23 Cerebral Organic Acid Disorders and Other Disorders of Catabolism

Georg F. Hoffmann

23.1 Introduction – 295 23.2 / – 295 23.2.1 Clinical Presentation – 295 23.2.2 Metabolic Derangement – 295 23.2.3 Genetics – 296 23.2.4 Diagnostic Tests – 296 23.2.5 Treatment and Prognosis – 296 23.3 Hydroxylysinuria – 296 23.4 2-Amino-/2-Oxo-Adipic Aciduria – 296 23.4.1 Clinical Presentation – 296 23.4.2 Metabolic Derangement – 296 23.4.3 Genetics – 296 23.4.4 Diagnostic Tests – 296 23.4.5 Treatment and Prognosis – 297 23.5 Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency) – 297 23.5.1 Clinical Presentation – 297 23.5.2 Metabolic Derangement – 297 23.5.3 Genetics – 300 23.5.4 Diagnostic Tests – 300 23.5.5 Treatment and Prognosis – 301 23.6 L-2-Hydroxyglutaric Aciduria – 302 23.6.1 Clinical Presentation – 302 23.6.2 Metabolic Derangement – 303 23.6.3 Genetics – 303 23.6.4 Diagnostic Tests – 303 23.6.5 Treatment and Prognosis – 303 23.7 D-2-Hydroxyglutaric Aciduria – 303 23.7.1 Clinical Presentation – 303 23.7.2 Metabolic Derangement – 303 23.7.3 Genetics – 303 23.7.4 Diagnostic Tests – 304 23.7.5 Treatment and Prognosis – 304 23.8 N-Acetylaspartic Aciduria (Canavan Disease) – 304 23.8.1 Clinical Presentation – 304 23.8.2 Metabolic Derangement – 304 23.8.3 Genetics – 304 23.8.4 Diagnostic Tests – 304 23.8.5 Treatment and Prognosis – 305

References – 305 294 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

Catabolism of Lysine, Hydroxylysine, and Lysine, hydroxylysine and tryptophan are degraded with- otide (FAD) and hence to the respiratory chain (. Fig. in the mitochodrion initially via separate pathways but 13.1) via electron transfer protein (ETF)/ETF-dehy- which then converge in a common pathway starting with drogenase (ETF-DH). From the five distinct de- 2-aminoadipic and 2-oxoadipic acids (. Fig. 23.1). The ficiencies identified in the degradation of lysine, only en- initial catabolism of lysine proceeds mainly via the bifunc- zymes 4 and 6 have proven relevance as neurometabolic tional enzyme, 2-aminoadipic-6-semialdehyde synthase disorders. Glutaric aciduria type I is caused by the isolated (enzyme 1). A small amount of lysine is cata bolized via deficiency of glutaryl-CoA dehydrogenase/glutaconyl- IV pipecolic acid and the peroxisomal enzyme, pipecolic acid CoA decarboxylase. Glutaric aciduria type II, caused by oxidase (enzyme 2). Hydroxylysine enters this pathway ETF/ETF-DH deficiencies, is discussed in 7 Chap. 13. after phosphorylation by hydroxylysine (enzyme Pipecolic acid oxidase deficiency is discussed in 7 Chap. 3). 2-Aminoadipic-6-semialdehyde is converted into glu- 40 and antiquitin deficiency in 7 Chap. 29. taryl-CoA by antiquitin (enzyme 4, deficient in B6 respon- The metabolic origins and fates of L- and D-2-hydro- sive seizures) and a second bifunctional enzyme, 2-ami- xyglutaric acids have not been completely unravelled in noadipate aminotransferase/2-oxoadipate dehydrogenase mammals. Yet, L- and D-2-hydroxyglutaric aciduria (enzyme 5). Glutaryl-CoA is converted into crotonyl- have recently been shown to be caused by deficiencies CoA by a third bifunctional enzyme, glutaryl-CoA dehy- of specific dehydrogenases. Aspartoacylase irreversibly drogenase/glutaconyl-CoA decarboxylase (enzyme 6). splits N-acetylaspartic acid into acetate and aspartate This enzyme tranfers electrons to flavin adenine dinucle- (not illustrated).

