or penia, and generalized hypotonia in association with related disorders. When ketoacidosis is present at the chronic diar rhea are the presenting symptoms and signs time of hypoglycemia, organic acidurias, ketolytic in a number of constitutional and acquired diseases in defects, late-onset MSUD, and glycerol kinase defi- pediatrics. They are easily misdiagnosed as cow’s milk ciencies should be considered. Here, hypoglycemia is protein intolerance, celiac disease, chronic ear, nose, and very rarely the initial metabolic abnormality. Adrenal throat infections, late-onset chronic pyloric stenosis etc. insufficiencies must be considered in the differential Congenital im muno-deficiencies are also frequently con- diagnosis, especially when vascular hypotension, sidered, although only a few present early in infancy with de hydration, and hyponatremia are present. Severe this clinical picture. hypoglycemia with metabolic acidosis and absence of From a pathophysiological point of view, it is possible to ketosis, in the context of Reye syndrome, suggests define two groups of inborn errors of metabolism present- HMG-CoA lyase deficiency, HMG-CoA synthase ing with chronic diarrhea and failure to thrive: deficiency or fatty acid oxidation disorders. Fasting 4 Disorders of the intestinal mucosa or the exocrine func- hypoglycemia with ketosis occurring mainly in the tion of the pancreas with almost exclusive intestinal morning and in the absence of metabolic acidosis effects, for example congenital chloride diarrhea, glu- suggests recurrent functional ketotic hypoglycemia, cose-galactose malabsorption, lactase and sucrase- which presents mostly in late infancy or childhood in isomaltase deficiencies, abetalipoproteinemia type II those who were small for gestational age or with macro- (Anderson disease), enterokinase deficiency, acroder- cephaly. All types of adrenal insufficiencies (peripheral matitis enteropathica, and selective intestinal malab- or central) can share this presentation. SCHAD and sorption of folate and vitamin B12, the latter also causing MCAD deficiency can on occasions present as recur- systemic disease. rent attacks of ketotic hypoglycemia [19] as can glyco- 4 Systemic disorders which also give rise to GI abnor- gen synthase deficiency. However, in our experience, malities. 25 1 1.4 · Chronic and Progressive General Symptoms

. Table 1.12. Chronic diarrhea, poor feeding, vomiting, failure to thrive

Leading symptoms Other signs Age of onset Diagnosis (disorder or enzyme deficiency)

Severe watery diarrhea Nonacidic diarrhea, Congenital Congenital chloride diarrhea Attacks of dehydration Hypochloremic alkalosis to infancy

Acidic diarrhea, Neonatal Glucose galactose malabsorption Reducing substances in stools Lactase

Acidic diarrhea, Neonatal Sucrase isomaltase Reducing substances in stools after weaning to infancy

Skin lesions, alopecia Neonatal or Acrodermatitis enteropathica post weaning

Protein losing entero- Cholangitis crisis Infancy CDG type Ib and Ih pathy Hypoglycemia

Fat-soluble vitamins Cholestatic jaundice Neonatal Bile acid synthesis defects malabsorption to infancy Infantile Refsum Severe hypo- Hepatomegaly, hypotonia, retinitis pigmen tosa, Infancy Infantile Refsum cholesterolemia deafness CDG type I Osteopenia Steatorrhea Abdominal distension, ataxia, acanthocytosis, Infancy ABL I and II (no acanthocytes, no peripheral neuropathy, retinitis pigmentosa neurological signs in type II)

Pancreatic insufficiency, neutropenia, Early in Pearson syndrome pancytopenia infancy Schwachman syndrome

Severe failure to thrive, Severe hypoglycemia, inflammatory bowel Neonatal to Glycogenosis type Ib anorexia, poor feeding, disease, neutropenia, early infancy (no splenomegaly) with predominant Hypotonia, vacuolated lymphocytes, adrenal gland Neonatal Wolman disease hepato-splenomegaly calcifications

Recurrent infections, inflammatory bowel Infancy Chronic granulomatosis disease, (X-linked)

Megaloblastic anemia, neuropathy, homocystin- 1–5 years Intrinsic factor uria, MMA

Leuconeutropenia, osteopenia, hyperammonemia, Infancy Lysinuric protein intolerance interstitial pneumonia,

Recurrent fever, inflammatory bowel syndrome, Infancy Mevalonate kinase hyper-IgD

Severe failure to thrive, Oral lesion, neuropathy, infections, pancyto penia, 1-2 years TC II anorexia, poor feeding, homocystinuria, MMA Intrinsic factor with megaloblastic Stomatitis, peripheral neuropathy, infections, Infancy Congenital folate malabsorption anemia intracranial calcifications

Severe pancytopenia, abnormal marrow Neonatal Pearson syndrome precursors, lactic acidosis

Severe failure to thrive, Severe hypoproteinemia, putrefaction diarrhea Infancy Enterokinase anorexia, poor feeding, Diarrhea after weaning, cutaneous lesions Infancy Acrodermatitis enteropathica no significant hepato- (periorificial), low plasma zinc splenomegaly, no megaloblastic Ketoacidotic attacks, vomiting Infancy Organic acidurias MMA, PA anemia Mitochondrial DNA deletions

Vomiting, lethargy, hypotonia, hyperammonemia Infancy Urea cycle defects (mainly OTC

Frequent infections, lymphopenia, Infancy Adenosine deaminase

Developmental delay, relapsing petechiae, Infancy EPEMA syndrome [13] orthostatic acrocyanosis

ABL, abetalipoproteinemia; CDG, congenital disorders of glycosylation; EPEMA, encephalopathy, petechiae, and ethylmalonic aciduria; MMA, methylmalonic acidemia; OTC, ornithine transcarb amylase; PA, propionic acidemia; TC, transcobalamin; bold face, treatable disorders. 26 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

In clinical practice, these groups are sometimes very dif- more and more difficult to screen patients on clinical I ficult to distinguish, because a number of specific intestinal grounds when the clinical symptoms consist only of rather disorders can give rise to various systemic clinical abnormal- non specific signs such as developmental delay, micro- ities and vice versa. This is summarized in . Table 1.12. cephaly, hypotonia or convulsions. Among the new categories of inborn errors of intermediary metabolism that can present with uninformative clinical manifestations are, 1.4.2 Muscle Symptoms for example, adenylosuccinase deficiency, dihydropyrimi- dine dehydrogenase deficiency, 4-hydroxybutyric aciduria, Many inborn errors of metabolism can present with severe L-2- and D-2-hydroxyglutaric acidurias, late onset NKH hypotonia, muscular weakness, and poor muscle mass. and a number of other inborn errors (7 bottom of . Table These include most of the late-onset forms of urea cycle 1.14). These disorders rarely, if ever, cause true development defects and many organic acidurias. Severe neonatal gener- arrest; rather, they cause progressive subacute developmen- alized hypotonia, progressive myopathy with or without an tal delay. Conversely, there is still an important gap between associated nonobstructive idiopathic cardiomyopathy, can neurological descriptions and biological investigations. be the specific presenting findings in a number of inherited Many well-known heritable neurological or polymalforma- energy deficiencies; the most frequent conditions are mito- tive syndromes have not been considered from a patho- chondrial respiratory chain disorders and other congenital physiological perspective and should be submitted to a hyperlactatemias, fatty acid oxidation defects, peroxisomal comprehensive biochemical evaluation. This is illustrated disorders, muscular glycogenolysis defects, alpha-glucosi- for example by the story of Canavan disease, in which dase deficiency, and some other lysosomal disorders (7 also N-acetylaspartic aciduria was only found in 1988, even Sect. 1.2.1 and 1.5.8). Hypotonia, generalized weakness, re- though the clinical phenotype had been identified in 1949 duced muscle mass and developmental delay are also and the procedure for identifying N-acetylaspartate in urine the presenting features of the Allan-Herndon-Dudley syn- was available in 1972. drome due to mutations in the monocarboxylate transport- In the following pages, IEM are listed: er 8 gene. This X-linked mental retardation syndrome in- a. according to their age at onset and their association volves the transport of triiodothyronine into neurones and with particular abnormalities, both neurological and disturbs blood levels of thyroid hormone [22]. extraneurological (7 Tables 1.13–1.17) and also b. alphabetically, under specific associated neurological abnormalities that they can cause (7 Sect. 1.4.4). 1.4.3 Neurological Symptoms Of course, these two categorizations are complementary Neurological symptoms are very frequent in inborn errors and inevitably involve redundancies. It is recommended and encompass progressive psychomotor retardation, sei- that one looks at both. zures, and a number of neurological abnormalities, in both the central and peripheral system, sensorineural defects and psychiatric symptoms. Progressive Neurological and Mental A large number of inborn errors of intermediary meta- Deterioration Related to Age (Overview) bolism present with an early and non-specific progressive . Tables 1.13 to 1.17 present a general approach to inborn developmental delay, poor feeding, hypotonia, some errors of metabolism involving neurological and/or mental degree of ataxia, and frequent autistic features. The list has deterioration. Diseases are classified according to their age lengthened rapidly as new laboratory techniques have been at onset, the presence or absence of associated extraneuro- applied. The relationship between clinical and biochemical logical signs, and the neurological presentation itself; the abnormalities is not always firmly established. Many amino- last is based largely on the clinical classification of Lyon acidopathies that were first described in the late 1950s and and Adams [24]. Inborn errors of metabolism with neuro- 1960s, when plasma and urine amino acid chromatography logical signs presenting in the neonate (birth to 1 month; was systematically used in studying mentally retarded . Table 1.2) and those presenting intermittently as acute children, must now be questioned as definitely being the attacks of coma, lethargy, ataxia, or acute psychiatric symp- cause of neurological disease. This is the case for histidine- toms, were discussed earlier (. Tables 1.5 to 1.7). mia, hyperlysinemia, hyperprolinemia, alpha-amino-adipic aciduria, saccharopinuria, Hartnup »disease« and the re- Early Infancy (. Table 1.13) cently described acetyl amino aciduria due to amino acy- Three general categories can be identified: lase I deficiency [23a]. 4 Category 1: Disorders Associated with Extraneuro- A similar picture is now emerging with organic aci- logical Symptoms. Visceral signs appear in lysosomal durias and it is therefore important to link clinical symp- dis orders. A cardiomyopathy (associated with early toms and metabolic disturbances. Conversely, it becomes neurological dysfunction, failure to thrive, and hypo- 27 1 1.4 · Chronic and Progressive General Symptoms

. Table 1.13. Progressive neurological and mental deterioration with extraneurological symptoms (1 to 12 months) (7 also Tables 1.2 and 1.4)

Leading symptoms Other signs Diagnosis (disorder or enzyme deficiency)

Visceral signs Hepatosplenomegaly Landing, I-Cell disease Storage signs, coarse facies Sialidosis type II, Niemann-Pick A Lactosyl ceramidosis

Hepatosplenomegaly Gaucher type II Opisthotonos, spasticity

Hepatomegaly Peroxisomal defects Retinitis pigmentosa CDG

Hair and cutaneous symptoms Steely brittle hair Menkes (X-linked) Trichothiodystrophy

Trichorrexis nodosa Argininosuccinic aciduria

Ichthyosis, spastic paraplegia Sjögren-Larsson syndrome Serine deficiency syndrome, CDG

