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Journal of Child Neurology http://jcn.sagepub.com/

Topical Review Article: Organic Acidurias: A Review. Part 1 Pinar T. Ozand and Generoso G. Gascon J Child Neurol 1991 6: 196 DOI: 10.1177/088307389100600302

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Topical Review Article Organic Acidurias: A Review. Part 1

Pinar T. Ozand, MD, PhD; Generoso G. Gascon, MD

Organic acidemias are disorders of intermediary that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resul- tant systemic disease and progressive . While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, , glucose, lipids, glutathione, and γ-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic man- ifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations. (J Child Neurol 1991;6:196-219).

organic acid is a compound that generates exercise. An excessive rate of production, however, nprotons at the prevailing pH of the human will lead to overt metabolic acidosis, as in diabetic organism. The accumulation of an organic acid in ketoacidosis. Another disorder, glycogen storage cells and fluids (plasma, cerebrospinal fluid, or disease type 1, is associated with impaired gluconeo- urine) indicates impaired intermediary metabolism genesis and produces significant hyper-lactic aci- and leads to a disease state called demia under normal physiologic conditions or 3 or organic aciduria. Since , the following a load of a sugar, such as fructose.3 oldest known and treated, was described in 1966,12 more than 50 phenotypically different organic aci- Excess Organic Acids demias are now known, thanks to gas chromatogra- Besides ketone bodies and lactate, other organic phy/mass spectrometry (GC/MS). acids may be produced in excess. While they are barely detectable under normal physiologic condi- tions, such compounds accumulate in large amounts Pathogenesis when an activity related to their further breakdown is deficient. Traditionally, the term or- Ketonuria and Hyper- Lactic Acidemia ganic acidemia has been confined to these latter Many organic acids are produced during the catabo- conditions. Good examples are methylmalonic aci- lism of , lipids, and amino acids. Un- demia,4 ,5 isovaleric acidemia,66 der usual physiologic conditions, the protons and 3-hydroxy-3-methylglutaric aciduria secondary generated by these compounds are neutralized by to 3-hydroxy-3-methylglutaryl coenzyme A (CoA) the buffer systems available in cells and biologic flu- deficiency.’ The accumulation of such organic ids. Examples of normally compensated metabolic acids not only causes compensated or overt acidosis acidosis are ketone body production in the fasting but is usually associated with grave systemic or neu- state and lactic acid accumulation following vigorous rologic disease. The primary enzyme deficiency re- sponsible for the generation of these compounds Received Nov 9, 1990. Received revised Feb 26, 1991. Ac- causes significant derangements of intracellular and cepted for publication March 4, 1991. mitochondrial metabolism. From the Department of Pediatrics (Drs Ozand and Gascon), and Biological and Medical Research (Dr Ozand), King Faisal Spe- cialist Hospital and Research Centre, Riyadh, Saudi Arabia. Interference With Intracellular Metabolism Address correspondence to Dr Ozand, Department of Pedi- An is the accumulation of and atrics (MBC-58), King Faisal Specialist Hospital and Research Cen- example glutaric tre, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. 3-methylglutaric acids in .8

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 These two compounds accumulate because the en- Mitochondriopathies zyme responsible for further metabolism of glutaryl- Energy is generated by adenosine triphosphate syn- CoA, glutaryl-CoA dehydrogenase, is deficient.8 The thesis in a specific cellular organelle, the mitochon- disease is diagnosed by the accumulation of these drion, while electrons are transported to oxygen. two organic acids in biologic fluids. This accumula- The transport of electrons requires several cofactors tion is usually associated with compensated meta- and a complex machinery whose synthesis is bolic acidosis and causes mild overt acidosis only controlled both by cellular and mitochondrial DNA.19 when excessive glutaryl-CoA is produced from a Any derangement in this process will lead to the ac- load of the precursor.’ Nevertheless, glutaric acid- cumulation of lactate or fatty acid intermediates. By uria type 1 may remain inconsequential, except that definition, such disorders should be included in or- the intracellular accumulation of glutaryl-CoA inhib- ganic acidemias, since not only do they lead to the its glutamate decarboxylase,l° ie, the synthesis of generation of protons that alters the buffer metabo- y-aminobutyric acid in the central nervous system lism, but they also lead to progressive disease be- and the malate-aspartate shuttle in the liver.11 The cause of the derangement of intracellular pathways first of these events is possibly responsible for necro- affecting many aspects of normal cell function. How- sis of the IO, 12 and the second, for hypo- ever, they are commonly considered as mitochondri- glycemia.11 opathies because a distinct cell organelle is Another example is the accumulation of methyl- implicated .20 We shall include some mitochondriop- malonyl-CoA intramitochondrially in patients with athies in this review because their symptom complex .44 Increased excretion of shows significant overlap with other organic aci- methylmalonic acid results from its increased hy- demias. drolysis. Hyperammonemial3 and hypoglycemia 14 result from inhibitory effects of methylmalonyl-CoA Versus Organic Aciduria on ureagenesis and on pyruvate carboxylase (and Disorders of metabolism are associated hence on gluconeogenesis). with the accumulation of organic acids but are not These two examples can be extended to other or- usually classified within the organic acidemias. ganic acidemias. These disease states lead to accumu- Branched-chain aminoacidemia or maple syrup lation of organic acids in biologic fluids that might urine disease, for example, is caused by the defi- cause compensated or overt metabolic acidosis but ex- ciency of a dehydrogenase specific for branched- ert most of their progressive neurologic and systemic chain 2-keto acids.21 This leads to significant effects as a result of increasing derangements of the elevation of three branched-chain amino acids-leu- intracellular biochemical pathways. cine, , and -as well as significant accumulation of their 2-keto acids. Maple syrup Interference With Energy Metabolism urine disease can be diagnosed by detection of either Glycolysis and ketone body and fatty acid utilization amino acids or 2-keto acids in urine. Traditionally, it constitute the bulk of energy metabolism in humans. is considered an aminoacidemia, since it is primarily These pathways culminate in the generation of four diagnosed through the increased levels of branched- organic acids: pyruvate, lactate, 3-ketobutyrate (ace- chain amino acids. A related disorder, dihydrolipoyl toacetate), and 3-hydroxybutyrate, the turnover and dehydrogenase (or E3) deficiency, is caused by the pool of which are large.15,16 The pool size and rate of deficiency of one component of the branched-chain metabolism of these organic acids show significant 2-ketoacid dehydrogenase component, the E3.22 This increase and decrease under normal physiologic unit is shared by other dehydrogenases, such as conditions, since they are finely tuned by hormones pyruvate dehydrogenase, and 2-ketoglutaric dehy- through secondary messengers. 17,11 It is therefore drogenase. Therefore, in E3 deficiency, in addition not surprising to observe significant increases in to a moderate accumulation of branched-chain their levels, leading to compensated or overt meta- amino acids and their 2-keto intermediates, derange- bolic acidosis when the intracellular pathways are ment of several occurs. E3 deficiency is deranged secondary to the accumulation of organic therefore traditionally classified as an organic aci- acid intermediates. Therefore, in a large number of demia. While E3 deficiency is discussed below, organic acidemias, acidosis occurs not only because branched-chain aminoacidemia is not included in of the accumulation of the organic acid, but also be- this review. cause of increasing levels of lactate, pyruvate, 3- In disorders such as , 23 Hawk- ketobutyrate, and 3-hydroxybutyrate. insinuria,24 and type 1,25 the enzyme