. Fig. 23.1. Tryptophan, hydroxylysine and lysine catabolic dehydro genase; 6, glutaryl-CoA dehydrogenase/glutaconyl-CoA pathways. CoA, coenzyme A. 1, 2-aminoadipic-6-semialdehyde decarboxylase. Enzyme deficiencies are indicated by solid bars synthase; 2, pipecolic acid oxidase; 3, hydroxylysine kinase; across the arrows 4, antiquitin; 5, 2-aminoadipate aminotransferase/2-oxoadipate 295 23 23.2 · Hyperlysinemia/Saccharopinuria

share structural similarities with the excitatory Seven inborn errors are described in this chapter: glutamate (D-2-, L-2-, 3-hydroxyglutarate, glutarate) or Hyperlysinemia I/hyperlysinemia II or saccharopinuria, have been suggested to be neurotransmitters/neuromodu- hydroxylysinuria and 2-amino-/2-oxo-adipic aciduria lators (J-hydroxybutyrate, N-acetylaspartylglutamate) [2]. may all have no clinical significance, but some patients Evidence from in vitro and in vivo studies is growing that are retarded and show variable neurological abnorma- these acids indeed interfere with glutamatergic or gamma lities. amino butyric acid (GABA)-ergic neurotransmission or Glutaric aciduria type I (GA I, synonym glutaryl-CoA impair energy metabolism. Delayed myelination or pro- dehydrogenase deficiency) causes severe neurometa- gressive demyelination, and cerebellum patho- bolic disease. The first months may be uneventful with logy, the main pathologies in cerebral organic acid disor ders, only subtle neurological abnormalities and/or macro- are also characteristic of mitochondrial disorders suggest- cephaly, but progressive cerebral atrophy or subdural ing at least partial common pathological mechanisms. hemorrhages on neuroimaging. Between age 6 to Patients with cerebral organic acid disorders often 18 months most untreated patients suffer an acute en- suffer a diagnostic odyssey and may even remain undiag- cephalopathy resulting in irreversible destruction of nosed. Metabolic hallmarks such as hypoglycemia, meta- suscep tible regions, in particular the striatum, bolic acidosis or lactic acidemia, the usual concomitants of a dystonic-dyskinetic syndrome and, ultimately, often disorders of organic acid metabolism, are generally absent. early death. Restriction of lysine, administration of Furthermore, elevations of diagnostic metabolites may be L- and timely vigorous treatment during inter- small and therefore missed on »routine« organic acid ana- current illness is able to completely prevent or at least lysis, e.g. in glutaric aciduria type I. The correct diagnosis halt the disease. requires an increased awareness of these disorders by the L-2-Hydroxyglutaric aciduria shows an insidious referring physician as well as the biochemist in the meta- onset with delay of unsupported walking and speech, bolic laboratory. Diagnostic clues can be derived from neuro- febrile convulsions, and . Over the years, imaging findings . Fig. 23.2). Progressive disturbances of severe mental retardation and cerebellar ataxia devel- myelination, cerebellar atrophy, frontotemporal atrophy, op with or without , pyramidal signs, and hypodensities and/or infarcts of the basal ganglia and any seizures. symmetrical (fluctuating) pathology, apparently indepen- D-2-Hydroxyglutaric aciduria causes severe early- dent of defined regions of vascular supply, are suggestive of onset epileptic encephalopathy with neonatal seizures, cerebral organic acid disorders. lack of psychomotor development and early death. In contrast to the cerebral organic acid disorders, the Some patients exhibit milder neurological symptoms other know defects of lysine and hydroxylysine degradation such as mild developmental delay, delayed speech and all appear to be rare biochemical variants of human meta- febrile convulsions. bolism without clinical significance. N-Acetylaspartic aciduria (synonyms: aspartoacylase deficiency, spongy degeneration of the brain, Van Bogaert- Bertrand disease or Canavan disease) is an infantile 23.2 Hyperlysinemia/Saccharopinuria degenerative disease primarily affecting the cerebral white matter. It commonly manifests with poor head 23.2.1 Clinical Presentation control and hypotonia at 2-4 months, macrocephaly, marked developmental delay, optic nerve atrophy, Hyperlysinemia/saccharopinuria appears to be a rare »non- progressive , opisthotonic posturing, seizures disease«. About half of the patients described were detected and death in childhood. incidentally and are healthy [3]. Symptoms have included psychomotor retardation, epilepsy, spasticity, ataxia and short stature. Individual patients have been described with joint laxity and spherophakia, respectively. 23.1 Introduction