Alopecia, cutaneous rashes Biotinidase Respiratory chain defects

Peculiar fat pads on buttocks CDG

Cyanosis, hypertonicity Cytochrome b-5 reductase

Kernicterus, athetosis Crigler-Najjar

Acrocyanosis, petechiae EPEMA syndrome [13]

Megabloblastic anemia Failure to thrive, RP Folate and cobalamin defects UMP synthase

Cardiac symptoms Cardiomyopathy D-2-hydroxyglutaric acidemia Heart failure, heart beat disorders Respiratory chain defects, CDG

Ocular symptoms Cherry-red spot, hydrops fetalis Landing, Galactosialidosis, Sialidosis type I

Myoclonic jerks, macrocephaly Tay-Sachs, Sandhoff

Optic atrophy, macrocephaly Canavan

Nystagmus, dystonia, stridor Pelizaeus-Merzbacher (X-linked)

Retinitis pigmentosa 7 Section 1.4.4

Abnormal eye movements Aromatic amino acid decarboxylase

Strabism CDG

Supranuclear paralysis Gaucher, Niemann-Pick type C

CDG, congenital disorders of glycosylation; EPEMA, encephalopathy, petechiae, and ethylmalonic aciduria; RP, retinitis pigmentosa; UMP, uridine monophosphate; bold face, treatable disorders.

tonia), sometimes responsible for cardiac failure, is sug- tallow, peau d’orange), and inverted nipples are highly gestive of respiratory-chain disorders, D-2-hydroxy- suggestive of CDG. A generalized cyanosis, unrespon- glutaric aciduria (with atrioventricular block), or CDG. sive to oxygen, suggests methemoglobinemia, which is Abnormal hair and cutaneous signs appear in Menkes associated with severe hypertonicity in cytochrome- disease, Sjögren-Larsson syndrome, biotinidase defi- b5 reductase deficiency. Kernicterus and athe tosis are ciency, and respiratory-chain disorders. Peculiar fat complications of Criggler-Najjar syndrome. The re- pads of the buttocks and thick and sticky skin (like cently described EPEMA syndrome is characterized by 28 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

an orthostatic acrocyanosis, relapsing petechiae, py- forms of hyperammonemia (usually OTC deficiency I ramidal signs, mental retardation, and recurrent attacks in girls) can present with an apparently non-specific of lactic acidosis. The presence of megaloblastic anemia early encephalopathy and inborn errors of neurotrans- suggests an inborn error of folate and cobalamin (Cbl) mitter synthesis, especially dopa-responsive dystonia metabolism. Ocular abnormalities can be extremely due to cyclohydrolase deficiency, tyrosine hydroxylase helpful diagnostic signs, for example cherry-red spot, deficiency, and aromatic-L-amino-acid decarboxylase optic atrophy, nystagmus, abnormal eye movements, deficiency, can masquerade as cerebral palsy. Recurrent and retinitis pigmentosa. attacks of seizures unresponsive to anticonvulsant drugs 4 Category 2: Disorders with Specific or Suggestive occurring in the first year of life is the presenting symp- Neurological Signs. Predominant extrapyramidal symptom of the blood brain-barrier glucose-transporter toms are associated with inborn errors of biopterin and (GLUT1) defect, a disorder that is improved by a hyper- aromatic-amino-acid metabolism, pyridox(am)ine ketotic diet. The diagnosis relies on the finding of a low phosphate oxidase, Lesch-Nyhan syndrome, cyto- glucose level in the CSF while the simultaneous blood chrome-b5 reductase deficiency, Criggler-Najjar syn- glucose level is normal. The new treatable cerebral drome, the early-onset form of GA type I, and cerebral folate deficiency syndrome [25] (improved by folinic creatine deficiency. Dystonia can also be observed as acid) should be also systematically screened for. a subtle but presenting sign in X-linked Pelizaeus- Merzbacher syndrome. It can be also associated with Late Infancy to Early Childhood (1–5 years) (. Table 1.15) psychomotor retardation, spastic paraplegia and ataxia In this period, diagnosis becomes easier. Five general cate- in the cerebral folate deficiency syndrome [25]. gories can be defined (. Table 1.15): Macrocephaly with a startle response to sound, 4 Category 1: with visceral, craniovertebral, ocular, or incessant crying, and irritability are frequent early signs other somatic abnormalities. These symptoms associ- in GM-2 gangliosidosis, Canavan disease, Alexander ated with a slowing or regression of development, leukodystrophy, infantile Krabbe disease, and GA type suggest mucopolysaccharidosis types I and II, muco- I. Macrocephaly can be also an initial sign in L-2-hy- lipidosis type III, oligosaccharidosis, Austin disease, droxyglutaric aciduria and in respiratory-chain dis- Niemann-Pick disease type C, Gaucher disease type III, orders due to complex-I deficiency (association with and lactosyl ceramidosis, all disorders which are usually hypertrophic cardiomyopathy). easy to recognize. Mucolipidosis type IV, which causes Recurrent attacks of neurological crisis associated major visual impairment by the end of the first year of with progressive neurological and mental deterioration life, sometimes associated with dystonia, presents with suggest Leigh syndrome, which can present at any age characteristic cytoplasmic membranous bodies in cells. from early in infancy to late childhood. Leigh syndrome In Sanfilippo syndrome, coarse facies and bone changes is not a specific disorder but, rather, the clinical pheno- may be very subtle or absent. Peroxisomal disorders type of any of several inborn errors of metabolism, some may present at this age, with progressive mental dete- of which still remain to be identified. Recurrent stroke- rioration, retinitis pigmentosa, and deafness, and in a like episodes often associated with anorexia, failure to very similar manner to Usher syndrome type II. Pyrro- thrive, and hypotonia can be presenting symptoms in line-5-carboxylate synthase deficiency presents with urea-cycle defects (mostly OTC deficiency), late-onset slowly progressive neurological and mental deteriora- MSUD, organic acidurias, GA type I, CDG and respi- tion, severe hypotonia, joint laxity, and congenital cata- ratory-chain disorders. Thromboembolic events can be racts. the presenting sign of classical homocystinuria and 4 Category 2: with progressive paraplegia and spasticity. CDG. Angelman syndrome sometimes displays a very Progressive paraplegia and spasticity are characteristic suggestive picture, with early-onset encephalopathy, of six IEM. Metachromatic leukodystrophy and neu- happy-puppet appearance, and epilepsy with a highly roaxonal dystrophy present between 12 and 24 months suggestive EEG pattern. of age with flaccid paraparesis, hypotonia, and weak- 4 Category 3: Disorders with Non-specific Develop- ness. CSF protein content and nerve conduction veloc- mental Delay. A large number of inborn errors present ity are disturbed in the former but normal in the with non-specific early progressive developmental latter. Schindler disease is roughly similar to neuro- delay, poor feeding, hypotonia, some degree of ataxia, axonal dystrophy, though it is often associated with frequent autistic features, and seizures. Many IEM can myoclonic jerks. Arginase deficiency is a rare disorder masquerade as a cerebral palsy by presenting as a per- that presents early in infancy to childhood (2 months to manent impairment of movement or posture (. Table 5 years) with progressive spastic diplegia, scissoring or 1.14). Consequently, it is mandatory to systematically tiptoe gait, and developmental arrest. A rapidly progres- screen such children for those IEM which can be at least sive flaccid paraparesis resembling subacute degenera- partly treatable. In this context, late-onset subacute tion of the cord can be the presenting sign of inherited 29 1 1.4 · Chronic and Progressive General Symptoms

. Table 1.14. Progressive neurological and mental deterioration (1 to 12 months)

Leading symptoms Other signs Diagnosis (disorder or enzyme deficiency)

With suggestive neurological signs

Extrapyramidal signs Major parkinsonism Inborn errors of biopterin metabolism Abnormal neurotransmittors Aromatic amino acid decarboxylase Tyrosine hydroxylase, PNPO

Choreoathetotis, self-mutilation Lesch-Nyhan (X-linked)

Bilateral athetosis, hypertonicity Cytochrome b5 reductase

Dystonia, stridor Pelizaeus Merzbacher (X-linked)

Kernicterus syndrome Criggler-Najjar

Acute-onset pseudoencephalitis Glutaric aciduria type I

Low cerebral creatine Creatine deficiency (GAMT)

Spastic paraplegia, ataxia, epilepsy Cerebral folate deficiency

Leigh syndrome PDH, complex I

Painful pyramidal hypertonia Opisthotonos Krabbe, Gaucher III, Nieman-Pick type C

Early epilepsy infantile spasm Spasticity NKH, SO, untreated MSUD & OA MCD, Menkes

Macrocephaly, startle response to sound Cherry red spot, myoclonic jerks Tay Sachs, Sandhoff, Canavan, Alexander Vacuolizing leucoencephalopathy

Ocular symptoms Optic atrophy, incessant crying Krabbe (infantile)

Dystonia, choreoathetosis GA I, L-2-hydroxyglutaric aciduria

Progressive irritability Respiratory chain, peroxisomal defects

Recurrent attacks of neurological crisis Failure to thrive, hyperventilation Leigh syndrome PC, PDH, respiratory chain, (7 also Sect. 1.3.1) attacks MAMEL syndrome [27])

Stroke-like episodes Urea cycle defects, MSUD, OA, GA I CDG, respiratory chain

Thromboembolic accidents Homocystinurias, CDG

Without suggestive neurological signs

Evidence of developmental arrest Infantile spasms, hypsarrhythmia Untreated PKU, biopterin defects autistic features Peroxisomal defects, Rett syndrome

Non specific symptoms, Frequent autistic features Hyperammonemia (late-onset subacute) Apparently non-progressive disorder Poor feeding, failure to thrive 4-OH-butyric, L-2-OH-, D-2-OH-glutaric acidurias

Hypotonia, seizures Mevalonic aciduria

With diverse neurological findings Adenylosuccinase, pyrimidine defects simulating cerebral palsy 3-methylglutaconic, fumarase Other OA, creatine deficiency 3-PGD, 3-phosphoserine phosphatase Homocystinurias, Salla Neurotransmittor defects, Cerebral folate deficiency Angelman, GLUT1

CDG, congenital disorders of glycosylation; GA, glutaric aciduria; GAMT, guanidino acetate methyltransferase; MAMEL, methylmalonic aciduria, mitochondrial encephalopathy Leigh-like; MCD, multiple carboxylase deficiency; MSUD, maple syrup urine disease; NKH, non ketotic hyperglycinemia; OA, organic acidurias; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; 3-PGD, 3-phosphoglycerate dehydrogenase; PNPO, pyridox(am)ine phosphate oxidase; SO, sulfite oxidase; bold face, treatable disorders. 30 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.15. Progressive neurological and mental deterioration (1 to 5 years) Symptoms Diagnosis (disorder or enzyme deficiency) With visceral, craniovertebral, or other somatic abnormalities 4 Coarse facies, skeletal changes, hirsutism, corneal opacities MPS I, MPS II, MPS III, MLP III 4 Coarse facies, subtle bone changes, lens/corneal opacities, Mannosidosis (gingival hyperplasia) hepatosplenomegaly, vacuolated lymphocytes, Fucosidosis (angiokeratoma) Aspartylglucosaminuria (joint laxity) Austin (ichthyosis) 4 Hepatosplenomegaly, progressive dementia, myoclonic jerks Niemann-Pick type C and related disorders (vertical supranuclear ophtalmoplegia) 4 Splenomegaly + hepatomegaly, osseous lesions, Gaucher type III (supranuclear ophtalmoplegia) (ataxia, myoclonus) 4 Major visual impairment, blindness Mucolipidosis type IV (corneal clouding) 4 Retinitis pigmentosa, deafness Peroxisomal defects, Usher type II 4 Cataract, joint laxity, hypotonia Pyrroline-5-carboxylase synthase With paraplegia, hypotonia, or spasticity due to corticospinal tract involvement or to peripheral neuropathy