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 deficiency leads to the accumulation of aromatic or- This prodrome rapidly progresses to or pyram- ganic acids in the urine, which are used to diag- idal, extrapyramidal, cerebellar, or -stem signs. nose the disease. However these three disorders are The primary or secondary derangement of gluconeo- usually discussed as derangements of phenylala- genesis, ketogenesis, and ureagenesis leads to hypo- nine and metabolism, despite the fact that glycemia, , and acidosis secondary and succinylacetonuria are preferably to the accumulation of a variety of organic acids. Or- diagnosed by GC/MS. Another example is N-acety- ganic acidemias associated with such episodes of laspartic aciduria in Canavan disease.26 The com- periodic acidosis are listed in Appendix A. Isova- pound excreted is a substituted amino acid, essential- leric acidemia,l 3-hydroxy-3-methylglutaryl-CoA ly- ly an organic acid. The condition can be diagnosed ase deficienCY,7 propionic acidemia,5 methylmalonic either by the increased excretion of N-acetylaspartic acidemia,4 pyruvate dehydrogenase deficiency,’7 acid in urine by GC/MS26 or by enzymic determina- pyruvate carboxylase deficiency,33,34 and complex IV tions in cultured fibroblasts or brain 2’ but is ex- deficiency35 are prototypes. Repeated acidotic epi- cluded from this review because it is traditionally sodes lead to severe central nervous system damage considered a primary disease of the glia. and death if left untreated. In this group of disor- Although these preliminary considerations indi- ders, a careful history will often reveal the presence cate that the terms organic acidemia and organic ac- of central nervous system symptoms that were not iduria are used arbitrarily, we have decided to keep appreciated before the acidotic attack. The clinical them and review those disorders that are tradition- symptoms at and after the time of acidosis indicate ally considered within these categories. global involvement of the central nervous system; eg, developmental delay and pyramidal tract signs are common. Specific symptoms may be associated with Diagnostic Aspects certain diseases (see following section on specific The diagnostic approach synthesizes clinical and lab- disorders). For example, 3-methylglutaconic aciduria oratory assessments. Clinical assessment considers with normal hydratase36 and D-glyceric aciduria presentation and signs. Laboratory assessment (dis- with defective fructose metabolism3~-4o manifest cussed in part 2 of this review) uses clinical bio- myoclonus. Infantile-onset pyruvate dehydrogenase chemical screening tests and confirmatory GC/MS deficiency presents predominantly with cerebellar techniques. signs. 41-47 Impairment of oxidative metabolism ~ z due to severe deficiency of pyruvate dehydroge- Neurologic Clinical Assessment/Presentation nase 41,42,48 or of complex IV49-54 manifests as brain- The prototypical presentation of organic acidemias is stem symptoms. Accumulation of fatty acyl-CoA is either intermittent attacks of acidotic coma or pro- thought to be detrimental to normal muscle mito- gressive encephalopathy. Less well appreciated are chondrial function and could be responsible for the presentations such as static , brain myopathy observed in fatty acyl-CoA dehydroge- dysgenesis, myelopathy-neuropathy, and myopa- nase deficiencies.55-59 thy. Some organic acidemias present with episodic attacks reminiscent of Reye syndrome, ie, Reye-like Intermittent Attacks. One clinical presentation of syndrome. An acute accumulation of fatty acyl-CoA an organic acidemia is periodic acidosis-a life- esters in medium-chain acyl-CoA dehydrogenase threatening episode of metabolic acidosis that may deficiency often presents as Reye-like syndrome take place at any age and may repeat at any (Appendix B). 57,60-63 The presentation of some pa- time .28,29 These episodes are preceded by a pro- tients with 3-hydroxy-3-methylglutaryl-CoA lyase drome of , , , and deficiency is similar to Reye syndrome. sometimes, . Attacks are precipitated by in- fections, excessive protein intake, surgical proce- Progressive Neurologic Disease. A much-encountered dures that lead to increased protein catabolism in clinical presentation in Saudi Arabia is that of an disorders related to amino acids or glutathione syn- acute or subacute progressive neurologic disease thesis, and large load in some mito- without overt acidosis. An organic acidemia may be chondriopathies. When compensated or overt meta- discovered in a child with progressive encephalopa- bolic acidosis is not appreciated, the severe episode thy who slowly develops pyramidal, extrapyrami- of vomiting may lead to erroneous laparotomy for dal, or cerebellar signs and mental deterioration. intestinal obstruction or even pyloromyotomy.3o-32 There may be preceding motor developmental de-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 lay, but more striking is impairment of later matur- nevertheless, pyruvate dehydrogenase deficiency ing functions like speech and language and both causes significant dysmorphia.41 gross and fine motor coordination. Appendix B lists these disorders and presenting neurologic signs. Spinal Cord Symptomatology and Peripheral Neuropathy. The best example is the recognition of glutaric acid- The presenting symptom of an organic acidemia, uria type 1 among patients with otherwise asymp- with or without periodic acidosis, can be with spinal 1165 tomatic &dquo;dystonic . It is assumed cord symptomatology, eg, methylcrotonyl-CoA that a chronic accumulation of glutaryl-CoA is re- carboxylase deficiency1o9,111 and cobalamin D muta- sponsible for necrosis of basal ganglia. 10,66,67 Long- tion.81-83 Peripheral neuropathy has been docu- term deprivation, as in deficiency, mented in a patient with mitochondrial acetoacetyl- manifests as pyramidal tract and cerebellar symp- CoA thiolase deficiency toms. 68-70 Cobalamin C,~l-8° D,SI-S3 and F 84-86 present with pyramidal tract signs and abnor- Myopathic Presentation. Flavoprotein-linked dis- mal eye movements. The later-onset forms of pyru- eases, 55,58,59,112 oxidative defects such as late-onset vate dehydrogenase deficiency due to partial pyruvate dehydrogenase deficiency, 14,47 complex I deficiency of the enzyme lead to extrapyramidal and and III deficiencies,113,114 and mitochondriopathies, cerebellar signs. 41,42,45-47 The initial symptom of particularly those with large deletions of mitochon- myoclonic epilepsy with ragged-red fibers syndrome drial DNA will show myopathy or cardiomyopathy is that of a disorder with interictal myoclo- in addition to disturbed central nervous system nus or tremors. 87-90 Occasionally, disorders charac- function, vision, and hearing (Appendix B). An ex- terized by periodic acidosis will manifest with only ample is Kearns-Sayre syndrome.115-11’ neurologic signs. These exceptions are also listed in Appendix B. Asymptomatic Organic Acidemias. Rarely, an organic acidemia occurs in an apparently normal individual. This variability is documented for Presentation As Static or Central Ner- phenotypic propi- Slowly Progressive onic acidemia,118 ketothio- vous Disease. An acidemia be methylacetoacetyl-CoA System organic may lase (3-ketothiolase) methylmalonic discovered the of a child with en- deficiency,119,12o during study static acidemia,121,122 medium-chain acyl-CoA dehydroge- cephalopathy. Good examples are: a patient with nase deficiency,123 and glutathione synthetase defi- isovaleric acidemia,91 a patient with 3-methylgluta- ciency.124 These are discovered accidentally when conic aciduria with normal and a hydratase,92 pa- unaffected and of the are in- tient with fumaric aciduria93 whose chief siblings parents patient complaints vestigated. Some other organic acidemias, such as are difficulties. A with succinic semi- speech patient 2-ketoadipic aciduria,125 usually remain asymptom- arrive with autistic fea- ’ aldehyde deficiency might matic. tures. 94-97 The development of mental retardation in a with is a patient glutathione synthetase deficiency Presentation. acidemias slowly progressive event..98-100 Age of Many organic present different phenotypic expression at different ages. This phenotypic variability is observed even among Congenital Brain Anomalies and Dysmorphia. A recent affected members of the same family, eg, with meth- report,101 as well as our experience, suggests that ylmalonic acidemia.126 It is important to recognize the fetus with organic acidemia might be affected be- this phenotypic variability, since it carries prognostic fore birth and might be born with congenital anom- importance. For example, while neonatal-onset alies of the brain. The brain anomalies may be a part pyruvate carboxylase deficiency is invariably lethal, of the dysmorphic features associated with certain the late-onset form can be compatible with life. 127-129 organic acidemias (Appendix C). In these disorders, Appendix D categorizes each disorder according to the derangement of a function vital to the fetus phenotypes at different ages. When phenotypic vari- causes teratogenesis. The absence of may ability is encountered, it can be explained by the na- be responsible for dysmorphia in the neonatal form of ture of the enzyme defect; eg, different phenotypes multiple acyl-CoA dehydrogenase deficiency.lo2-l06 of methylmalonic acidemia 130 and isovaleric aci- A normal cobalamin pathway is essential for the fe- demia131 are caused by different types of mutations. tus, since methylmalonic acidemia and cobalamin C The availability of a secondary limited source of the appear with dysmorphic features .76,77,79 Fe- deficient product will alter the appearance and pro- tal metabolism is mainly anaerobic glycolytic;107,108 gression of clinical symptoms, as in biotinidase defi-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 ciency. 68,132 In some instances, the excessive carboxylase,154 and short-chain acyl-CoA dehydro- production of an organic acid is caused by different genase155 can impair renal tubular function. Renal defects appearing as different phenotypes; eg, 3- failure has been documented in methylmalonic aci- methylglutaconic aciduria with normal hydratase is demia156 and glutaric aciduria type 1.12 clinically quite varied and probably represents sev- eral different disorders.36 Organic acidemias caused Immunologic Defects. The deranged organic acid by mitochondrial DNA defects will manifest at dif- pathway may impair normal immune function (Ap- ferent ages with different clinical expression, de- pendix E). Organic acidemias related to the path- pending on the degree of heteroplasmic inheritance way of branched-chain amino acids, eg, methyl- of the mitochondrial genome, 19,20,133 for example, malonic acidemia, 157,158 isovaleric acidemia,159pro- complex I113,134 and complex IV49,135 deficiencies. pionic acidemia, 160 and mitochondrial 3-ketothiolase deficiency, 157 are associated with dysfunction of Nonspecific Symptoms and Signs of the immune system. Suppression of granulopoietic Organic Acidemias progenitor-cell proliferation 157 and impaired T- and The clinical presentation of an organic acidemia with B-cell function16o,161 have been implicated. Im- periodic acidosis or with primarily neurologic symp- paired availability of biotin and riboflavin accounts toms includes nonspecific symptoms. The pertinent for the association of infections in biotinidase69,111,161 nonspecific manifestations include and multiple acyl-CoA dehydrogenase deficien- and associated systemic and immunologic findings. cies.149 Defective glutathione synthesis as in 5- oxoprolinurial62,163 or impaired oxidative phospho- Failure to Thrive. and frequent infec- rylation, as in complex IV deficiency,164,165 will im- tions associated with organic acidemias may explain pair granulocytic function. the commonly encountered retarded growth. How- ever, some organic acidemias impair normal growth directly, and when there is no obvious cause, failure Specific Disorders to thrive should alert the clinician to the possibility of organic acidemia. Infants may be born with signs Organic Acidemias Related to Branched-Chain of intrauterine growth retardation. Examples are Amino Acids the neonatal form of multiple acyl-CoA dehydro- genase deficiency136,13’ and deficiencies of pyruvate . Isovaleric acidemia is caused by the deficien- dehydrogenase E1,41,42,48 E2, 138,139 and E3 sub- cy of isovaleryl-CoA dehydrogenase and presents units 107,140-142 and mevalonate kinase. 143,144 In pa- with periodic acidotic attacks in neonatal, 6,166-168 in- I, 166, 169-172 tients with deletions or mutations of mitochondrial fantile, and childhood forms. The acidotic DNA, eg, mitochondrial encephalopathy lactic aci- episodes are preceded by’69 or associated with infec- dosis with strokelike episodes syndrome145,146 and tions, 159,169,172,173 since the disease inhibits the mat- myoclonic epilepsy with ragged-red fibers syn- uration of hematopoietic cells.159 A &dquo;cheesy&dquo; smell drome, ~’~’~ failure to thrive is universally present. emanates during attacks. Neurologic signs include In Kearns-Sayre syndrome, it occurs before the pre- hypotonia, tremor, 168 pyramidal 170 and extrapyrami- sentation of ophthalmologic, muscular, and cardiac dal signs, ISO and developmental retardation. 169 conductive defects.116 In some instances, failure to and speech problems169 can occur when age of onset thrive persists despite adequate therapy, as in meth- is late.91 Mental retardation is already present when ylmalonic acidemia.l4 the disease is recognized late (20% neonatally versus 50% childhood-diagnosed patients).169 Isovaleric aci- Systemic Manifestations. In some organic acidemias, demia may present with compensated acidosis and other organ systems are significantly involved. neurologic signs only; eg, unsteady gait,91 spastic di- Long-chain fatty acyl-CoA dehydrogenase, 55,58,59 plegia, mental retardation,1’° and Reye-like syn- multiple acyl-CoA dehydrogenase, 148,149 and meval- drome.169 Despite the dramatic presentation of onate kinase143 deficiencies are associated with isovaleric acidemia in the neonate, death is not a com- chronic liver disease. has been mon occurrence (30% ). 169 Rarely, the disease is associ- observed in isovaleric acidemia, 150 phosphoenol- ated with cerebellar hemorrhage,16~ cataracts, pyruvate carboxykinase deficiency,151 and complex dwarfism, and congenital anomalies 172 and with Fan- IV defects.49-54 Methylmalonic acidemia152 and defi- coni syndrome and renal tubular acidosis. 150 ciencies of glutathione synthetase,153 pyruvate 3-Methylcrotonyl-CoA carboxylase deficiency (methyl-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 crotonic aciduria)109, 174-178 is characterized by periodic sents with intermittent severe acidosis. 31,119,120,185-190 acidosis without specific neurologic signs. 175 An ex- Neurologic signs preceding the acidosis include ception is one patient who presented with hypoto- early developmental delay,119,185,189 hypotonia, 119,189 nia, fasciculations, and muscle atrophy without myoclonus,185 unstable gait, 185 ataxia, 120 and diple- acidosis at 4.5 months.109 The earlier-described pa- gia. 120 A newborn who mistakenly underwent py- tients may have been cases of holocarboxylase syn- loromyotomy at 4 weeks for persistent vomiting thetase deficiency. The acidosis can present shortly showed hypotonia before the first acidotic attack at after birth 171 or can be induced by high-protein feed- 12 weeks and developed cardiomyopathy.31 Be- ing 177 later during childhood. tween acidotic episodes, patients may show no evi- 3-Methylglutaconic aciduria occurs with two differ- dence of neurologic involvement. 12~,185-189 Family ent presentations, one with normal and the other history may reveal infantile deaths following misdi- with deficient 3-methylglutaconic acid hydratase. agnosed acidotic attacks. 187 However, the disease In 3-methylglutaconic aciduria with normal hy- has also been diagnosed in a healthy sibling119 or dratase, the defective pathway is unknown.36 It is a parent 120 during studies of the index patient’s fam- progressive neurodegenerative disease with periodic ily. acidotic episodes179-182 precipitated either by exces- Propionic acidemia is a deficiency of propionyl- sive protein intake 181 or by severe infections.lso,isi CoA carboxylase, which requires biotin as . Failure to thrive is prominent. 181 Intrauterine growth The incidence is 1 in 350,000 births in the Massachu- retardation 182 and dysmorphic featureslso,~s2 suggest setts screening program.191 It causes an infantile on- onset before birth. Neurologic signs include hypoto- set metabolic encephalopathy with periodic acidosis. nia, dyskinesia, choreoathetosis, myoclonus, senso- Vomiting, , dehydration, lethargy, and hy- rineural deafness, optic atrophy, and tapetoretinal potonia precede the acidotic attack.192,193 Severe degeneration. 36,179-182 In some cases, the presenting vomiting may mimic pyloric stenosis.32 Preceding or symptom is infantile syndrome.36,1s2 Neuro- intercurrent infections, particularly diarrhea, are radiologic studies reveal white-matter abnormali- common,192 due to a concomitant immune defi- ties. 182 The disease leads to microcephaly, 181 spastic ciency. 160 Severe malnutrition and chronic muco- quadriplegia, and eventually, dementia in all pa- cutaneous candidiasisl6o cause with wide- tIents, 36, 179-182 with early death.36 spread erythematous patches of scaly skin, particu- 3-Methylglutaconic aciduria with deficient hydratase larly in the intertriginous areas.194,195 begins in childhood with developmental retardation, Seizures and myoclonus are associated with or particularly in receptive and expressive language.92 precede propionic acidemia in approximately 25% of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency cases.192 Two children with seizure disorder and leads to a rapidly progressing acidosis, precipitated mental retardation but without acidosis were subse- by leucine load and fasting, 183,184 that becomes irre- quently diagnosed as having propionic acidemia.194 versible. The patient dies within hours if the disease A child with a history of early childhood seizures is not recognized and treated, particularly in the but subsequent normal development was found to neonatal period. 183 Acidotic attacks are associated have the disease after a sibling was diagnosed. 118 with or preceded by seizures, hypotonia, and pyra- Approximately 60% of patients progress to severe midal tract signs.ls3,1s4 In surviving patients treated failure to thrive, mental retardation, spastic quadri- adequately, few neurologic or neuroradiologic se- plegia, microcephaly, and focal seizures, especially quelae remain, with normal physical and mental de- when recognized late.192,194 Propionic acidemia is velopment.ls3,ls4 among the severest organic acidemias of infancy, Deficiency of dihydrolipoyl dehydrogenase (E3), a leading to death in 40% of patients during an unit shared by several mitochondrial dehydroge- acidotic attack5 and causing severe neurologic mor- nases, presents as intermittent metabolic acidosis bidity in the remaining 60%.32,192,196 When recog- with severe failure to thrive and increased suscepti- nized and treated promptly, intelligence remains bility to infections. 107,108,140-142 Neurologic signs in- normal. 192,195-198 clude hypotonia, respiratory difficulties, pyramidal tract signs, severe developmental retardation, and Organic Acidemias Related to Metabolism optic atrophy but no seizures. 107,108,140-142 of Vitamins Derangements of metabolism lead to defi- Isoleucine. 2-Methyl acetoacetyl-CoA 3-ketothiolase (mi- ciencies of cofactors shared by several enzymes af- tochondrial 3-keto or @-ketothiolase) deficiency usually pre- fecting more than one intermediary pathway.