A group of organic acid disorders presents exclusively with 23.2.2 Metabolic Derangement progressive neurological symptoms of ataxia, epilepsy, myo- clonus, extrapyramidal symptoms, metabolic stroke, and Hyperlysinemia/saccharopinuria is caused by deficiency macrocephaly [1]. The core »cerebral« organic acid dis- of the bifunctional protein 2-aminoadipic semialdehyde orders are glutaric aciduria type I, D-2-hydroxyglutaric acid- synthase, the first enzyme of the main route of lysine de- uria, L-2-hydroxyglutaric aciduria, 4-hydroxybutyric acid- gradation [4]. The two functions, lysine-2-oxoglutarate uria and N-acetylaspartic aciduria. Strikingly, in all these reductase and dehydrogenase, may be differ- disorders the pathological compounds that accumulate ently affected by mutations. Most often, both activities are 296 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

severely reduced, resulting predominantly in hyperlysine- 23.3 Hydroxylysinuria mia and hyperlysinuria, accompanied by relatively mild sacccharopinuria (hyperlysinemia I). In hyperlysinemia II Hydroxylysinuria and concomitant hydroxylysinemia has or saccharopinuria [5], there is a relatively more pronounced been identified in only six patients, all of whom showed decrease in saccharopine dehydrogenase activity with re- some degree of mental retardation [8]. No further clinical sidual activity of lysine-2-oxoglutarate reductase causing a and/or biochemical studies were reported. The abnormality predominant excretion of sacccharopine. can be assumed to be caused by a defect of hydroxylysine Failure to remove the H-amino group results in an over- kinase. flow of the minor lysine degradation pathway with removal IV of the D-amino group by oxidative deamination. The oxo- acid cyclizes and is reduced to pipecolic acid. As a con- 23.4 2-Amino-/2-Oxo-Adipic Aciduria sequence, hyperpipecolatemia is regularly observed in hyperlysinemia. 23.4.1 Clinical Presentation Hyperlysinuria can also result from impaired renal tubular transport, often as part of a genetic transport defect As with hyperlysinemia/saccharopinemia, 2-amino-/2-oxo- of dibasic amino acids (7 Chap. 26), but in this situation it adipic aciduria is probably of no clinical significance. Over occurs without hyperlysinemia. 20 patients are known, of whom more than half are asymp- tomatic ([9]; Hoffmann, unpublished observation). Symp- toms include psychomotor retardation, muscular hypo- 23.2.3 Genetics tonia, epilepsy, ataxia and failure to thrive.