4 Flaccid paraparesis, pyramidal signs, hyperproteinorrachia Metachromatic leukodystrophy (abnormal NCV) 4 Flaccid paraparesis, no change in CSF, optic atrophy Neuro-axonal dystrophy Schindler (normal NCV) 4 Progressive spastic diplegia, scissoring or »tiptoe« gait Arginase (high arginine, high orotic) Cbl C (subacute cord degeneration)

Triple H (recurrent attacks of hyper NH3) Costeff syndrome (OPA3 gene mutation with 3-methylglutaconic aciduria) With unsteady gait, uncoordinated movements due to cerebellar syndrome, sensory defects or myoclonia 4 Without disturbances of organic acid excretion – Ataxia, choreoathetosis, oculocephalic asynergia Ataxia telangiectasia – Ataxia, difficulty in walking, mental/speech deterioration GM1 (spastic quadriparesis, pseudobulbar signs) BBGD (caudate nucleus, putamen necrosis) – Ataxia, spinocerebellar degeneration, psychotic behavior GM2 (Tay-Sachs, Sandhoff) (late infantile form) – Ataxia, pyramidal signs, vision loss Krabbe (late infantile, peripheral neuropathy) – Ataxia, muscular atrophy, peripheral neuropathy CDG, trifunctional enzyme, peroxisomal defects – Seizures, myoclonic jerks, postictal coma, transient hemiplegia Alpers (hepatic signs, hyperlactatemia) 4 With disturbances of organic and amino acid excretion – Progressive ataxia, intention tremor, cerebellar atrophy L-2-OH-glutaric (spongiform encephalopathy) Combined degeneration of the spinal cord Cobalamin defects (CblC, CblE, CblF, CblG) – Ataxia, peripheral neuropathy, dystonia PDH (moderate hyperlactactemia) – Ataxia, weakness, RP, myoclonic epilepsy Respiratory chain, MERFF, methylglutaconic – Extrapyramidal signs Creatine deficiency (GAMT) – Ataxia, peripheral neuropathy, RP LCHAD (organic acids, acylcarnitine) – Acute attacks encephalitis-like, temporal lobe atrophy GA I (dystonia, macrocephaly) – Dystonia, athetosis, acute attacks MMA, PA, homocystinurias – Ataxia, dysarthria, optic atrophy, nystagmus Ribose-5-phosphate isomerase (polyols) With seizures and myoclonus, ataxia, frequent falling due to intention myoclonus or to the cerebellar ataxia 4 Rapid mental regression, myoclonic jerks, blindness INCL (early-flattening EEG, CLN1 mutations) 4 Akinetic myoclonic petit mal, RP, typical EEG pattern LINCL (misdiagnosed with Lennox-Gastaut) 4 Rapid regression, myoclonic seizures, spasticity Schindler (optic atrophy, severe osteoporosis) 4 Myoclonic epilepsy, volitional and intentional myoclonias, muscular MERFF, Niemann-Pick C, Gaucher III (ophtalmoplegia, weakness hepatosplenomegaly) 4 Seizures and myoclonic jerks, uncoordinated movements Alpers (hepatic symptoms, hyperlactatemia) Disorders with arrest or regression of psychic and perceptual functions as presenting symptom 4 Autistic behaviour, regression of high-level achievements, stereo- Rett syndrome (girls), sporadic (acquired microcephaly, typed movements of fingers secondary epilepsy) 4 Regression of high-level achievements, loss of speech, Sanfilippo (hirsutism, agitation) BBGD, biotin-responsive basal ganglia disease; Cbl, cobalamin; CoA, coenzyme A; CSF, cerebrospinal fluid; EEG, electroencephalogram; GAMT, guanidino acetate methyltransferase; Ig, immunoglobulin; INCL, Infantile ceroid lipofuscinosis (CLN1 mutations); LINCL, late infantile ceroid lipofuscinosis (CLN2 mutations); MERRF, myoclonic epilepsy with ragged red fibers; MLP, mucolipidosis; MPS, mucopolysaccharidosis; NCV, nerve conduction velocity; OPA, optic atrophy; PDH, pyruvate dehydrogenase; RP, retinitis pigmentosa; bold face, treatable disorders. 31 1 1.4 · Chronic and Progressive General Symptoms

Cbl-synthesis defects. Spastic paraparesis is an almost 4 Category 5: isolated developmental arrest or regres- constant finding in the triple H syndrome. sion. Only a few disorders present between 1 and 5 years 4 Category 3: with unsteady gait and uncoordinated of age with an isolated developmental arrest or regres- movements (when standing, walking, sitting, reaching sion of cognitive and perceptual abilities without other for objects, speaking, and swallowing). Several groups significant neurological or extraneurological signs. of disorders must be considered. A careful investigation Sanfilippo disease is one, although regression of high- of organic acid and amino acid metabolism is always level achievements, loss of speech, and agitation usually mandatory, especially during episodes of metabolic begin later than 5 years of age. Although non-metabolic, stress. Rett syndrome is another such disease; it should be 5 Disorders without disturbances of urinary organic considered when a girl, without a family history, presents acid excretion and lactic acid metabolism are the between 1 and 2 years of age with autistic behavior, late-onset forms of GM-1 and GM-2 gangliosido- developmental regression, typical stereotyped hand sis, late infantile Krabbe disease, ataxia telangiecta- movements, and microcephaly. sia, and CDG; each presents with signs that are sufficiently characteristic to warrant specific in- Late Childhood to Adolescence (5–15 years) vestigation. A severe early-onset encephalopathy (. Table 1.16) with seizures and myoclonic jerks associated with It is important to distinguish between conditions in which hepatic disease is highly suggestive of Alpers syn- cognitive function is primarily affected and those disorders drome due to respiratory-chain disorders. Crea- with more extensive neurological involvement with normal tine deficiency due to guanidinoacetate-methyl- or subnormal intellectual functioning. According to Lyon transferase deficiency can present in infancy, with and Adams [23], there are six clinical categories. an extrapyramidal disorder associated with epi- 4 Category 1: with predominant extrapyramidal signs lepsy, neurological regression, and failure to (parkinsonian syndrome, dystonia, choreoathetosis). thrive. 4 Category 2: with severe neurological and mental 5 Disorders with disturbances of organic and amino deterioration and diffuse central nervous system acid metabolism are numerous. PDH deficiency involvement. Category-2 patients have in common presents frequently with peripheral neuropathy, severe neurological dysfunction with bipyramidal para- intermittent ataxia, dystonia and slight or mode- lysis, incoordination, seizures, visual failure, impaired rate hyperlactatemia (7 Hyperlactatemias above). school performance, and dementia. In association with Several respiratory-chain disorders initially cause spleno megaly or hepatomegaly, these signs suggest ataxia, intention tremor, dysarthria, epilepsy, myo- Niemann-Pick disease type C or Gaucher disease type pathy, and (eventually) multiorgan failure. LCHAD III. When visceral signs are absent, they may indicate deficiency, L-2-hydroxyglutaric aciduria, 3-methyl- juvenile metachromatic leukodystrophy, X-linked glutaconic aciduria, MMA, and PA significantly adrenoleuko d ystrophy, Krabbe disease, juvenile GM-1 disturb organic acid excretion, although sometimes and GM-2 gangliosidoses, or respiratory-chain disor- only slightly and intermittently. In these disorders, ders. Peroxisomal biogenesis defects can also present in the acylcarnitine profile determined (by tandem the second decade of life with peripheral neuropathy MS) from blood spots collected on dry filter paper initially mimicking Charcot-Marie-Tooth type II dis- can be very helpful in identifying characteristic ab- ease, but which then evolves into a pyramidal syndrome, normalities. GA type I can also present with a per- intellectual deterioration, dementia and, shortly there- manent unsteady gait due to choreoathetosis and after, a neurovegetative state. with dystonia developing abruptly after an acute 4 Category 3: with polymyoclonus and epilepsy. The episode resembling encephalitis. juvenile form of ceroid lipofuscinosis (Spielmeyer-Vogt 4 Category 4: with predominant epilepsy and myo- or Batten disease due to CLN3 gene mutations), which clonus. Predominant epilepsy and myoclonus result in presents with loss of sight, retinitis, ataxia, and (at an ataxia and frequent falling and include two ceroid lipo- advanced stage) extrapyramidal signs, should be sus- fuscinoses: Santavuori-Hagberg disease (CLN1) and pected with the onset of polymyoclonus and epilepsy. Jansky-Bielchowski disease (CLN2), which is similar to After puberty, Lafora disease should also be considered. Lennox-Gastaut syndrome (akinetic myoclonic petit Gaucher disease type III, late onset GM-2 gangliosido- mal). Late-onset forms of Niemann-Pick type C and sis, Niemann-Pick disease type C, and respiratory-chain Gaucher disease are easily suspected because of hepa- disorders can also begin with polymyoclonus as an tosplenomegaly and supranuclear paralysis. Two other early major sign. disorders must also be considered: myoclonic-epilepsy 4 Category 4: with predominant cerebellar ataxia. Fried- with ragged red fibers (MERRF) syndrome and Schind- reich ataxia and other hereditary ataxias should be con- ler d isease, which is similar to neuroaxonal dystrophy. sidered and are recognized on clinical and genetic 32 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.16. Progressive neurological and mental deterioration (5 to 15 years) Symptoms Diagnosis (disorder or enzyme deficiency) With predominant extrapyramidal signs, parkinson syndrome, dystonia, choreoathetosis 4 Torsion, dystonia, no mental retardation Dystonia musculorum deformans 4 Dystonia on lower extremities, gait difficulties, normal IQ Segawa (GTP cyclohydrolase) Tyrosine hydroxylase 4 Lens dislocation, marfanoid morphology Classic homocystinuria 4 Generalized parkinsonian rigidity, scholastic failure Wilson 4 Parkinsonism, reading/writing difficulties, alacrima, dysphagia Familial glucocorticoid deficiency (with hypoglycemia) 4 Dysarthria, dysphagia, cogwhill rigidity Biotin responsive basal ganglia disease 4 Walking difficulties, dystonic posture, mental regression Panthotenate kinase (RP, acanthocytosis) 4 Orofacial dyskinesia HARP syndrome (panthotenate kinase) 4 Acute psychosis, pallidal necrosis Neuroferritinopathy [17,18] With diffuse central nervous system disorders, seizures, visual failure, dementia 4 With hepatosplenomegaly Niemann Pick type C, Gaucher type III 4 Without visceral signs Metachromatic leucodystrophy, X-ALD Peroxisomal biogenesis defects Krabbe, GM1 and GM2 Leigh syndrome, respiratory chain defects With polymyoclonia 4 Intellectual deterioration, loss of sight, RP JNCL (Batten, CLN3 mutations) 4 Proeminent seizures, myoclonic epilepsy, dementia Gaucher type III (splenomegaly, osseous signs) 4 Cerebellar ataxia, cherry red spot Late GM2 gangliosidosis (Sandhoff, Tay-Sachs) 4 Hepatomegaly, splenomegaly Niemann-Pick type C 4 Myoclonic epilepsy, lactic acidosis Respiratory chain defects (MERFF, etc.) With predominant cerebellar ataxia 4 Without significant mental deterioration – Dysarthria, pes cavus, cardiomyopathy Friedreich ataxia – Spinocerebellar degeneration Other hereditary ataxias, Peroxisomal defects – Chronic diarrhea, low cholesterol, acanthocytosis Abetalipoproteinemia – Retinitis pigmentosa, peripheral neuropathy Refsum, peroxisomal defects, CDG – Oculocephalic asynergia, conjunctival telangiectasias Ataxia telangiectasia 4 With deterioration and dementia CTX, Lafora, GM1, GM2, Gaucher, Niemann-Pick type C, Krabbe Metachromatic leukodystrophy, respiratory chain With predominant polyneuropathy 4 Acute attacks Porphyrias, tyrosinemia type I 4 Progressive – With demyelination (low NCV) Metachromatic leucodystrophy, Krabbe β-mannosidase, Refsum, peroxisomal biogenesis MNGIE syndrome – Predominantly axonal (normal NCV) LCHAD, trifunctional enzyme, PDH, homocysteine remethylation defects, CTX, peroxisomal biogenesis defects, α-methylacyl-CoA racemase, serine deficiency, P5C synthase, ornithine amino transferase Leigh syndrome, respiratory chain defects Abetalipoproteinemia With psychiatric symptoms as the only presenting sign Behaviour disturbances, personality and character OTC, homocystinurias CBS, MTHFR, CblC changes, mental regression, dementia, schizophrenia Sanfilippo, metachromatic leucodystrophy, before any significant neurological or extraneurologic sign Krabbe, Niemann-Pick C, X-ALD Leigh syndrome, JNCL (Batten), Hallervorden-Spatz (PK deficiency), Wilson, CTX, Huntington chorea (juvenile form) Neuroferritinopathy [17,18] CBS, cystathionine β-synthase; CDG, congenital disorders of glycosylation; CTX, cerebrotendinous xanthomatosis; HARP, hypobetalipopro- teinemia, acanthosis, retinitis pigmentosa, pallidal degeneration; JNCL, juvenile neuronal ceroid lipofuscinosis; MTHFR, methylene tetrahydrofolate reductase; NCV, nerve conduction velocity; OTC, ornithine transcarbamylase; RP, retinitis pigmentosa; X-ALD, X-linked adrenoleukodystrophy; bold face, treatable disorders. 33 1 1.4 · Chronic and Progressive General Symptoms