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Cobalamin-, biotin-, and riboflavin-linked deficien- include seizures,’6 myoclonus ’72 pyramidal tract cies constitute a large percentage of organic aci- signs,’6 microcephaly,’1 abnormal vision 72,75,77 with demias. macular and retinal abnormalities,72,75 and ?7 Organic Acidemias Related to Cobalamin Metabolism. Cobalamin D mutation is a late-onset disease81-83 Dietary cobalamin is converted in steps to its cofac- presenting with ataxia,81,82 abnormal eye move- tors adenosylcobalamin and methylcobalamin, ments or nystagmus,82,83 mental retardation,82,83 which are involved in amino acid and nucleic acid and psychosis.83 Seizures,82 hypotonia,82 pyramidal metabolism. An interruption at any step leads to dis- tract signs,83 and spinal cord signs81,83 in a child or eases sharing the clinical symptoms of cobalamin de- adolescent should prompt a search for this disease. ficiency. Cobalamin F mutation was described in an infant Methylmalonic acidemia is caused by the absence with seizures, hypotonia, abnormal eye movements, or deficiency of methylmalonyl-CoA mutase or by and opisthotonus.84-86 abnormal intramitochondrial metabolism of cobal- amin, ie, a deficiency of adenosylcobalamin (cobal- Organic Acidemias Related to Biotin Metabolism. Bio- amin A or B mutants). 130 Its incidence is 1 in 48,000.126 tin is a cofactor for carboxylases. It is converted In classic methylmalonic acidemia, attacks of ketoac- into biotinyl-5-adenosine monophosphate and then idosis and hyperammonemia are precipitated by bound to the E amino group of a in the active heavy protein feeding65 or viral, bacterial, or fungal center of different carboxylases by a single enzyme infections. 4,157,158 Metabolic acidosis at the time of holocarboxylase synthetase. The breakdown of car- initial investigation may be absent, particularly in boxylases liberates lysine-bound biotin (), methylmalonyl-CoA mutase deficiency and cobal- which is cleaved by biotinidase to free biotin. 130 yield amin B genotypes. The endogenous pool of biotin is large compared to Hypotonia without overt acidosis may be the that provided by the diet or gut synthesis by intesti- only presenting sign of methylmalonic acidemia. 4,199 nal flora.68 The deficiency of either holocarboxylase 130,199,200 Developmental retardation, hypotonia, 130,199 synthetase or biotinidase leads to , and sensorineural deafnessl3o result when the dis- an organic acidemia known as multiple carboxylase ease is untreated. Developmental retardation, but deficiency. Biotin deficiency impairs the pathways of not growth retardation ’65 can be reversed by appro- various carboxylases; therefore, the clinical picture priate diet2ol and cobalamin administration. 130,199,202 combines features of propionic acidemia and defi- Renal proximal tubular acidosis and chronic renal ciencies of 3-methylcrotonyl-CoA carboxylase, pyru- failure can be associated.152,156 The death rate in vate carboxylase, and acetyl-CoA carboxylase. Holo- methylmalonyl-CoA mutase absence is higher than carboxylase synthetase deficiency presents as a more in other genotypes. 130 Infants with mutase deficiency severe condition than deficiency of biotinidase, since and methylmalonic aciduria may remain asymp- small amounts of biotin are always available through 68’132 tomatic.121 Two adults lived to old age without overt dietary intake or intestinal bacterial synthesis. disease.122 Holocarboxylase synthetase deficiency causes peri- Cobalamin mutations C, D, and F are associated odic acidotic attacks203-208 associated with anorexia, with severe neurologic symptomatology and methyl- stupor, hypotonia,2o6,20’ myoclonus, seizures, and malonic aciduria but occur without ketoacidosis and developmental delay. 204-208 In most instances, the hyperammonemia, differentiating them from classic enzyme deficiency is due to its decreased affinity to methylmalonic acidemia. Defects in the cytosolic ox- biotin. Therefore, some clinical response will be ob- idation of Co++ to Co+++ (cobalamin C and D mu- tained on administration of pharmacologic doses of tations) or of its lysosomal pathway (cobalamin F biotin. 206,207 mutation) simultaneously prevent the synthesis of presents initially with neuro- both adenosylcobalamin and methylcobalamin. The logic symptoms.68,209,21 Metabolic acidosis appears defective synthesis of adenosylcobalamin leads to later during the course of the disease and in only methylmalonic aciduria and of methylcobalamin to 60% of patients.69,209 Seborrheic or atopic dermatitis, . alopecia, and conjunctivitis are each present in 20% Cobalamin C mutation is an early-onset neurologic of cases. Susceptibility to Candida infections 69,111,161 disease presenting with severe failure to thrive, is caused by the associated T- and B-cell immune de- feeding difficulties, hypotonia, and developmental fects.111,161 Symptoms occur earlier in breast-fed in- retardation.71-8o Neurologic symptoms and signs fants, since human breast milk contains less biotin