Hyperlysinemia/saccharopinuria follows an autosomal re- cessive inheritance. The gene has been characterized and 23.4.2 Metabolic Derangement a homozygous out-of-frame 9bp deletion identified in an affected boy [4]. The metabolic profile is heterogeneous with most patients showing elevations of all three metabolites, whereas some excrete only 2-aminoadipic acid [10]. Normally 2-amino- 23.2.4 Diagnostic Tests adipic acid is deaminated to 2-oxoadipic acid by a mito- chondrial 2-aminoadipate aminotransferase. 2-Oxoadipic The initial observation in patients with hyperlysinemia/sac- acid is also formed from the degradation of tryptophan. charopinuria is an impressive lysinuria up to 15 000 mmol/ 2-Oxoadipic acid is further metabolized to glutaryl-CoA by mol creatinine (controls <70). Detailed amino acid analysis oxidative decarboxylation, probably differently from that will reveal additional accumulation of saccharopine, homo- of oxoglutarate. , 2-aminoadipic acid and pipecolic acid [6]. Eleva- Isolated 2-aminoadipic aciduria is probably caused by tions of the same metabolites can be documented in other a deficiency of 2-aminoadipate aminotransferase, and com- body fluids such as plasma and cerebrospinal fluid (CSF) bined 2-amino/2-oxoadipic aciduria by a deficiency of the with high lysine as the predominant abnormality (up to 2-oxoa dipate dehydrogenase complex. However a deficien- 1700 µmol/l in plasma, controls < 200, and up to 270 µmol/l cy of neither enzyme has yet been shown directly. in CSF, controls < 28). 2-Aminoadipic acid shows a complex excitatory amino The deficiency of 2-aminoadipic semialdehyde synthase acid synaptic pharmacology, which may be related to the can be ascertained in fibroblasts and tissue biopsies by neurological symptoms. determining the overall degradation of [1-14C] lysine to 14 CO2. Specific assays for lysine 2-oxoglutarate reductase and saccharopine dehydrogenase have been described [7]. 23.4.3 Genetics Molecular diagnosis has become possible [4]. Autosomal recessive inheritance is implied by the pedigrees and by the finding that parents can not be biochemically 23.2.5 Treatment and Prognosis differentiated from controls.

Long-term dietary restriction of lysine has no benefit. As patients do not suffer from metabolic decompensations, 23.4.4 Diagnostic Tests specific interventions during intercurrent illnesses are not necessary. As hyperlysinemia/saccharopinuria is a benign Patients are diagnosed by demonstrating variable elevations condition it is not associated with any increase in morbid- of 2-aminoadipic acid on amino acid chromatography and/ ity or mortality. or of 2-oxoadipic and 2-hydroxyadipic acids on urinary 297 23 23.5 · Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency)

organic acid analysis. Plasma lysine may be twofold elevated acute subdural hemorrhages including retinal hemorrhages and urinary glutaric acid up to 50 mmol/mol of creatinine after minor head trauma, particularly around the first (controls < 9) [11]. birthday when starting to walk (. Fig. 23.2b). Parents of Oral loading with lysine or tryptophan (100 mg/kg children with have been wrongly body weight) increases the pathological metabolites two- to charged with child abuse because of chronic or acute sub- sixfold [10]. Conclusive molecular or enzymatic analyses durals and/or hemorrhages [18]. have not yet been achieved. On average at an age of 9 months ≈ 75% of patients suffer an acute brain injury usually associated with an upper respiratory and/or gastrointestinal infection, but the ence- 23.4.5 Treatment and Prognosis phalopathic crisis may also develop in association with fasts required for surgery, after routine immunizations, or fol- As 2-amino-/2-oxoadipic aciduria is likely a non-disease, it lowing minor head traumas [12]. 87% of the encephalo- does not determine morbidity or mortality. Patients do not pathic crises occur by age 24 months. They have not yet suffer from metabolic decompensations, and specific inter- been described at school age or in older children. Neuro- ventions during intercurrent illnesses do not appear neces- logical functions are often acutely lost, including their sary. Administration of pharmacological doses of vitamins ability to sit, pull to standing, head control, suck and swal-