grounds. Abetalipoproteinemia and ataxia telangiec- present in the pediatric age with symptoms that are not re- tasia are usually suspected because of the associated cognised, misdiagnosed or inadequately interpreted. Meta- extraneurological signs. Peroxisomal disorders, CDG, bolic diagnosis in adults based on substrate measurements and Refsum disease (which can all present similarly to can be very difficult because metabolic changes can be very a peripheral neuropathy and retinitis pigmentosa) can moderate or even absent. A recent reappraisal of the meta- be demonstrated by the analysis of plasma very-long- bolic profile of the three infantile Refsum disease index cases chain fatty acids, glycosylated transferrin profile, and described in 1986 [26] showed an almost total normalization plasma phytanic acid, respectively. Cerebellar ataxia in of the initial characteristic biochemical abnormalities (per- association with progressive mental deterio ration, sonal unpublished observation). In . Table 1.17 is the »state d ementia, and epilepsy suggests Lafora disease, of the art« of adult metabolic neurology based upon the per- cerebrotendinous xanthomatosis, late-onset forms sonal experience of the adult metabolic clinic of La Pitié of gangliosidosis, Krabbe disease, Gaucher disease, Salpétrière hospital and on the literature analysis mostly Niemann-Pick disease type C, and metachromatic leu- composed of isolated case reports. There is no doubt that kodystrophy. Respiratory-chain disorders also can this will change significantly very soon. . Table 1.17 does not present with a predominant ataxia. d escribe the full phenotype of the listed disorders, but rather 4 Category 5: with predominant polyneuropathy. Por- emphasizes the main presenting symptom. phyrias and tyrosinemia type I can present with an acute attack of polyneuropathy mimicking Guillain- Barre syndrome. Many other disorders can present with 1.4.4 Specific Associated Neurological a late-onset progressive polyneuropathy that can mimic Abnormalities hereditary ataxia, such as Charcot-Marie-Tooth disease. These include lysosomal diseases (Krabbe disease, meta- Cherry-red Spot chromatic leukodystrophy, E-mannosidase), peroxiso- 4 Cytochrome C oxidase deficiency mal disorders (peroxin 7, other peroxisomal biogenesis 4 Galactosialidosis (neuraminidase deficiency) defects, Refsum disease with demyelination and re- 4 Gangliosidosis GM1 (Landing) duced nerve conduction velocities), defects of energy 4 Gangliosidosis GM2 (Sandhoff, Tay-Sachs) metabolism (Leigh syndrome, respiratory-chain dis- 4 Nephrosialidosis orders, PDH deficiency, LCHAD and trifunctional- 4 Niemann-Pick type A, C and D enzyme deficiencies), abetalipoproteinemia, CDG 4 Sialidosis type I (7 also Sect. 1.4.3). 4 Category 6: with behavioral disturbances as the pre- Deafness (Sensorineural) senting signs. Some inborn errors of metabolism can Detectable in neonatal to early infancy: present between 5 and 15 years of age as psychiatric 4 Acyl-CoA oxidase deficiency disorders. Behavioral disturbances (personality and 4 Alport syndrome character changes), loss of speech, scholastic failure, 4 Cockayne syndrome mental regression, dementia, psychosis, and schizo- 4 Encephalopathy with hyperkinurininuria phrenia-like syndrome are the most frequent symp- 4 Rhizomelic chondrodysplasia punctata toms. In addition OTC deficiency can present with 4 Zellweger and variants episodes of abnormal behavior and character change until hyperammonemia and coma reveal the true situa- Detectable in late infancy to childhood: tion (7 Recurrent Attacks of Coma above). Homocys- 4 Biotinidase deficiency (biotin responsive) (untreated tinuria due to methylenetetrahydrofolate reduc tase or treated late) deficiency has presented as isolated schizophrenia. 4 Infantile Refsum disease (pseudo Usher syndrome) Searching for these treatable disorders is always man- 4 Mannosidosis (alpha) datory including CTX and Wilson disease. 4 Megaloblastic anemia, diabetes and deafness (B1-responsive) Onset in Adulthood (15–70 years) 4 Mitochondrial encephalomyopathy As metabolic investigations become increasingly common 4 Mitochondrial encephalopathy with lactic acidosis and in adult neurological practice, a rapidly increasing number stroke-like episodes (MELAS), myoclonic epilepsy with of adults patients with IEM has been identified. When neu- ragged red fibers (MERFF), Kearns-Sayre syndrome rologists extend metabolic investigations to late-onset, pro- 4 Mucolipidosis type II (I cell disease) gressive, neurological deterioration, currently considered 4 Mucopolysaccharidosis type I, II and IV to be degenerative, inflammatory, or of vascular origin, it is 4 Neutral lipid storage disorder highly probable that many other disorders will be dis- 4 PRPP synthetase superactivity covered. Some disorders truely start in adulthood; others 4 Wolframm syndrome 34 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

I . Table 1.17. Progressive neurological and mental deterioration (adulthood)

Diseases Major presenting signs

(Disorder or enzyme Parkinson Dystonia, EMG poly- Epilepsy Psychiatric Spastic Cerebellar Multi- deficiency) syndrome chorea neurop athy signs paraparesia ataxia systemic

α-mannosidase +++

α-methylacyl-CoA race- ++ + mase

β-mannosidosis ++ +

L-2-OH-glutaric aciduria ++ + +

Acerulo-plasminemia ++ + + +

AMN +++

ANCL +++

Arginase +

Biotin responsive ++ encephalopathy

Cerebral ALD + (chorea) ++ +

Co-enzyme Q10 +

CTX +++++++

Dopa responsive dystonia ++

Fabry +* +

Gaucher III ++ (chorea) +++

GM1++

GM2 ++*+ +

GTP cyclohydrolase I ++ +

Hemochromatosis +

Homocysteine methyla- ++++ + tion defects

Homocystinuria ++ ++ + +

Huntington chorea ++ ++ +

Krabbe ++

Lafora ++ +

LCHAD ++

Leigh, MELAS, ++ ++ ++ Leber +

Lesch-Nyhan + + +

MAO-A +

Mevalonate kinase ++ 35 1 1.4 · Chronic and Progressive General Symptoms

. Table 1.17 (continued)

Diseases Major presenting signs

(Disorder or enzyme Parkinson Dystonia, EMG poly- Epilepsy Psychiatric Spastic Cerebellar Multi- deficiency) syndrome chorea neurop athy signs paraparesia ataxia systemic

Mitochondrial defects ++ + + + +

MLD ++ ++ +

MNGIE ++

MPS III +

Neuraminidase +

Neuro-ferritino pathy ++ +

Niemann-Pick C ++ ++ +

NKH + (chorea) ++

Oligosaccharidosis +

PA + (chorea)

PBD +++

PDH (E1) ++ + +

PK +

PKU +++

Polyglucosan body disease ++ +

Polymerase γ +++ +

Porphyria +* + +

PTP synthase +

Refsum +++

Serine deficiency + syndrome

Sjögren-Larsson +

Tangier +* +

Triple H syndrome +

Tyrosine hydroxylase ++

Urea cycle ++ +

Wilson ++ ++

ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; ANCL, adult neuronal ceroid lipofuscinosis (CLN4 mutations); CTX, cerebrotendinous xanthomatosis; LCHAD, 3-hydroxy long chain acyl-CoA dehydrogenase; MAO, mono amine oxidase; MLD, metachromatic l eucodystrophy; MNGIE, mitochondrial neuro-gastro-intestinal encephalopathy; MPS, mucopolysaccharidosis; NKH, non ketotic hyperglycinemia; PA, propionic acidemia; PBD, Peroxisome biogenesis defects; PDH, pyruvate dehydrogenase; PK, panthotenate kinase; PKU, phenylketonuria; PTP, 6-pyruvoyl tetrahydropterin; * polyneuropathy affecting small sensitive fibers and autonomic nervous system; bold face, treatable disorders. 36 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