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 than formulas.209,21O Seizures, myoclonus or tremor of elevated medium-chain fatty acids, which are (60%), sensorineural hearing loss (40%), develop- known to inhibit neuronal Na-K-ATPase.219 Pro- mental delay (40%), hypotonia (30%), visual difficul- longed fasting in these patients leads to unexpected ties with optic atrophy, stridor and episodes of death caused by increased lipolysis.55 Howat et a122° apnea, impaired gross and fine motor function, and and Allison et al221 detected MCAD and long-chain impaired speech with echolalia, precede the acidosis fatty acyl-CoA dehydrogenase deficiencies in tissues by months or years. 68-70,209-213 In its late-onset of 1% to 10% of children dying from sudden infant form, ataxia and cerebellar signs are the predomi- death syndrome. This disease should be considered nant neurologic findings, forming a triad with ery- in families with multiple cases of sudden infant thematous skin and alopecia. 69,111,209,211,212,214 death syndrome. 57,60,123 In any child younger than 2 Wolf et al recommend biotin treatment in all infants years with a Reye-like syndrome, MCAD is the and children exhibiting a progressive neurodegener- prime diagnosis, since Reye syndrome is rare in this ative disease, cutaneous manifestations, alopecia, can- age group. 57,60 It must be ruled out in any older didiasis, and immune deficiency, singly or in child with Reye-like syndrome and pernicious vom- combination, until biotinidase deficiency can be iting, absence of agitation or disorientation before ruled out.69 Death occurs in only 20% of cases.69,209 coma, and particularly in the absence of increased intracranial pressure. 57,60 Despite the severity and frequency of hypoglycemic attacks, intelligence is Organic Acidemias Related to Flavoprotein Metabolism. normal in 80% of the surviving patients. 55,61,222,223 Flavoproteins are mitochondrial dehydrogenases MCAD is the most common cause of nonketotic hy- that contain flavin adenine dinucleotide (FAD) as poglycemia in childhood and leads to death if unrec- the cofactor. Dehydrogenases specific for short-, me- ognized. 55,224 It also can occur without symptoms, dium-, and long-chain fatty acids, glutaryl-CoA, and having been detected in the father of three sudden 123 sarcosine are examples of such FAD-containing pro- infant death syndrome patients. Loading tests are teins.55 The E3 subunit of pyruvate, 2-ketoglutarate, diagnostic in asymptomatic members of a family and branched-chain ketoacid dehydrogenases also with sudden infant death syndrome.6o contain FAD.20,22,215 These matrix pass the Long-chain acyl-CoA dehydrogenase deficiency pre- electrons from their substrates to a dimer electron sents as a nonacidotic episodic hypoglycemia, as in transport flavoprotein (ETF). Another FAD dehy- MCAD, 55,218,225 with additional features of cardiomy- drogenase (ETFQO) transports electrons from ETF to opathy and hepatic fibrosis and cirrhosis. 55,58,59,218 coenzyme Q (CoQ). The electrons from CoQ are The nonketotic hypoglycemic episodes are triggered then transported into the main electron transport by infection or fasting. 55,58,59 Patients may experi- chain.55 Inborn errors of these flavoproteins impair ence repeated infections.58,59 Hypotonia is the main the utilization of these compounds as well as of neurologic sign and may be explained by mitochon- lysine and , which are normally catabo- drial damage caused by accumulating long-chain lized to glutaryl-CoA and sarcosine.55 fatty acyl-CoA esters.226 Mortality is 40%, and sur- Short-chain acyl-CoA dehydrogenase deficiency is a viving patients have severe to moderate mental re- rare disease with different phenotypic expressions: tardation and microcephaly. 55,59,218 severe metabolic acidoSiS,56 petechiae in infancy,216 Glutaric aciduria type 1 is caused by deficiency of childhood-onset nonketotic hypoglycemia, and Reye- glutaryl-CoA dehydrogenase, a flavoprotein that ox- like syndrome. 217 Another presentation is with de- idizes the glutaryl-CoA generated from lysine and velopmental deterioration after 6 months of age, tryptophan breakdown. 12 Its clinical presentation is with subsequent acidosis at 13 months.216 The heterogeneoUS,227 with intermittent acidosis or ex- downhill course proceeds with increasing muscle trapyramidal signs. 65,228-230 Acidosis is rare, is an weakness,218 intercurrent infections,56,216,21’ spastic associated rather than a presenting symptom,9, 12,228 diplegia, and death.56,216 and can appear late in the disease.231 The associated Medium-chain acyl-CoA dehydrogenase deficiency ketosis and hypoglycemia have been explained by (MCAD) presents primarily as a Reye-like syndrome inhibition of the malate-aspartate shuttle by glutaryl- with intermittent hypoglycemic attacks5’-63,21s but CoA.ll Other organs affected are myocardium, kid- with a mild ketosis inappropriately low for the de- ney, and liver.12 Intercurrent infections232 are not gree of hypoglycemia. Acidosis, when present, is common.229 mild and due to the accumulation of lactic acid.61 In the early-onset9, 11,228 and late-onset231 forms, Symptoms are attributed to the severe neurotoxicity the child presents acutely with , choreo-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 athetoid movements, grimacing, dysarthria,65 sub- and putamen, abnormal formation of bile ducts, gas- dural hematoma,11,231 seizures,9, 229 or hypotonia trointestinal tract abnormalities, kidney cysts, con- and quadriparesis.22’ can be pres- genital heart disease, and craniofacial dysmor- ent.228,230,231 White-matter changes around lateral phia.lo2-l06 A fetus can be stiIlborn.104 The surviving ventricles, striatal and lenticular necrosis, and bilat- newborn shows severe hypotonia, superimposed in- eral frontotemporal atrophy are detected at necropsy fections, 102,235,237 and resistant hypoglycemia and or on computed tomographic scan. 66,67,227,233 The acidosis, 102,104,236,238-240 but the disease is incompat- decreased 4-aminobutyric acid content in putamen ible with life. and caudate nucleuS22’ has been explained by the in- The nature of the enzyme defect in the infantile hibitory effect of glutaric acid on y-aminobutyric acid form is unknown, despite laboratory evidence for mul- synthesis.10 Bilateral striatal necrosis is seen in most tiple flavoprotein deficiencies .241-244 Following a pe- patients. 66,67,233 The clinical picture is more severe riod of severe developmental delay, failure to thrive, than the neuroradiologic findings, suggesting that and anorexia, 136,137 the infant experiences an attack neuronal dysfunction precedes neuronal death. 230 of severe hypoglycemia with acidosis. Frequent in- Glutaric aciduria can present with only dyskinesia, fections,242 cardiomyopathy,136 and hair loss136 have as first reported in five choreoathetotic cerebral been described. Two patients were normal until hy- palsy patients by Brandt et al .65 Three infantile met- poglycemic acidotic attacks at 6 weeks and 9 months abolic errors manifest primarily with dystonia: glu- of age.242 Another showed repeated seizures but an taric aciduria type 1, o-glyceric aciduria, and sulfite otherwise normal clinical appearance for 4 years.241 oxidase deficiency.65,231 A patient described by This infantile form may be responsive to riboflavin Gregersen et al232 presented with ataxia and diffi- treatment,245 which may permit normal develop- culty walking. Despite severe neurologic impair- ment.241,242 ment, 60% of patients show normal intellect.229 The childhood- and late-onset form manifests with Eighty percent of those patients who manifest with systemic involvement but mild or absent acidosis. only choreoathetosis are of normal intelligence.65 One child experienced repeated episodes of mild hy- Death occurs in approximately 15% .5,229,230 poglycemia and compensated acidosis, with gradu- Multiple acyl-CoA dehydrogenase deficiency (glutaric ally increasing hepatomegaly and worsening of liver aciduria type 2) is a family of disorders in which the functions until 3 years of age, when his symptoms linking flavoproteins ETF disappeared on riboflavin administration.246 A 19- and ETFQO are defective, creating distinctly differ- year-old patient who previously manifested re- ent phenotypes: a neonatal form, an infantile form, peated attacks of hypoglycemia, infections, and and childhood and late-onset forms.55 Different de- hepatic dysfunction, was diagnosed after she devel- fects occur among patients with the severe infantile oped proximal myopathy.149 Another 17-year-old form, such as absent ETF, ETFQO, and other CoQ girl was diagnosed following 2 years of progressive coupling proteins.234 Heterogeneity of the enzymic lipid storage myopathy.112 None of the patients had defect may explain why riboflavin may be therapeu- mental retardation. tic, particularly in the second and third phenotypes.55 Although the disease is autosomal recessive, an Organic Acidemias Related to X-linked inheritance proposed in one family with Lipid Metabolism the neonatal form235 suggests different mechanisms. Since the defect commonly affects fatty acyl-CoA, Acetyl-CoA Carboxylase Deficiency. Acetyl-CoA car- glutaryl-CoA, and sarcosine dehydrogenases, the boxylase is a biotin-dependent enzyme that initiates clinical and laboratory features include those of re- fatty acid synthesis. One infant with this deficiency lated organic acidurias. presented with severe failure to thrive, hypotonic The neonatal form is a disease with multisystem myopathy, and respiratory difficulties. 241 involvement and with dysmorphic features reminis- cent of peroxisomal disorders at birth, leading to Mevalonic Aciduria. Mevalonic acid is formed from rapid death.236 The dysmorphic features and con- 3-hydroxy-3-methylglutaryl-CoA and converted to genital brain anomalies may be due to absent ribo- mevalonate-5-phosphate by a kinase that is the first flavin function in the fetus, since experimental intermediate in cholesterol synthesis.143 A patient riboflavin deficiency causes similar findings. These with mevalonate kinase deficiency had dysmorphic are cerebral dysgenesis, abnormal gyrus formation, features and acidosis at birth, cataracts at 2 months, cerebral degeneration with fibrous gliosis of caudate repeated systemic and gastrointestinal infections, re-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 current anemia with hepatosplenomegaly, seizures, subunit is a lipoamide transacetylase, and the E3 sub- and growth and developmental retardation until unit is a dihydrolipoyl dehydrogenases death at 2 years of age.143,1~ Mevalonic aciduria was Pyruvate dehydrogenase El subunit (pyruvate decar- discovered in a 6-year-old boy with cerebellar ataxia boxylase) deficiency occurs in three different pheno- and elevated serum kinase.248 types with decreasing severity: neonatal, infantile, and childhood forms. Severity inversely correlates with residual activity in tiSSUeS.251 The enzyme is Thiolase Two Cytosolic Acetoacetyl-CoA Deficiency. pa- unevenly distributed in the central nervous system, tients with severe presented developmental delay, and the may reflect the most de- abnormal brain symptoms actively atrophy, region at a particular time of brain develop- and liver disease.155,24electroencephalograms, Both infants had continuous eloping ment.25 Some mutations of a or J3 subunits may be ketonuria and acidosis.155 The compensated patient more deleterious than others.252,255 Nevertheless, El described Bennett et a1155 remained by profoundly deficiency causes atrophy and patchy white-matter retarded. changes affecting cerebrum, basal ganglia, cerebel- lum, and brain stem in all phenotypes.41 These Mitochondrial Acetoacetyl-CoA Thiolase Deficiency. A changes are responsible for seizures, hypotonia, reflexes, 5-year-old patient had growth retardation, severe exaggerated deep-tendon dystonia, choreoathetosis, ataxia, abnormal movements, progressive neuropathy, and ataxia.110 Motor nerve eye and The disease af- conduction velocities were slow. She was respiratory difficulties, apnea. eventually fects the unable to walk but had normal mentation, vision, fetus, since dysmorphia and brain dysgen- esis are observed in 50% of the cases, of and hearing She was continuously ketotic with regardless compensated acidosis. 110 phenotype.41 The neonatal form presents at or before birth. The infant shows severe failure to thrive (60%), hypoto- Organic Acidemias Related to Glycolysis nia, seizures, dysphagia, tremors, abnormal eye movements, respiratory difficulties, stridor, and ap- Pyruvate Dehydrogenase Deficiency. This deficiency is nea, in association with severe lactic and pyruvic the most common cause of neonatal-, infantile-, and acidosis. 41,42,48 The dysmorphic features are reminis- early childhood-onset primary . Pyru- cent of fetal alcohol syndrome.41,48 Four infants also vate dehydrogenase is a mitochondrial enzyme con- had agenesis of corpus callosum, and one infant had sisting of three subunits with different catalytic agenesis of olivary nuclei.41 Autopsy findings reveal functions, El, E2, and E3, and a protein X.250,251 All cystic white- and gray-matter changes. The disease units are coded in the nuclear genome .250,251 The El leads to severe retardation and microcephaly.41,42 subunit contains two E1a and two E1~ components Approximately 50% of the patients expire because of and decarboxylates pyruvate (pyruvate decarbox- respiratory difficulties and irretractable acidosis be- ylase). The E1a component is coded on chromo- fore 6 months of age, and the remainder before 3 some X p22.1, and the E1~ component on chromo- years of age.41,48,250, 56-259 some 3.25° Thiamine pyrophosphate is the cofactor for The infantile form is three times more com- E1. Most deficiencies of pyruvate decarboxylase are mon than the early infantile form and is less se- caused by mutations of the E1a component. 250-252 vere. 41-44,48,260-263 This is the classic Leigh disease Varied phenotypic expression of E1a defects can be ex- or subacute necrotizing encephalomyelopathy, al- plained by selective inactivation of the X chromo- though other enzyme deficiencies can result in the some.251 The activity of the El subunit is controlled by same clinical syndrome. All infants have severe fail- 1,42,48 acetyl-CoA/free reduced CoA and reduced nicotin- ure to thrive. Approximately 50% will show amide adenine dinucleotide (NADH)/nicotinamide dysmorphia such as narrow head with frontal boss- adenine dinucleotide (NAD) ratios and thus is subject ing, wide and depressed nasal bridge, upturned to different metabolic regulations. 17 El is inactivated nose, long filtrum, and flared nostrils.41 Findings by a kinase that phosphorylates the enzyme and acti- include developmental delay, seizures,43,44,262 hypo- vated by a phosphatase that cleaves this phosphate tonia or ,43,262 ataxia,43,44 dystonic postur- ester.253 The deficiency of phosphatase causes a simi- ing or choreoathetosis,41,42,48 ophthalmoplegia,~·260 lar clinical picture to that of El deficiency.253 Pyru- purposeless eye movements, 44,260 bulbar paresis,~ vate, thiamine pyrophosphate, and dichloroacetate irregular respirations, stridor, apnea, 260 and periph- stabilize the enzyme by inhibiting the kinase. 17 The E2 eral neuropathy. 41,42,48 At necropsy, myelin loss,