B1 and B6 had no effect on the levels of pathological me- low reflexes. The infants appear alert with profound hypo- tabolites [10]. Dietary restriction of lysine also failed to tonia of the neck and trunk, stiff arms and legs, and twisting correct the biochemical abnormalities in some patients [10] (athetoid) movements of hands and feet. There may also and has no proven long-term benefit. be generalized seizures. Mostly, there are no or only mild metabolic derangements. A severe dys-/hypotonic move- ment disorder develops. At this point the distinctive clinical 23.5 Glutaric Aciduria Type I picture of a dystonic-dyskinetic syndrome in an alert look- (Glutaryl-CoA Dehydrogenase ing child with relatively well preserved intellectual func- Deficiency) tions and a prominent forehead may be recognized. If the underlying remains undiagnosed, addi- 23.5.1 Clinical Presentation tional cerebral systems are slowly but progressively affected. A generalized cerebral atrophy emerges (. Figs. 23.2c and d), Glutaric aciduria type I should be strongly considered in giving rise to pyramidal tract signs and mental retardation. the differential diagnosis of any infant with macrocephaly Impaired chewing and swallowing, vomiting and aspiration together with progressive atrophic changes on computer- as well as increased energy demand due to increased muscle ized tomography (CT) or nuclear magenetic resonance tone frequently results in failure to thrive and malnutrition. (NMR) (. Fig. 23.2a–d) and/or acute profound dyskinesia Kyphoscoliosis and chest wall dystonia can cause restrictive or subacute motor delay accompanied by increasingly lung disease. Early death (|40% of symptomatic patients by severe choreoathetosis and dystonia [11–17, 17a]. In many the age of 20 years) may occur in the course of intercurrent patients macrocephaly is present at or shortly after birth pneumonia and respiratory failure, during hyperpyrexic and precedes the severe neurological disease. An important crises or suddenly without warning. clue to early diagnosis is the observation of a pathologically Although the majority of patients present with charac- increased head growth crossing the percentiles and peaking teristic symptoms and disease course, the natural history of at the age of 3-6 months. Furthermore, affected babies often glutaric aciduria type I can be variable even within families. present additional »soft« neurological symptoms of hypo- A minority of patients (≤20%) presents with developmental tonia with prominent head lag, irritability, jitteriness, and delay from birth and (progressive) dystonic . feeding difficulties. Neonatal posture and tone may persist Some individuals, mainly diagnosed in adolescence or adult- until 4 to 8 months of age. During febrile illnesses or after hood during family studies, have not developed neuro logical immunizations, hypotonia is often aggravated and unusual disease despite never having been treated. Finally, adult on- movements and postures of hands appear. All these symp- set-type glutaric aciduria type I has recently been described toms are still reversible and of little prognostic significance. in five previously unaffected adolescent/adult patients pre- Neuroimaging studies have been performed in a number of senting with leukoencephalopathy [19, 20], suggesting an patients during this »presymptomatic« period revealing the additional distinct clinical manifestation of this disease. characteristic findings of frontotemporal atrophy (95% of all patients) delayed myelination, and high-signal intensity in the dentate nucleus (. Fig. 23.2a). The clinical signifi- 23.5.2 Metabolic Derangement cance of enlarged subdural fluid spaces in infants with glutaric aciduria type I is the unprotected crossing of these Glutaric aciduria type I is caused by a deficiency of glu - spaces by bridging veins. Such infants are prone to suffer t aryl-CoA dehydrogenase, a mitochondrial flavin adenine 298 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