Detectable in late childhood to adolescence: White matter hyperintensity: I 4 Beta-mannosidosis 4 With increased head circumference 4 MERFF, Kearns-Sayre syndromes 5 Alexander (anterior) 4 Refsum disease (adult form) 5 Canavan 4 Usher syndrome type II 5 Glutaric aciduria type I (bi-temporal atrophy) 5 L-2-hydroxyglutaric aciduria Leigh Syndrome 5 Mucopolysaccharidosis (with vacuoles) 4 Biotinidase deficiency 5 Vacuolizing leucoencephalopathy 4 EPEMA syndrome [13] 4 Fumarase deficiency 4 With normal head circumference 4 MAMEL syndrome [26] Predominantly periventricular white matter 4 Pyruvate carboxylase deficiency 5 Aicardi-Goutières syndrome (with calcifications) 4 Pyruvate dehydrogenase deficiency 5 CACH (vanishing white matter disease) 4 Respiratory chain disorders 5 Cerebrotendinous xanthomatosis* 4 Sulfite oxidase deficiency 5 Cockayne (with calcifications) 4 3-methylglutaconic aciduria 5 Homocysteine remethylation defects* 5 Glutaric aciduria type I* Macrocephaly 5 Kearns-Sayre 4 Alexander 5 L-2-hydroxyglutaric aciduria 4 Canavan (acetylaspartaturia) 5 Menkes 4 Gangliosidosis GM2 (Sandhoff, Tay-Sachs) 5 Metachromatic leucodystrophy* 4 Glutaric aciduria type I 5 Mitochondrial cytopathy 4 Krabbe (infantile form) 5 MNGIE (with supratentorial cortical atrophy) 4 L-2-hydroglutaric aciduria 5 Pelizaeus-Merzbacher (myelination arrest) 4 Respiratory chain disorders 5 Peroxisomal biogenesis defects*, PEX-7 4 Vacuolizing encephalopathy 5 PKU (untreated, reversible)* 5 Polyglucosan body disease* Microcephaly 5 Ribose-5-phosphate isomerase* (arabitol, ribitol) Congenital: 5 X-ALD (posterior) 4 Infant born to untreated PKU mother 5 3-methylglutaryl-CoA lyase* 4 Sulfite oxidase deficiency Predominant pyramidal tracts 4 3P-Glycerate phosphate dehydrogenase (improved by 5 Adrenomyeloneuropathy* serine) 5 Cerebrotendinous xanthomatosis* 5 Krabbe disease* Acquired: 5 Mitochondrial cytopathies* 4 Rett syndrome Affecting U fibers 4 Many untreated disorders in which microcephaly is a 5 Mitochondrial cytopathies* symptom of a non specific cerebral atrophy 5 Polyglucosan body disease* 5 Ribose-5-phosphate isomerase* (arabitol, ribitol) 1 Neuro-imaging (CT Scan, MRI, H-MRS) 5 L-2-hydroxyglutaric aciduria* Abnormalities (Bold face, treatable disorders; *reported in adults as pre- Basal ganglia/brain stem hyperintensities: senting or preponderant symptoms) 4 Biotin-responsive basal ganglia disease [12] (bilateral Calcifications on CT-scan: necrosis of caudate nucleus and putamen) 4 Aicardi-Goutières syndrome 4 Cerebrotendinous xanthomatosis* 4 Biopterin metabolism defects 4 GM1 Gangliosidosis* 4 Cockayne syndrome 4 Hypoceruleoplasminemia* (diffuse hypointensity) 4 Congenital lactic acidemias 4 Infantile bilateral striatal necrosis [28] 4 Folic acid metabolism defects 4 Leigh syndrome (putamen, caudate nuclei) 4 GM2 Gangliosidosis 4 L-2-hydroxyglutaric aciduria 4 Kearns-Sayre 4 Methylmalonic aciduria (pallidum) 4 Leigh syndrome 4 Mitochondrial cytopathies* 4 MELAS syndrome 4 Neuroferritinopathy* (pallidum) [17, 18] 4 Respiratory chain disorders 4 PKAN* (Hallervorden-Spatz, HARP syndrome: hypo- 4 3-hydroxyisobutyric aciduria intensity: tiger eye) 37 1 1.4 · Chronic and Progressive General Symptoms

4 Pyruvate dehydrogenase deficiency* Nystagmus 4 Wernicke encephalopathy* (thalami, brain stem) With retinitis pigmentosa: 4 Wilson disease* 4 Abetalipoproteinemia* 4 Ceroid lipofuscinosis (CLN1, CLN2, CLN3*, CLN4*) Dentate nuclei of the cerebellum (hyperintensities): 4 LCHAD* 4 Cerebrotendinous xanthomatosis* 4 Mitochondrial cytopathies (Kearns-Sayre* etc.) 4 L-2-hydroxyglutaric aciduria 4 Peroxisomal defects (infantile to childhood) 4 Mitochondrial encephalopathy* 4 Sjögren-Larsson (fatty acid alcohol oxido-reductase) 4 Polyglucosan body disease* 4 All causes of severe retinitis pigmentosa 4 Semialdehyde succinate dehydrogenase* 4 Wilson disease* With optic atrophy: 4 All causes of optic atrophy in adulthood* Gyration abnormalities: 4 Canavan disease (early sign) 4 CEDNIK (snare protein mutation) [29] 4 Ceroid lipofuscinosis (CLN3*, CLN4*) 4 Glutamine synthetase 4 Krabbe disease (infantile) 4 Congenital muscular dystrophy: DMC1-C (fukutin 4 Leber due to mitochondrial DNA deletions* related protein), DMC1-D (LARGE protein) 4 Leigh syndrome (all causes) 4 O-glycosylation disorders: muscle-eye-brain disease, 4 Metachromatic leucodystrophy* Walker-Warburg syndrome, Fukuyama disease 4 Mitochondrial cytopathies* 4 Peroxisomal disorders (Zellweger and others) 4 Neuroaxonal dystrophy – Schindler (infantile) 4 Pelizaeus-Merzbacher (presenting sign early in infancy) Corpus callosum agenesis: 4 Peroxisomal biogenesis defects* 4 With gyration abnormalities (7 above) 4 Pyruvate dehydrogenase deficiency* 4 ACTH deficiency 4 Ribose-5-phosphate isomerase* 4 Aicardi syndrome (with calcifications) 4 Sulfite oxidase (infantile) 4 Complex II mitochondrial cytopathies (with leucodys- 4 X-ALD* trophy) 4 3-methylglutaconic aciduria 4 Non ketotic hyperglycinemia 4 PDH (with basal ganglia abnormalities) With corneal opacities, cataract: 4 3-hydroxyisobutyric aciduria 4 Fabry disease* 4 Homocystinurias* Posterior fossa (and olivo-ponto-cerebellar): 4 Lowe syndrome (infancy) 4 Hypoplasia 4 Mucopolysaccharidosis (childhood) 5 CDG 4 Wilson disease* 5 Congenital muscular dystrophies 5 Joubert syndrome Opthalmoplegia, Ptosis, Eye Movements, 5 Mitochondrial cytopathies Strabismus (7 also Sect. 1.4.3) 5 Peroxisomal disorders Neonatal to early infancy (oculogyric crisis): 4 Progressive atrophy 4 Aromatic amino acid decarboxylase 5 Ceroid lipofuscinosis* 4 CDG Ia (with congenital strabismus) 5 GM1 Gangliosidosis (Landing) 4 Cogan syndrome (ocular contraversion) 5 L-2-hydroxyglutaric aciduria 4 Pyridox(am)ine-5-phosphate oxidase 5 Mevalonic aciduria (mevalonate kinase) 4 Tyrosine hydroxylase 5 Neuroaxonal dystrophy (infantile) 5 Schindler Infancy to childhood: 5 Smith-Lemli-Opitz 4 Ataxia telangiectasia (ocular contraversion, telangiecta- 5 Succinyl semialdehyde dehydrogenase deficiency sia) 5 3-methylglutaconic aciduria 4 Gaucher type III (horizontal supranuclear paralysis) 4 Leigh syndrome (acute attacks of abnormal move- Stroke and stroke-like episodes: ments) 4 CDG 4 Niemann-Pick C and D (vertical supranuclear paralysis) 4 Homocystinurias* 4 Pyruvate dehydrogenase (acute attacks of abnormal 4 MELAS syndrome* movements) 4 Respiratory chain (acute attacks of abnormal movements) 38 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

Adulthood: – Porphyria* I 4 Glutaric aciduria type I – Pyroglutamic aciduria (late complication) 4 GM2 gangliosidosis (abnormal eye movements) – Respiratory chain (early childhood to adoles- 4 Mitochondrial cytopathies: Kearns-Sayre (abnormal cence) move ments) – Serine deficiency syndrome (adolescence) 4 Niemann-Pick C, Gaucher III (7 above) – Triose phosphate isomerase 4 Non ketotic hyperglycinemia 5 Affecting small sensitive fibers and the autonomic 4 Pyruvate dehydrogenase (abnormal movements) nervous system 4 Wilson disease – Fabry disease* (presenting sign) – GM2 gangliosidosis* Peripheral Neuropathy – EMG, NCV Findings – Porphyria* Acute (recurrent attacks): – Tangier disease* 4 Porphyrias* 5 Affecting anterior horn 4 Tyrosinemia type I – GM2 gangliosidosis, Krabbe disease – Homocysteine remethylation defects (ClbC) Chronic: – Non ketotic hyperglycinemia 4 Predominantly demyelination (low NCV) – Panthotenate kinase (Hallervorden-Spatz) (basal 5 Presenting or preponderant ganglia) – Refsum disease (late childhood to adulthood) – Polyglucosan body disease* – X-ALD (childhood to adulthood): leucodystrophy – AMN (adulthood) Retinitis Pigmentosa 5 Accompanying symptom 4 Aceruleoplasminemia* – Austin disease 4 Congenital disorders of glycosylation – E-mannosidosis 4 Ceroid lipofuscinosis: CLN1, CLN2; LCN3 – Farber lipogranulomatosis 4 Cobalamin metabolism defects: CblC* – Homocysteine remethylation defects (MTHFR, 4 Gyrate atrophy with ornithine aminotransferase defi- CblC) ciency – Krabbe (leucodystrophy) 4 Inborn errors of lipid metabolism: – Metachromatic leucodystrophy (leucodystrophy) 5 Abetalipoproteinemia – MNGIE syndrome (leucodystrophy) 5 Sjögren-Larsson syndrome – Refsum disease 5 Vitamin E malabsorption (tocopherol carrier), – Tangier disease 5 3-hydroxyacyl-CoA dehydrogenase 4 Predominantly axonal (normal NCV) 4 Panthothenate kinase* (Hallervorden-Spatz, 5 Presenting or preponderant HARP syndrome) – Abetalipoproteinemia (childhood) 4 Peroxisomal biogenesis defects: – D-methylacyl-CoA racemase (adolescence to 5D-methylacyl-CoA racemase* adult hood) 5 Classical Refsum disease* – CDG type I (childhood) 5 Isolated fatty acid oxidation defects – GM2 gangliosidosis* 5 Peroxisomal biogenesis defects (Zellweger, NALD, – LCHAD, trifunctional (childhood to adoles- Refsum and variant forms) cence) 4 Respiratory chain disorders: – Peroxisomal biogenesis defects (late childhood 5 Kearns-Sayre syndrome* to adult) 5 NARP – Polyglucosan body disease* (leucodystrophy) 5 Other mitochondrial DNA deletions – Pyruvate dehydrogenase (childhood to adult- 4 Recessive autosomal syndromes (Cockayne, Laurence- hood) Moon-Biedl, Usher type II, Joubert, Senior-Loken etc.) – Vitamin E malabsorption (tocopherol carrier) 4 »Primary retinitis pigmentosa« X-linked, autosomal 5 Accompanying symptom recessive or dominant – Cerebrotendinous xanthomatosis* (leucodystrophy) Self Mutilation, Auto-aggression – Neuroaxonal dystrophy, Schindler (early child- 4 Lesch-Nyhan syndrome hood) (leucodystrophy) 4 Phenylketonuria (untreated) – Ornithine amino transferase (late complica- 4 Tyrosinemia type I (crisis) tions) 4 3-methylglutaconic aciduria – P5C synthase (late childhood) 39 1 1.5 · Specific Organ Symptoms