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 cavitation of basal ganglia and brain stem, and path- form manifests at birth with severe metabolic acido- ologic findings of encephalomyelopathy are ob- sis. Despite the key role of pyruvate carboxylase in served.43,263 Neuroradiologic studies show brain gluconeogenesis, hypoglycemia is rare and was ob- atrophy and brain-stem, basal ganglia, cerebral, and served in only three patients .34,268 Neurologic symp- cerebellar hypodensities with cystic lesions.41 Death toms include hypotonia and lethargy or hypertonia, occurs between 10 and 36 months. 41,42,48,260-263 Age seizures, and hepatomegaly.34 Death occurs within of death is inversely related to the residual activity 10 days to 3 monthS.33,34,127,128,268,269 of pyruvate decarboxylase in fibroblasts.41,42 In the infantile form, patients manifest with epi- The childhood form was seen in six boys present- sodes of acidosis, severe developmental delay, and ing between 3 and 13 years of age.41,42,45,46,264 Pre- hypoglycemia (40%). 129,154,270-273 Neurologic symp- senting symptoms were ataxia, 41,42,45-47,264 choreo- toms include respiratory difficulties, axial hypotonia athetosis with dystonic posturing,46 and muscle (50%),271-273 seizures (50%),270,271-273 and micro- weakness, with periodic exacerbations related to cephaly (10%).272,273 Neuroradiologic studies273 or consumption of a high-carbohydrate diet. 47 Seizures necropsy272 reveal brain atrophy and dysmyelina- and dysmorphia were uncommon.41,42 All patients tion. Fifty percent of patients die during an acidotic 33,34,129,154,270-273 showed growth and psychomotor delay and some attack had microcephaly, impaired external ocular motil- ity, 47 and muscle atrophy.264 Lactic and pyruvic aci- dosis was mild, becoming prominent when the pa- Phosphoenol Pyruvate Carboxykinase Deficiency. It tient was given a carbohydrate load. 47 The residual manifests with hypotonia (60%), developmental de- enzyme activity in this group was usually greater lay (60%), and difficult-to-control hypoglycemia, but than 30% .41,42,46,47 All were alive when re- patients mild to moderate lactic acidosis. 151,274-276 It is easily ported. confused with nesidioblastosis and diagnosed when E2 subunit was Pyruvate dehydrogenase deficiency pancreatic surgery or diazoxide treatment fail to con- in four who showed severe diagnosed patients trol the hypoglycemia .227-230 Sixty percent of pa- developmental delay, failure to thrive with hypoto- tients die.15i,274-276 nia, hyperreflexia, spastic tetraparesis, nystagmoid eye movements, optic atrophy, and dystonic rigid- ity. 138,139 Dysmorphia included bilateral epicanthic Acidemias Related to the Citric folds.138 Moderate lactic and pyruvic acidosis was ex- Organic acerbated by the administration of carbohydrates.139 Acid Cycle All four patients described with pyruvate dehy- Fumaric Aciduria. Five have been drogenase phosphatase deficiency 253,260,265,266 had neona- patients reported with fumaric and succinic aciduria and mild tal onset Leigh encephalomyelopathy, one with un- primary or absent acidosis. 93,277,278 Three infants had remitting acidosis253 and death within the first year. hypoto- nia, developmental delay, and or failure to thrive and fibrosis.2microcephaly, Profound 277,278 D-Glyceric Aciduria. The enzyme deficiencies associ- hepatic of both and mitochondrial fuma- ated with two different phenotypes are unknown. deficiency cytosolic rases were found. 277,278 In two 19 and 25 One type presents with severe neonatal acidosis, siblings with subsequent moderate mental retardation. Load- years old, fumaric aciduria was associated with ing with L-serine increases urine and plasma levels normal childhood developmental milestones, but and mental retardation of D-glyceric acid, a defect in the serine speech delay global ap- suggesting later.93 metabolic pathway.26 The second phenotype pre- peared sents at birth or early infancy with myoclonus, dystonia, spastic tetraparesis, and severe encepha- lopathy leading to early death .37-40 Here, D-glyceric 2-Keto Glutaric Aciduria. The partial deficiency of aciduria is associated with a defect in fructose me- 2-ketoglutaric acid dehydrogenase, possibly involv- tabolism. ing the E2 component of the enzyme, was associated in two siblings from one family, with massive 2- Organic Acidemias Related to Gluconeogensis ketoglutaric aciduria and early developmental delay followed by choreoathetosis at 2 years of life, lead- Pyruvate Carboxylase Deficiency. There are two phe- ing to loss of language skills and dystonic postur- notypes : neonatal and infantile forms. The neonatal ing. 280