IV

a c

d

b

. Fig. 23.2. Neuroimaging findings, which are characteristic for cere- type I, who suffered an encephalopathic crisis at the age of 11 months, bral organic acid disorders. a Transversal NMR image of a 2-month-old illustrating regression of the temporal lobes, more pronoun ced on the presymptomatic boy with glutaric aciduria type I deficiency showing left side, with dilatation of the Sylvian fissures anterior to them as well as enlargement of CSF spaces anterior to the temporal lobes with marked dilated insular cisterns (frontotemporal atrophy), delayed myelination extension of sylvian fissures (frontotemporal atrophy). Spin echo tech- and bilateral hypodensities of the basal ganglia. Spin echo technique nique (1.0 tesla): time of repetition 660 ms, time of echo 20 ms, slice (1.0 tesla): time of repetition 2660 ms, time of echo 100 ms, slice thick- thickness 5.5 mm. b CT scan of a 9-month-old presymptomatic boy with ness 5 mm. d Coronal section of CNS of a 8-month-old girl with glutaric glutaric aciduria type I. In addition to frontotemporal atrophy sub dural aciduria type I with dilatation of CSF spaces prominently at the Sylvian effusions and hematomas causing midline shift are visible. There is no fissures by NMR. At the age of 6 months a ventric ularperitoneal shunt pathology of the basal ganglia, and the child continued to develop nor- was inserted in an attempt to drain »bilateral subdural hygromas« with- mally. c Transversal NMR image of a 2-year-old boy with glutaric aciduria out knowledge of the underlying metabolic disorder. The catabolic 7 299 23 23.5 · Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency)

e g

fh

. Fig. 23.2 (continued) stress following the operation resulted in an encephalopathic crisis and illustrating symmetric involvement of the dentate nuclei. Reproduced consecutively destruction of the basal ganglia and a severe dystonic- with permission from Kölker et al [2]. g Transversal NMR image of a dyskinetic syndrome. Spin echo technique (1.0 tesla): time of repetition 2-month-old girl with D-2-hydroxyglutaric aciduria. Please note delayed 380 ms, time of echo 25 ms, slice thickness 6 mm. e Transversal NMR myelination and considerable occipitally pronounced enlargement of image of a 3-year-old boy with L-2-hydroxyg lutaric aciduria, illustrating lateral ventricles. Spin echo technique (1.0 tesla): time of repetition characteristic involvement of the subcortical white matter (U fibres), the 618 ms, time of echo 15 ms, slice thickness 6 mm. h Axial fast spin echo N. caudati and the putamina. In this boy the periventicular white matter image of a 6.5-year-old girl suffering from N-acetylaspartic aciduria. was also affected early on. Spin echo technique (1.0 tesla): time of re- Note the marked discrepancy between the severely affected subcortical petition 2660 ms, time of echo 100 ms, slice thickness 5 mm. f Axial T2- white matter and the relatively spared central white matter, at least weighted MRI of an 8.5-year-old boy with L-2-hydroxyglutaric aciduria, frontally. Reproduced with permission from Kölker et al [2] 300 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