1.5 Specific Organ Symptoms Cardiomyopathy 4 AMP activated protein kinase (presenting sign) A number of clinical or biological abnormalities can be [30, 31] associated with inherited inborn errors of metabolism. 4 Barth syndrome Some of these phenotypes are rare and very distinctive (e.g., 4 Congenital disorders of glycosylation (with pericardial lens dislocation and thromboembolic accidents in homo- effusion, can be the presenting sign) cystinuria) whereas others are common and rather non- 4 Congenital muscle dystrophies specific (e.g., hepatomegaly, seizures, mental retardation). 4 D-2-hydroxyglutaric aciduria The most important ones are listed below. The following 4 Fabry disease diagnostic checklist presented is primarily based upon the 4 Fatty acid oxidation disorders (presenting sign) authors’ personal experience and, of course, is not exhaus- 4 Friedreich ataxia (presenting sign) tive. It should be progressively extended by the personal 4 Glycogenosis type III and IV experiences of all readers. 4 GM1 gangliosidosis It is important to reemphasise the difference between a 4 Isobutyryl-CoA dehydrogenase syndrome where the underlying pathophysiology has not 4 Methylmalonic aciduria (Cbl C), malonic aciduria been described and a disorder where the aetiology is known. 4 Mucopolysaccharidosis Some well-known recessive syndromes (such as Joubert, 4 Muscle glycogen synthase (presenting sign) [32] Usher, Cockayne etc.) have been listed under inborn errors 4 Pompe disease, Danon disease (presenting sign) of metabolism, highlighting the need to perform extensive 4 Propionic acidemia metabolic and genetic investigations. The demonstration of 4 Respiratory chain disorders (presenting sign) cholesterol synthesis defects in a number of malformative 4 Selenium deficiency syndromes or the more recent demonstration of O-glyco- 4 Steinert disease – myotonic dystrophy sylation defects in congenital muscular dystrophies illus- 4 Thiamine deficiency (presenting sign) trate this statement. 4 Thiamine-responsive anemia 4 3-methylglutaconic aciduria

1.5.1 Cardiology 1.5.2 Dermatology Arrhythmias, Conduction Defects (Heart Beat Disorders) Acrocyanosis (Orthostatic) Primitive heart beat disorders: 4 EPEMA syndrome [13] 4 Adrenal dysfunction (hyperkalemia) 4 AMP activated protein kinase (PRKAG2 mutations Alopecia with cardiac glycogenosis and Wolf-Parkinson-White) Age at onset: neonatal to infancy 4 Triose phosphate isomerase deficiency 4 Acrodermatitis enteropathica 4 D-2-hydroxyglutaric aciduria (AV block) 4 Biotin-responsive multiple carboxylase defects 4 Fatty acid oxidation disorders (CPT II, carnitine trans- 4 Calciferol metabolism defects (vitamin-D-dependent locase, LCAD, LCHAD, TF, VLCAD) rickets) 4 Hypoparathyroidism (hypocalcemia) 4 Congenital erythropoietic porphyria 4 Kearns-Sayre syndrome (respiratory chain disorders) 4 Conradi-Hünermann syndrome 4 Thiamine deficiency-dependent states 4 Ehlers-Danlos type IV 4 Essential fatty acid deficiency With cardiac/multiorgan failure: 7 below 4 Hepatoerythropoietic porphyria With cardiomyopathy: 7 below 4 Menkes disease (X-linked) 4 Methylmalonic and propionic acidurias Cardiac Failure, Collapse 4 Netherton syndrome With tamponade, multiorgan failure: 4 Zinc deficiency 4 Congenital disorders of glycosylation Age at onset: adulthood With apparently primitive heart beat disorders: 7 above 4 Porphyria cutanea tarda With cardiomyopathy: 7 below 4 Steinert 40 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

Angiokeratosis 4 Erythropoietic protoporphyria I 4 Aspartylglucosaminuria 4 Hartnup disease 4E-mannosidosis 4 Mevalonic aciduria (with fever and arthralgia) 4 Fabry disease (presenting sign) 4 Respiratory chain disorders 4 Fucosidosis 4 Xeroderma pigmentosa (nine varieties) 4 Galactosialidosis 4 Kanzaki disease Age at onset: adulthood 4 Schindler disease (adult form) 4 Hereditary coproporphyria 4 Porphyria variegata Brittle Hair 4 Porphyria cutanea tarda 4 Argininosuccinic aciduria 4 Citrullinemia Pili Torti 4 Menkes syndrome 4 Menkes disease 4 Pollitt’s syndrome 4 Netherton syndrome 4 Trichothiodystrophy Telangiectasias - Purpuras - Petechiae Hyperkeratosis 4 Ethylmalonic aciduria (EPEMA syndrome) 4 CEDNIK (neuro-cutaneous syndrome: keratosis on 4 Prolidase deficiency palms and soles) [29] 4 Ichthyosis (7 below) Trichorrhexis Nodosa 4 Tyrosinemia type II (keratosis on palms and soles) 4 Argininemia 4 Argininosuccinic aciduria Ichthyosis (with Congenital Erythrodermia) 4 Lysinuric protein intolerance 4 Austin disease 4 Menkes disease 4 CEDNIK (neuro-cutaneous syndrome: SNARE protein 4 Netherton syndrome mutation) [29] 4 Conradi-Hünermann syndrome (chondrodysplasia Ulceration (Skin Ulcers) punctata X-linked) 4 Prolidase deficiency 4 Multisystemic triglyceride storage disease 4 Netherton syndrome Vesiculo-Bullous Skin Lesions 4 Refsum disease (adult form) 4 Acrodermatitis enteropathica 4 Serine deficiency syndrome 4 Biotinidase deficiency (biotin-responsive) 4 Sjögren-Larsson syndrome 4 Holocarboxylase synthetase deficiency (biotin-respon- 4 Steroid sulfatase deficiency (X-linked) sive) 4 Methylmalonic, propionic acidemias (isoleucine defi- Laxity (Dysmorphic Scarring, Easy Bruising) ciency) Inborn errors of collagen: 4 Zinc deficiency 4 Cutis laxa 4 Ehlers-Danlos syndrome (nine types) Xanthoma 4 Occipital horn syndrome 4 Apo CII (eruptive) 4 Pyrroline-5-carboxylate synthase 4 Apolipoprotein A1 (planar) 4 Familial dominant hypercholesterolemia: Nodules 5 homozygote (childhood) 4 Congenital disorders of glycosylation 5 heterozygote (adulthood) 4 Farber lipogranulomatosis 4 Dysbetalipoproteinemia (hyperlipoproteinemia type III) Pellagra 4 Hepatic lipase 4 Hartnup disease 4 Lipoprotein lipase (eruptive) 4 Sitosterolemia (childhood) Photosensitivity and Skin Rashes Age at onset: neonatal to childhood 4 Congenital erythropoietic porphyria 4 Erythrohepatic porphyria 41 1 1.5 · Specific Organ Symptoms

1.5.3 Dysmorphism Malformations 4 3-OH-isobutyryl-CoA deacylase deficiency (limbs, Coarse Facies verte brae) Age at onset: present at birth 4 Cholesterol synthesis defects: 4 Galactosialidosis (early infancy) 5 Smith-Lemli-Opitz 4 I-cell disease 5 Conradi-Hünermann-Happle syndrome 4 Landing 5 Desmosterolosis 4 Sialidosis type II 5 Greenberg dysplasia 4 Sly (mucopolysaccharidosis (MPS) type VII) (rare) 5 Antley-Bixler syndrome 5 Mevalonic aciduria Age at onset: early infancy 5 CHILD syndrome 4 Austin 5 Lathosterolosis 4 Fucosidosis type I 4 Glutamine synthetase 4 Hurler (MPS type IH) 4 Non-ketotic hyperglycinemia 4 Mannosidosis 4 O-glycosylation and related defects: 4 Maroteaux-Lamy (MPS type V) 5 Walter-Warburg (POMT1) 4 Salla disease 5 Muscle-eye-brain disease (POMGMT), 4 Sialidosis type II 5 Fukuyama (Fukutin) 4 Sly (MPS type VII) 5 DMC1-C (fukutin related protein) 5 DMC1-D (LARGE protein) Age at onset: childhood 4 Aspartylglucosaminuria Intra-uterine Growth Retardation 4 Hunter (MPS type II) 4 Fetal alcoholic syndrome 4 Pseudo-Hurler polydystrophy 4 Infants born to mothers with untreated phenylketon- 4 Sanfilippo (MPS type III) uria 4 Cholesterol biosynthesis defects Dysplasia, Dysmorphic 4 Lysosomal storage disorders Maternal metabolic disturbances (untreated pregnancy): 4 Many non-metabolic polymalformative syndromes 4 PKU (dysmaturity, heart defect, microcephaly, specific 4 Peroxisomal disorders face, hypotrophy) 4 Respiratory chain disorders 4 Alcohol (dysmorphic, hypotrophy) 4 Transaldolase deficiency 4 Diabetes (macrosomia) 4 Drugs (dysmorphic, hypotrophy) 4 Vitamin deficiencies (riboflavin) 1.5.4 Endocrinology

Inborn errors affecting the fetus: Diabetes (and Pseudodiabetes) 4 Carnitine palmitoyl transferase II deficiency (renal 4 Abnormal pro-insulin cleavage cysts) 4 Diabetes, deafness and thiamine responsive megalo- 4 D-2-hydroxyglutaric aciduria blastic anemia 4 Glutaric aciduria type II (MADD) (renal cysts) 4 Diabetes type II: fatty acid oxidation disorders, Kir 6.2, 4 Inborn errors of collagen glucokinase 4 Hyperinsulinism (macrosomia, dysmorphia) 4 Organic acidurias (methylmalonic, propionic, isova- 4 Hypoparathyroidism leric acidemias, ketolysis defects) 4 Hypophosphatasia 4 Respiratory chain disorders – Wolfram syndrome 4 Leprechaunism 4 Lysosomal storage disorders (hydrops fetalis) Hyperinsulinism 4 Mevalonic aciduria (mevalonate kinase deficiency) 4 SUR1 and KIR6.2 mutations (potassium channel) 4 Peroxisomal biogenesis defects (renal cysts, migration 4 Glucokinase overactivity defects) 4 Glutamate dehydrogenase overactivity 4 Chondrodysplasia punctata 4 Short chain L-3-OH-acyl-CoA dehydrogenase 4 Pyruvate dehydrogenase deficiency 4 Wiedemann-Beckwith syndrome 4 Respiratory chain defects 4 Serine synthesis (microcephaly) Hyperthyroidism 4 Transaldolase deficiency (hydrops fetalis) 4 Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) 42 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