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Organic Acidemias Related to Defects of the mitochondrially encoded polypeptides of com- Oxidative Phosphorylation plex IV can lead to milder and different phenotypic A large number of muscle and central nervous sys- expressions within the same family. 284 Complex IV tem diseases are caused by mitochondrial abnormal- deficiency with cardiomyopathy has been described in ities. The is the primary oxidative three girls with onset at 2.5 to 4 months of age, with phosphorylation organelle of the cell. It performs severe hypotonia, myopathy, cardiomyopathy, mac- this function through five multienzyme complexes roglossia, and , but no renal involve- embedded within the inner membrane of a double ment. 164,165 Benign infantile mitochondriopathy or membrane structure and through two low molecular reversible cytochrome c oxidase deficiency has been re- weight redox carriers, CoQ and cytochrome c.133 ported in two patients. The onset at 2 to 6 weeks of These are complex I: NADH-CoQ ; age was with severe lactic acidosis, myopathy, mac- complex II: succinate-CoQ oxidoreductase; complex roglossia, and respiratory difficulties. The disease III: CoQ-cytochrome c oxidoreductase; complex IV: and muscle pathology improved by 6 to 12 months cytochrome c oxidase; and complex V: adenosine of age, with minimal residual damage, as confirmed triphosphate synthetase. Specific diseases of the oxi- by biochemical and pathologic findings.285,286 Cy- dative phosphorylative chain associated with lactic tochrome c oxidase deficiency was found in nine pa- and pyruvic acidemia are as follows: tients with Leigh encephalomyelopathy. 115,287,288 The onset was with respiratory difficulties, weak cry, Complex I (NADH-CoQ Reductase) Deficiency. Four loss of vision and hearing, and seizures, with even- phenotypes have been reported: oculoskeletal myop- tual dementia and death. In one patient with onset athy, progressive encephalopathy, fatal infantile at 2 years, the presenting symptom was ataxia. 287 form, and myopathy with exercise tolerance. The latter two are diseases of childhood and early ado- Myoclonic Epilepsy With Ragged-Red Fibers (MERRF), lescence. The fatal infantile form manifests with se- Mitochondrial Encephalomyopathy Lactic Acidosis With vere lactic acidosis and neonatal hypotonia, followed Strokelike Episodes (MELAS), and Kearns-Sayre Syn- by delayed motor development, respiratory difficul- dromes. The phenotypic expression of these mito- ties, apnea, and sJiasticity, leading to death by 4 chondriopathies, which show variable lactic acido- months of age.134,2 1 Myopathy with exercise intolerance sis, is listed in Table 1. was observed in a 10-year-old patient with tiredness, shortness of and muscle aches and Acidemia Related to breath, cramps Organic , following exercise, which induced lactic acidosis.l 3 Glutathione Metabolism