Hypogonadism – Sterility With pain in extremities: I 4 CDG type I 4 Fabry disease 4 Galactosemia 4 δ-aminolevulinate dehydratase deficiency 4 Sickle cell anemia Hypoparathyroidism 4 Long-chain 3-hydroxyacyl-CoA dehydrogenase With hemolytic anemia: deficiency 4 Coproporphyria 4 Respiratory chain disorders 4 Hereditary spherocytosis 4 Trifunctional enzyme deficiency 4 Sickle cell anemia 4 Nocturnal paroxysmal hemoglobinuria Hypothyroidism 4 Allan-Herndon-Dudley syndrome (monocarboxylate With Crohn disease (and pseudo-Crohn): transporter 8) [22] 4 Glycogenosis type 1b 4 Trifunctional enzyme deficiency Salt-Losing Syndrome 4 Carnitine transporter (OCTN2) 4 Disorders of adrenal steroid metabolism 4 Fatty acid oxidation disorders (carnitine palmitoyl With inflammatory syndrome (fever rash, IC reactive pro- trans ferase II) tein): 4 Respiratory chain disorders (mitochondrial DNA dele- 4 HyperIgD syndrome (mevalonate kinase deficiency) tions) Acute Pancreatitis Sexual Ambiguity 4 Hyperlipoproteinemia type I and IV 4 Congenital adrenal hyper- and hypoplasia 4 Lysinuric protein intolerance 4 Disorders of adrenal steroid metabolism 4 Organic acidurias (MMA, PA, IVA, MSUD) 4 Respiratory chain disorders (Pearson, MELAS) Short Stature – Growth Hormone Deficiency 4 Respiratory chain disorders Chronic Diarrhea, Failure to Thrive, Osteoporosis (7 Table 1.12)

1.5.5 Gastroenterology Hypocholesterolemia 4 Abetalipoproteinemia type I and II Abdominal Pain (Recurrent) 4 Congenital disorders of glycosylation type I With flatulence, diarrhea, lose stools: 4 Infantile Refsum disease 4 Lactose malabsorption 4 Mevalonic aciduria 4 Congenital sucrase isomaltase deficiency 4 Peroxisomal disorders 4 Smith-Lemli-Opitz syndrome With vomiting, lethargy, ketoacidosis: 4 Tangier disease (alpha-lipoprotein deficiency) 4 Urea cycle defects (OTC, ASA) 4 Organic acidurias (MMA, PA, IVA) HELLP Syndrome (Baby Born to Mothers with) 4 Ketolysis defects 4 Carnitine palmitoyl transferase I deficiency 4 Respiratory chain disorders 4 LCHAD deficiency and other fatty acid E-oxidation 4 Diabetes disorders 4 Respiratory chain defects With neuropathy, psychiatric symptoms: 4 MNGIE syndrome Intestinal Obstruction 4 OTC (late onset) 4 MNGIE syndrome (mitochondrial cytopathy) 4 Porphyrias 4 Tyrosinemia type I 1.5.6 Hematology With hepatomegaly and splenomegaly: 4 Cholesterol ester storage disease Acanthocytosis 4 Lipoprotein lipase deficiency 4 Abetalipoproteinemia 4 Lysinuric protein intolerance 4 Hallervorden-Spatz syndrome (panthothenate kinase) 4 Hemochromatosis 4 Inborn errors of cobalamin (Cbl C) 4 Mevalonate kinase deficiency 4 Wolman disease 43 1 1.5 · Specific Organ Symptoms

Anemias (Macrocytic) 4 Pearson syndrome 4 Hereditary orotic aciduria 4 Respiratory chain disorders 4 Inborn errors of cobalamin metabolism: 4 Schwachman syndrome 5 Imerslund-Gräsbeck syndrome 4 Transaldolase deficiency 5 Intrinsic factor deficiency 5 TC II deficiency Vacuolated Lymphocytes 5 Cbl C, Cbl E, Cbl G 4 Aspartylglucosaminuria 5 Methionine synthase deficiency 4 Austin disease 4 Inborn errors of folate metabolism: 4 Ceroid lipofuscinosis 5 Dihydrofolate reductase deficiency, 4 I-cell disease (mucolipidosis type II) 5 Glutamate formimino transferase deficiency 4 Landing disease (GM1) 5 Congenital folate malabsorption 4 Mucopolysaccharidosis 4 Mevalonic aciduria 4 Niemann-Pick type Ia 4 Pearson syndrome (due to mitochondrial DNA deletion) 4 Pompe disease (dyserythropoiesis) 4 Sialidosis 4 Respiratory chain disorders 4 Wolman disease 4 Thiamine responsive megaloblastic anemia Hyperleucocytosis (>100.000/mm3) Anemias (Non-macrocytic, Hemolytic or 4 Leucocyte adhesion deficiency syndrome (CDG IIc: Due to Combined Mechanisms) GDP fucose transporter 1) 4 Abetalipoproteinemia 4 Carnitine transport defect Hemophagocytosis 4 Congenital erythropoietic porphyria 4 Gaucher disease 4 Erythropoietic porphyria 4 Lysinuric protein intolerance 4 Erythropoietic protoporphyria 4 Niemann-Pick 4 Galactosemia 4 Hemochromatosis 4 Lecithin cholesterol acyltransferase deficiency 1.5.7 Hepatology 4 Mevalonic aciduria 4 Pyroglutamic aciduria Cholestatic Jaundice 4 Red blood cells glycolysis defects 4D-1-antitrypsin deficiency 4 Severe liver failure 4 Arginase deficiency 4 Transaldolase deficiency 4 Byler disease 4 Wilson disease 4 Congenital disorders of glycosylation 4 Wolman disease 4 Cerebrotendinous xanthomatosis 4 Cholesterol synthesis defects (Smith-Lemli-Opitz) Bleeding Tendency, Hemorragic Syndromes 4 Citrin deficiency 4 Gaucher disease 4 COG 7 deficiency 4 Glycogenosis type Ia and Ib 4 Cystic fibrosis 4 Inborn errors with severe liver failure 4 Galactosemia 4 Primitive disorders of homeostasis 4 Inborn errors of bile acid metabolism 4 Severe thrombocytopenia 4 Long-chain 3-hydroxyacyl-CoA dehydrogenase 4D-methylacyl-CoA racemase Pancytopenia – Thrombocytopenia – Leucopenia 4 Mevalonic aciduria 4 Aspartylglucosaminuria 4 Niemann-Pick type C 4 CDG IIf (CMP sialic acid transporter) 4 Peroxisomal disorders 4 Gaucher type I and III 4 Transaldolase deficiency 4 Glycogenosis type Ib (neutropenia) 4 Tyrosinemia type I 4 Inborn errors of cobalamin metabolism 4 Inborn errors of folate metabolism Cirrhosis 4 Johansson-Blizzard syndrome 4 Alpers progressive infantile polydystrophy 4 Lysinuric protein intolerance 4 Alpha-1-antitrypsin deficiency 4 Organic acidurias (methylmalonic, propionic, iso- 4 Arginase deficiency valeric) 4 Congenital disorders of glycosylation 4 Other conditions with large splenomegaly 4 Cholesterol ester storage disease 44 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

4 Cystic fibrosis 4 S-adenosylhomocysteine hydrolase deficiency I 4 CDG Ib 4 Urea cycle defects 4 Galactosemia 4 Wolman disease 4 Gaucher disease 4 Glycogenosis type IV Age at onset: childhood to adolescence 4 Hemochromatosis 4 Wilson disease 4 Hereditary fructose intolerance 4 Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 1.5.8 Immune System 4 Niemann-Pick disease 4 Peroxisomal disorders Inflammatory Syndrome 4 S-adenosylhomocysteine hydrolase deficiency 4 Hyper-IgD syndrome 4 Sitosterolemia 4 Mevalonate kinase deficiency 4 Transaldolase deficiency 4 Tyrosinemia type I Macrophage Activating Syndrome 4 Wilson disease 4 Gaucher disease 4 Wolman disease 4 Lysinuric protein intolerance 4 Niemann-Pick disease Liver Failure (Ascites, Edema) (7 also Reye Syndrome, 4 Propionic acidemia Sect. 1.3.1) Age at onset: congenital (hydrops fetalis) Severe Combined Immune Deficiency 4 Barth hemoglobin 4 Adenosine deaminase deficiency 4 CDG 4 Purine nucleoside phosphorylase deficiency 4 Erythropoietic porphyria 4 Hereditary orotic aciduria 4 Galactosialidosis 4 GM1 gangliosidosis (Landing) 4 Mevalonic aciduria 1.5.9 Myology 4 Mucopolysaccharidosis type VII 4 Niemann-Pick A and C Exercise Intolerance, Myoglobinuria, Cramps, 4 Sialidosis type II Muscle Pain, Elevated CK 4 Transaldolase deficiency Glycolytic defects (muscle glycogenosis): 4 Phosphorylase deficiency (McArdle) Age at onset: neonatal to early infancy 4 Phosphofructokinase deficiency 4 Fatty acid oxidation disorders 4 Phosphoglycerate kinase deficiency 4 Fructose-1,6-bisphosphatase deficiency 4 Phosphoglycerate mutase deficiency 4 Hereditary fructose intolerance 4 Lactate dehydrogenase deficiency 4 Galactosemia 4 Glucose-6-phosphate dehydrogenase deficiency 4 Mevalonic aciduria 4 Phosphorylase b kinase deficiency 4 Mitochondrial DNA depletion (DOGK) 4 Neonatal hemochromatosis (prevented by immuno- Fatty acid oxidation defects: globulin to the pregnant mother) 4 Carnitine palmitoyl transferase II 4 Respiratory chain disorders 4 VLCAD, LCHAD, translocase, trifunctional 4 Tyrosinemia type I (after 3 weeks) 4 SCHAD (restricted to muscles), MCKAT 4 Others undescribed (CPT I, SCAD ?) Age at onset: infancy 4 Same defects as in neonatal period Miscellaneous: 4 ACAD 9 4 Channelopathies (hyperkalemic paralysis) 4 Alpha-1-antitrypsin deficiency 4 Duchenne and Becker muscular dystrophies 4 Congenital disorders of glycosylation 4 Idiopathic familial recurrent myoglobinuria 4 Cholesterol ester storage disease 4 Lipoamide dehydrogenase deficiency 4 Cystic fibrosis 4 Acid maltase (adult) 4 Familial hepatic fibrosis with exudative enteropathy 4 Myoadenylate deaminase deficiency (CDG Ib) 4 Respiratory chain disorders 4 Ketogenesis defects 4 Pyruvate carboxylase deficiency 45 1 1.5 · Specific Organ Symptoms