Complex III (Ubiquinol-Cytochrome c Reductase) Defi- Glutathione Synthetase Deficiency (5-Oxoprolinuria, Py- ciency. The clinical presentation in a girl with onset roglutamic Aciduria). Nineteen patients have been at 9 years was similar to complex I deficiency.114 reported up to 1989.9s-100,124,13,162,163,296-298 The majority manifested the disease neonatally with Complex IV (Cytochrome c Oxidase) Deficiency. Three mild to severe hemolytic anemia, increased suscepti- phenotypes exist: infantile mitochondriopathy, sub- bility to infections due to neutropenia and defective acute necrotizing encephalomyelopathy, and partial neutrophil function,162,163 and moderate to severe deficiency. Only the first two occur during child- intermittent acidosis occurring as early as 20 hours hood. Infantile mitochondriopathy can be either fa- after birth,297 initially confused with renal tubular tal or benign. The fatal form has three distinct acidosis.153 The patients remain asymptomatic be- phenotypes: with Fanconi syndrome, without renal tween crises. Some patients never manifest acidosis involvement, and with cardiomyopathy. Fatal infan- except during stress, such as surgery-99 Mental retar- tile mitochondriopathy with Fanconi syndrome has been dation is followed by slowly progressive ataxia, in- described in seven Its onset at birth is tention tremor, dysarthria, and pyramidal tract signs patients. 49-54 s with severe lactic acidosis and hypotonia, which during adolescent years.98,9<’,124, leads to increased impairment of respirations and swallowing and to death by 4 months of age. Gluco- Organic Acidemia Related to 4-Aminobutyric suria, aminoaciduria, phosphaturia, and calciuria are Acid Metabolism present. Fatal infantile mitochondriopathy without renal involvement but with the same clinical pic- Succinic Semialdehyde Dehydrogenase Deficiency (4- presentingg2-2~ ture has been described. Mutations involving Hydroxybutyric Aciduria). Acidosis is rare and is de-

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 TABLE 1 Comparative Symptomatology of MERRF, MELAS, and Kearns-Sayre Syndromes*

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*References reviewed: MERRF syndrome, 87-90,147,289-291 MELAS syndrome, 145,146,153,292-294 and KSS. 116,117,295 MERRF = myoclonic epilepsy with ragged-red fibers; MELAS = mitochondrial encephalo- myopathy lactic acidosis with strokelike episodes; KSS = Kearns-Sayre syndrome; NR = not reported; EEG = electroencephalogram; VER = visual-evoked response; SSER = somatosen- sory-evoked response; CNS = central nervous system; CT = computed tomographic; CSF = cerebrospinal fluid. scribed only in one patient.96 This is a slowly Research Centre of King Faisal Specialist Hospital and Research progressive neurologic disorder with mental retarda- Centre. The project was realized through a grant donated by tion, autistic features, truncal and limb Sheik Rafiq Al Hariri (85-0030). hypotonia, We would like to thank Mrs Lilia Fernandez for the article ataxia, intention tremors, and ocular dyspraxia.94-9’ preparation. Its onset can be as early as 6 months95 or as late as 11 years of age, 97 but it generally manifests early. and of treatment Laboratory diagnosis principles APPENDIX A of organic acidemias will be discussed in Part 2 of this review, which will appear in the October 1991 Organic Acidemias Characterized by Periodic issue of the Journal of Child Neurology. Episodes of Acidosis Isovaleric acidemia16s,169 3-Methyl crotonyl-CoA carboxylase deficiencyl°9,~’6,1&dquo; 3-Methylglutaconic aciduria with normal hydratase 179-111 Acknowledgments 3-Hydroxy-3-methylglutaryl-CoA deficiency 183,184 Dihydrolipoyl dehydrogenase (E3) deficiency 107,108,140-142 We are grateful for the administrative monetary, and hu- 2-Methylacetoacetyl-CoA ketothiolase (mitochondrial 3-ketothio- manitarian support of Drs Fahad Al Abdul Jabbar, Chief Execu- lase) deficiency’, 116-190 tive Director, and Abbass H. Al-Marzouky, Executive Director, Propionyl-CoA carboxylase deficiency (propionic acidemia192)192)

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Methylmalonic acidemia 14,201,202 Succinic semialdehyde dehydrogenase deficiency (autistic fea- Holocarboxylase synthetase deficientCy2ll-206 tures)94-9’ Short-chain acyl-CoA dehydrogenase deficiency*s6,zls*56,218 Glutaric aciduria type 1*lz,2z’ Psychotic Episodes Multiple acyl-CoA dehydrogenase deficiency Isovaleric acidemia9l Neonatal form with dysmorphialoz,lo4,2s6, ss-z4o Cobalamin D mutation 83 . Infantile form without dysmorphia 245 Malonyl-CoA decarboxylase deficiency&dquo; Speech Difficulties Mevalonate kinase deficiency 143 Isovaleric acidemia9’ Pyruvate dehydrogenase deficiency 3-Methylglutaconic aciduria with normal hydratase’ El subunit deficiency 41,43,44, 48,250,255-263 Biotinidase deficiency69 E2 subunit deficiencyl3s,ls9 Glutaric aciduria type 16s Pyruvate dehydrogenase phosphatase deficiencyy253,265,266 Fumaric aciduria93 Isolated glycerol kinase deficiency and glycerol intolerance 301-303 2-Ketoglutaric aciduria 280 D-Glyceric aciduria with defect in serine metabolism3’,z6’ Glutathione synthetase deficiency94,98,99,124 Pyruvate carboxylase deficiency Succinic Neonatal forM33,34,127,128,268,Z69 semialdehyde dehydrogenase deficiency9s,9’ Infantile formI29,154,270-273 Phosphoenolpyruvate carboxykinase Reye-Like Syndrome Fumaric aciduria with deficient fumarasez&dquo;,z’deficiency 151,276 3-Hydroxy-3-methyl glutaryl-CoA lyase deficiency’4 Medium-chain I fatal infantile form134,281 acyl-CoA dehydrogenase Complex deficiency, Long-chain acyl-CoA deficiency 18,2255760 Complex IV (cytochrome c oxidase) deficiency dehydrogenase deficiency55, With Fanconi syndrome 49-54 Without renal dysfunction 282,284 Seizure Disorder With benign reversible infantile myopathyl3s,zs6 Propionic acidemia118,194 With cardiomyopathy&dquo;, 165,299 Cobalamin C mutation’6 Cobalamin F mutation’ Presenting as Leigh encephalomyelopathyl’s,zs7,2ss Mitochondrial encephalopathy, lactic acidosis with strokelike Biotinidase deficiency69,209 episodes syndrome115, 5,146,292-294 Glutaric aciduria type 19,229 Glutathione synthetase deficiency98 Myoclonic epilepsy with ragged-red fibers syndromess,s918,89

Myoclonus or Tremors Mitochondrial 3-ketothiolase deficiency&dquo; APPENDIX B Cobalamin C mutation Biotinidase deficiency 69,175 and D-Glyceric aciduria associated with defect in fructose metabo- Presenting Neurologic Symptoms Signs lism3’-4o of Organic Acidemias Manifesting Primarily Myoclonic epilepsy with ragged-red fibers syndrome88,&dquo;9 With Neurologic Disease Pyramidal Tract Signs Such As Central Hypotonia The and or in com- following neurologic signs symptoms, singly or Spastic Paresis or Plegia bination, might be present at the time of initial presentation be- Isovaleric acidemia 170 fore acidotic attack or in organic acidemias that may manifest Mitochondrial 3-ketothiolase deficiency 121 without acidosis. Methylmalonic acidemia 4,199 Cobalmin C mutation’6 Developmental Dela Cobalamin D mutation 82,83 Isovaleric acidemia~I,170170 Cobalamin F mutations4 3-Methylglutaconic aciduria with normal hydratase 92 Biotinidase deficiency69,z°9 Mitochondrial 3-ketothiolase deficiency’ 19,185,189 Short-chain acyl-CoA dehydrogenase deficitnay56,217 Cobalamin C mutation 72,74-79 Glutathione synthetase deficiency94,98,99,124 Cobalamin D mutations2,s3 Succinic semialdehyde dehydrogenase deficiency,9’,95,91 Biotinidase deficiency69,209 . Short-chain acyl-CoA dehydrogenase deficiency2l’217 Extrapyramidal Symptoms Such As Dystonic Posturing Long-chain acyl-CoA dehydrogenase deficiencyss,s9 and Choreoathetosis Glutaric aciduria type 19,1 ,228 Glutaric aciduria type 19·11,66,227,228·231,233 Multiple acyl-CoA dehydrogenase deficiency, late-onset Pyruvate dehydrogenase El subunit deficiency, late childhood form112,14’9,246 ~~41,42,48 Cytosolic acetoacetyl-CoA thiolase deficiencylss,249 D-Glyceric aciduria with defect in fructose metabolism 37-40 Pyruvate dehydrogenase El subunit deficiency, childhood 2-Ketoglutaric aciduria 280 form41,42,45-47,2a Glycerol kinase deficiency with adrenal hypoplasia with- Cerebellar Signs With Truncal and Extremity Ataxia ou~-306 and with 307-309 Duchenne muscular dystrophy Isovaleric acidemia9l Fumaric aciduria93 Mitochondrial 3-ketothiolase deficiency 120,185 2-Ketoglutaric aciduria 280 Cobalamin D mutation 81,82 Glutathione synthetase deficiency98-100 Mevalonic aciduria 248 Mitochondrial acetoacetyl-CoA thiolase deficiencyllo Pyruvate dehydrogenase El subunit deficiency, late childhood *Some patients will manifest without acidosis and with neu- ~~41,42,45-47 rologic symptoms or will manifest the acidosis after the neuro- Glutathione synthetase deficiency94,98.99,124 logic symptoms. Succinic semialdehyde dehydrogenase deficientCy94,91,97

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Downloaded from jcn.sagepub.com at UNIVERSITE LAVAL on July 1, 2014 Myoclonic epilepsy with ragged-red fibers syndrome88,89 Mevalonic aciduria Kearns-Sayre syndrome’ 15-117,295 Dolicocephaly, cataracts, triangular face, posteriorly rotated low-set ears, down-slanted eyes 143,144 Respiratory Difficulties, or Stridor Glycerol kinase deficiency associated with adrenal hypoplasia and Biotinidase deficiency69,zApnea, Duchenne muscular dystrophy Acetyl-CoA carboxylase deficientCyN7 , strabismus, wide-set eyes, drooping mouth, ab- normal genitalia 311-309 Abnormal Eye Movements, Nystagmus, Pyruvate dehydrogenase El subunit deficiency Dyspraxia, Strabismus Features reminiscent of fetal alcohol syndrome in early infantile Cobalamin D mutation 82,83 onset form,41 frontal bossing, wide and depressed nasal Cobalamin F mutation84 bridge, upturned nose, flared nostrils, long filtrum in late- Succinic semialdehyde dehydrogenase deficiency94,9s,9’ onset form, 41 agenesis of corpus callosum and of olivary nu- clei4l Disturbed Vision and Retinal Degeneration Pyruvate dehydrogenase E2 subunit deficiency Cobalamin C mutation72,75,77 Dysmorphic face, epicanthic foldsl3s Biotinidase deficiency69,z°9 Kearns-Sayre syndrome’ 16,117,295

Sensorineural Hearing Loss APPENDIX D Cobalamin C mutation&dquo; Biotinidase deficiency69,z°9 The Initial of in Various fibers Age Presentation Myoclonic epilepsy with ragged-red syndrome88,89 Acidemias Kearns-Sayre syndrome’16,117,295 Organic Birth to 2 Weeks of Life Spinal Cord Symptomatology 09 Isovaleric acidemia (7O%)6,167,168 Methylcrotonyl-CoA carboxylase deficiency’°9 Cobalamin D mutation 81,83 3-Methylcrotonyl-CoA carboxylase deficiency (isolated) (40%)1’4,1’s)174,175 3-Hydroxy-3-methylglutarvl-CoA lyase deficiency (50%)~’~ Propionic acidemia (40%) ,z32,193,196 Peripheral Neuropathy acidemia (80% of mutase ab- Mitochondrial acetoacetyl-CoA thiolase deficiency&dquo;o Methylmalonic methylmalonyl-CoA sence genotype) 130 Holocarboxylase synthetase deficiencyCy2O5 Myopathy or Cardiomyopathy Short-chain acyl-CoA dehydrogenase deficiency56Cy56 Long-chain acyl-CoA dehydrogenase deficiency (cardiomyopa- Multiple acyl-CoA dehydrogenase deficiency, neonatal thy)5,5, 58,59 form’o2,104,1 2,148,236’238-240 late onset’12,149,246 Multiple acyl-CoA dehydrogenase deficiency, Pyruvate dehydrogenase El subunit deficiency, neonatal form Acetyl-CoA carboxylase deficiency4’ (60% )41,42,48,256 Pyruvate dehydrogenase El subunit deficiency, childhood on- 3,265,266 set44,46, 264 Pyruvate dehydrogenase phosphatase deficiencf53,265,266 aciduria with defect of serine metabolism3’,26’ kinase associated with Duchenne muscular o-Glyceric Glycerol deficiency neonatal form33,34,127,128,268,269 dystrophy3o’,3’0 Pyruvate carboxylase deficiency, I with exercise intolerance&dquo;3 Phosphoenolpyruvate carboxykinase deficiency (40% )276 Complex deficiency Complex I deficiency fatal infantile form’~,z81 Complex III deficiency&dquo;4 194 Cytochrome c oxidase deficiency, neonatal form with renal in- Myoclonic epilepsy with ragged-red fibers syndrome90,294 volvement49-s3,zss + Kearns-Sayre syndrome (ocular facial)&dquo;’- 117,295 Glutathione synthetase deficiency~-~~3,i62,i63,296-298 Infancy (2 Weeks to 2 Years of Age) Isovaleric acidemia (30% )169-172 APPENDIX C 3-Methylcrotonyl-CoA carboxylase deficiency (60%)177 3-Methylglutaconic aciduria with normal hydratase 179-182 Features and Brain 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (50%)~’~ Dysmorphic Congenital Dihydrolipoyl dehydrogenase (E3) 108, 140-142 Anomalies Associated With Various Organic Mitochondrial 3-keto thiolase deficiency3’,11deficiencyl07, ,18s,186 Acidemias Propionic acidemia (60% )194,197,198 Methylmalonic acidemia (66% of mutase de- 3-Methylglutaconic aciduria with normal hydratase ficiency and cobalamin A and Bmethylmalonyl-COA genotypes)1 0 Facial dysmorphia with long featureless filtrum, malformed Methylmalonic aciduria due to cobalamin C and F muta- ears, penile hypospadias, undescended testicles, talipes equi- tions’z-8°,90-92 novarus 36,182 Holocarboxylase synthetase deficiencyz°6,zo’ Mitochondrial 3-ketothiolase deficiency Biotinidase deficiency69,175,209 , Facial dysmorphia with epicanthic folds’85 Short-chain acyl-CoA dehydrogenase deficiencyCy2l7 Methylmalonic acidemia Medium-chain dehydrogenase deficiency (90% between Epicanthic folds, prominent forehead, dysplasia of the midface, 1 and 2 years)sa7l-CoA high arched palate. 201 Long-chain acyl-CoA dehydrogenase deficiency55 Cobalamin C mutation Glutaric aciduria type 1, infantile or late-onset pheno- Hatchet-shaped head, arachnodactyly, facial dysmorphia, hy- types9, 66,227,229,231 pospadias~-~ Multiple acyl-CoA dehydrogenase deficiency, infantile Multiple acyl-CoA dehydrogenase deficiency, neonatal form form 136,137,241-244 Dysmorphic features generally observed with Zellweger syn- Malonyl-CoA decarboxylase deficiency300 drome, 103,104,238,239 cerebral dysgenesis, abnormal for- Mevalonic aciduria143,1 gyrus-’06 mation, cerebral degeneration with fibrous gliosis’° Cytosolic acetoacetyl-CoA thiolase deficiencylss,z49

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