Myopathy (Progressive) Renal tubular acidosis: 4 Adenylate deaminase deficiency 4 Renal tubular acidosis type I (distal) 4 Fatty acid oxidation disorders 4 Renal tubular acidosis type II (proximal) 4 Glycogenosis type II (acid maltase deficiency) 4 Pyruvate carboxylase deficiency 4 Glycogenosis type III 4 Methylmalonic aciduria 4 Multisystemic triglyceride storage disease 4 Glycogenosis type I 4 Respiratory chain disorders 4 Carnitine palmitoyl transferase I deficiency (Kearns-Sayre and others) 4 Dent disease (CLCN5 mutations) 4 Steinert disease Urine – Abnormal Color 4 Alkaptonuria (black) 1.5.10 Nephrology 4 Indicanuria (blue) 4 Myoglobinuria (red) Hemolytic Uremic Syndrome 4 Porphyria (red) 4 Inborn errors of cobalamin metabolism (Cbl C, Cbl G) Urine – Abnormal Odor 4 Dimethylglycine dehydrogenase (fish) Nephrolithiasis/Nephrocalcinosis 4 3-methyl-crotonylglycinuria (cat) 4 APRT deficiency (2-8 dihydroxyadenine) 4 Glutaric aciduria type II (sweaty feet) 4 Cystinuria (cystine) 4 Isovaleric acidemia (sweaty feet) 4 Hereditary hyperparathyroidism (calcium) 4 MSUD (maple syrup) 4 Hereditary renal hypouricemia (uric acid) 4 Phenylketonuria (musty odor) 4 Hyperoxaluria type I and II (oxalic) 4 Trimethylaminuria (fish) 4 Lesch-Nyhan (uric acid) 4 Tyrosinemia type I (boiled cabbage) 4 Molybdenum cofactor deficiency (xanthine) 4 PRPP synthase superactivity (uric acid) 4 Renal tubular acidosis type I 1.5.11 Neurology (7 Sect. 1.4.2) 4 Xanthine oxidase deficiency (xanthine) 4 Familial juvenile hyperuricemic nephropathy (uromo- 1.5.12 Ophthalmology (7 also Cherry-red Spot, dulin mutation) Ophthalmoplegia, and Retinitis Pigmentosa, Sect. 1.4.4) Nephrotic Syndrome 4 Respiratory chain disorders Cataracts Detectable at birth (congenital): Nephropathy (Tubulointerstitial) 4 Cockayne syndrome 4 Glycogenosis type I 4 Lowe syndrome (OCRL1 X-linked mutation) 4 Methylmalonic aciduria 4 Peroxisomal biogenesis defects (Zellweger and variants) 4 Respiratory chain disorders (pseudo Senior-Loken 4 Phosphoglycerate dehydrogenase deficiency syndrome) 4 Rhizomelic chondrodysplasia punctata 4 Sorbitol dehydrogenase deficiency Polycystic Kidneys 4 Congenital disorders of glycosylation Detectable in the newborn period (1st week to 1st month): 4 CPT II deficiency 4 Galactosemias 4 Glutaric aciduria type II 4 Marginal maternal galactokinase deficiency 4 Zellweger syndrome 4 Peripheral epimerase deficiency (homozygotes and heterozygotes) Tubulopathy Fanconi syndrome: Detectable in infancy (1st month to 1st year): 4 Galactosemia – hereditary fructose intolerance 4 Alpha-mannosidosis 4 Respiratory chain disorders (complex IV or mito DNA 4 Galactitol or sorbitol accumulation of unknown origin deletion) 4 Galactokinase deficiency 4 Tyrosinemia type I 4 Hypoglycemia (various origins) 4 Bickel-Fanconi syndrome: GLUT2 mutations 4 P5C synthase deficiency 4 Lowe syndrome (OCRL1 X-linked mutations) 4 Respiratory chain disorders 4 Cystinosis 4 Sialidosis 46 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

Detectable in childhood (1 to 15 years): Keratitis, Corneal Opacities I 4 Diabetes mellitus 4 Tyrosinemia type II 4 Dominant cataract with high serum ferritin 4 Fabry disease (X-linked) 4 Hypoparathyroidism 4 Lysinuric protein intolerance Microcornea 4 Mevalonic aciduria 4 Ehlers-Danlos type IV 4 Neutral lipid storage disorders (unknown cause) 4 Pseudo-hypoparathyroidism 4 Sjögren-Larsson syndrome 1.5.13 Osteology 4 Wilson disease Osteopenia Detectable in adulthood (> 15 years): 4 Cerebrotendinous xanthomatosis 4 Carriers for Lowe syndrome 4 CDG 4 Cerebrotendinous xanthomatosis 4 Glycogenosis type I 4 Fabry disease 4 Homocystinuria 4 Glucose-6-phosphate dehydrogenase deficiency 4 I-cell disease (mucolipidosis type II) 4 Heterozygotes for GALT and galactokinase 4 Infantile Refsum disease 4 Homocystinurias 4 Lysinuric protein intolerance 4 Lactose malabsorbers 4 All organic acidurias (chronic forms) 4 Mevalonate kinase 4 Mitochondrial cytopathies Punctate Epiphyseal Calcifications 4 Ornithine aminotransferase deficiency 4 Beta-glucuronidase deficiency 4 PEX 7 4 Chondrodysplasia punctata rhizomelic type 4 Refsum disease 4 Conradi-Hünermann syndrome 4 Steinert dystrophy (cataract can be presenting sign) 4 Familial resistance to thyroid hormone 4 Tangier disease 4 Peroxisomal disorders (Zellweger and variants) 4 Spondyloenchondromatosis Corneal Opacities (Clouding) 4 Warfarin embryopathy Visible in early infancy (3 to 12 months): 4 Tyrosinemia type II (presenting sign) Exostosis (Hereditary Multiple) 4 Cystinosis (presenting sign) 4 O-glycosylation defects (EXT1-EXT2) 4 Hurler, Sheie (MPS I) 4 I-cell disease (mucolipidosis type II) 4 Maroteaux-Lamy (MPS VI) 1.5.14 Pneumology 4 Steroid sulfatase deficiency Hyperventilation Attacks Visible in late infancy to early childhood (1 to 6 years): 4 Gazeous alkalosis 4 Mucolipidosis type IV (presenting sign) 4 Hyperammonemias 4 Alpha-mannosidosis (late-onset form) 4 Joubert syndrome 4 Lecithin cholesterol acyltransferase deficiency 4 Leigh syndrome (idiopathic or due to various inborn 4 Morquio (MPS IV) errors) 4 Pyroglutamic aciduria (presenting sign) 4 Metabolic acidosis 4 Tangier disease 4 Rett syndrome (only girls)

Visible in late childhood, adolescence to adulthood: Pneumopathy (Interstitial) 4 Fabry disease (X-linked) 4 Gaucher disease 4 Galactosialidosis (juvenile form) 4 Lysinuric protein intolerance 4 Wilson disease (green Kaiser Fleischer ring) 4 Niemann-Pick type B

Ectopia Lentis (Dislocation of the Lens) Stridor 4 Classical homocystinuria (downwards dislocation) 4 Biotinidase deficiency 4 Sulfite oxidase deficiency 4 Hypocalcemia 4 Marfan syndrome (upwards dislocation) 4 Hypomagnesemia 4 Marchesani syndrome 4 MADD (riboflavin responsive) 4 Pelizaeus-Merzbacher 47 1 References

Pulmonary Hypertension 4 Complex IV deficiency 4 Glycogenosis type I 4 Pompe disease 4 Non ketotic hyperglycinemia Hypodontia 4 Leucoencephalopathy with ataxia [33] 1.5.15 Psychiatry (7 Sect. 1.3.1 and 1.4.3)

1.5.16 Rheumatology 1.5.18 Vascular Symptoms

Arthritis – Joint Contractures – Bone Necrosis Raynaud Syndrome 4 Alkaptonuria 4 Fabry disease 4 Familial Gout 4 Farber disease Thromboembolic Accidents – Stroke-like 4 Gaucher type I Episodes (7 also Sect. 1.3.1) 4 Homocystinuria 4 CDG 4 I-cell disease, Mucolipidosis type III 4 Ehlers-Danlos type IV 4 Lesch-Nyhan syndrome 4 Fabry disease 4 Mevalonic aciduria (recurrent crisis of arthralgia) 4 Homocystinuria (all types) 4 Mucopolysaccharidosis type IS 4 Menkes disease 4 PRPP synthetase superactivity, HGPRT deficiency 4 Organic acidurias (methylmalonic, propionic) 4 Uromoduline mutation (familial hyperuricemic nephro- 4 Respiratory chain disorders (MELAS and others ...) pathy) 4 Urea cycle disorders (OTC deficiency)

Bone Crisis With bone changes (rickets): References 4 Calciferol metabolism deficiency 4 Hereditary hypophosphatemic rickets 1. De Koning TJ, Klomp LW, van Oppen AC et al (2004) Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase With hemolytic crises and abdominal pain: deficiency. Lancet 364: 2221-2222 4 Porphyrias 2. Van Spronsen FJ, Smit GPA, Erwich JJHM (2005) Inherited meta- 4 Sickle cell anemia bolic diseases and pregnancy. BJOG: an International Journal of 4 Obstetrics and Gynaecology 112: 2-11 Tyrosinemia type I 3. Saudubray JM (2002) Inborn errors of metabolism. Semin Neonatol 7 (issue 1) With progressive neurological signs: 4. Saudubray JM, Nassogne MC, de Lonlay P, Touati G (2002) Clinical 4 Gaucher type III approach to inherited metabolic disorders in neonates: an over- 4 Krabbe disease view. Semin Neonatol 7: 3-15 4 4a. Jaeken J, Martens K, François I et al (2006) Deletion of PREPL, a gene Metachromatic leucodystrophy encoding a putative serine oligopeptidase, in patients with hypotonia cystinuria syndrome. Am J Hum Genet 78: 38–51 Apparently isolated (presenting symptom): 5. Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO (1998) Iron-over- 4 Fabry disease load disease in infants involving fetal growth retardation, lactic 4 Gaucher type I acidosis, liver haemosiderosis, and aminoaciduria. Lancet 351: 490- 493 6. Visapaa I, Fellman V, Vesa J et al (2002) GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point muta- 1.5.17 Stomatology tion in BCS1L. Am J Hum Genet 71: 863-876 7. Tazawa Y, Kobayashi K, Abukawa D et al (2004) Clinical heterogene- Glossitis, Stomatitis ity of neonatal intrahepatic cholestasis caused by citrin deficiency: 4 case reports from 16 patients. Mol Genet Metab 83: 213-219 Clb F 8. Tazawa Y, Abukawa D, Sakamoto O et al (2005) A possible mecha- 4 Folate malabsorption nism of neonatal intrahepatic cholestasis caused by citrin deficien- 4 Intrinsic factor deficiency cy. Hepatol Res 31: 168-171 4 Transcobalamin II 9. Saudubray JM, Martin D, De Lonlay P et al (1999) Recognition and management of fatty acid oxidation defects: a series of 107 pa- Macroglossia tients. J Inherit Metab Dis 22: 488-502 10. Bonnet D, Martin D, De Lonlay P, Villain E, Jouvet P, Rabier D, Brivet 4 Beckwith-Wiedemann syndrome M, Kachaner J, Saudubray JM (1999) Arrhythmias and conduction 4 Congenital muscular dystrophies (DMC1C) defects as a presenting symptom of fatty-acid oxidation disorders in children. Circulation 100: 2248-2253 48 Chapter 1 · A Clinical Approach to Inherited Metabolic Diseases

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