dinucleoti de requiring enzyme, which catalyzes the dehy- zygous for the A421V mutation, incidence of 1:300–400) drogenation of glutaryl-CoA as well as the subsequent decar- [17], the Saulteaux/Ojibway Indians in Canada (homo- boxylation of glutaconyl-CoA to crotonyl-CoA (. Fig. 23.1). zygous for the splice site mutation IVS-1+5 g>t 1:300) [28] In glutaric aciduria type I, part of the accumulating glut- or the Irish travellers (homozygous for the E365K muta- aryl-CoA is esterified with carnitine by carnitine acyl- tion) [16]. leading to an increased ratio of acylcarnitines to More than 150 different disease-causing mutations in free carnitine in plasma and urine. Glutarylcarnitine is ex- the glutaryl-CoA dehydrogenase gene have been identified creted, contributing to secondary carnitine deficiency [11]. so far [31, 13] and unpublished data. There is a correlation Patients with glutaric aciduria type I often show increased between genotype and biochemical phenotype in that spe- IV urinary excretion of dicarboxylic acids, 2-oxoglutarate cific mutations with significant residual enzyme activity and succinate, indicative of disturbed mitochondrial func- may be associated with low excretions of metabolites in tion [11]. heterozygous patients who carry a severe mutation on the Secondary carnitine deficiency is probably a major other allele. However, no correlation between genotype and causative factor of metabolic crises. These can present with clinical phenotype has yet been found. Single common mu- hypoglycemia and variable metabolic acidosis and may tations are found in genetically homogenous communities quickly progress to a Reye-like syndrome (14% in one series (see above), but glutaric aciduria type I in general is geneti- [14]). Metabolic crises can develop at any age and respond cally quite heterogeneous: the most frequent mutation in well to intravenous therapy with glucose, carnitine and Caucasians, R402W, has been identified on 10–20% of bicarbonate [11, 14, 21]. alleles [31]. Apart from three short or single nucleotide The mechanism of age-specific destruction of specific deletions, the great majority of mutations are single base cerebral structures in glutaric aciduria type I has been sub- changes that are frequently found at hypermutable CpG ject of intense debates and generated different hypotheses sites. [22]: competitive inhibition of glutamate decarboxylase, the key enzyme in the biosynthesis of the inhibitory neuro- transmitter GABA [23] or an increased catabolism of tryp- 23.5.4 Diagnostic Tests tophan via the pathway [24], the latter sup- ported by the observation that a key enzyme of this pathway, Patients with glutaric aciduria type I are generally diag- indolamine-2,3-dioxygenase, is up-regulated by interferons nosed by urinary organic acid analysis [11, 25]. Repeated during acute viral infections, which could contribute to an and quantitative urinary organic acid analyses may be nec- encephalopathic crisis. essary. Additional diagnostic hints can be obtained by find- The most substantiated evidence points to an excito- ing carnitine deficiency in serum and/or a pathologically toxic sequence [22], initiated by glutaric and 3-hydroxy- increased ratio of acylcarnitines to free carnitine in serum glutaric acids which exhibit structural similarities to the and urine. Elevations of glutarylcarnitine in body fluids of excitotoxic amino acid glutamate. Massive activation of patients can be detected through acylcarnitine analysis [27]. glutaminergic neurons from cortex to putamen via the Application to analyses of blood spots (Guthrie cards) has caudate nucleus can be anticipated during encephalopathic enabled the recent inclusion of glutaric acidurias type I and crises. The inhibitory output of the thalamus would explain type II into several neonatal screening programs. However, the severe muscular hypotonia and also the temporary individuals with deficiency of glutaryl-CoA dehydrogenase improvement of dystonia during further catabolic episodes and severe characteristic neurological disease but with only as a consequence of overstimulation of the remaining glut- slight or inconsistent elevations of glutaric acid or glutaryl- aminergic neurons. Finally, maturation-dependent changes carnitine have been diagnosed in increasing numbers [25, in the expression of neuronal glutamate receptors and 27, 26]. Furthermore, elevated urinary excretion of glutaric thereby vulnerability to 3-hydroxyglutaric and glutaric acid acid can also be found in a number of other disease states toxicity are likely responsible for the specific time course mostly related to mitochondrial dysfunction [11]. Determi- and localization of neurological disease. nation of 3-hydroxyglutaric acid with a stable isotope dilu- tion assay in urine has the highest diagnostic power [25]. It proved to be reliably elevated except for patients from first 23.5.3 Genetics nations of Oji-Cree descent from North-eastern Manitoba and North-western Ontario [28]. Glutaric aciduria type I is an autosomal recessive disorder. Loading tests, e.g. with lysine or prolonged fasting Results of programs in various regions tests provoking catabolism may be extremely harmful and and cohorts worldwide enrolling approximately 2.5 million should be avoided. Alternatively, safe loading tests can newborns world-wide give an overall mean frequency of be performed in vitro using lymphoblasts or peripheral 1:106 900 [27]. The disease is very frequent in certain com- mononuclear blood cells [29]. Ultimately, demonstration of munities such as the Amish people in Pennsylvania (homo- two known pathogenic mutations or enzyme analysis of 301 23 23.5 · Glutaric Aciduria Type I (Glutaryl-CoA Dehydrogenase Deficiency)

glutaryl-CoA dehydrogenase is the only method that can (2) Oral Supplementations with Carnitine and Riboflavin establish the diagnosis of glutaric aciduria type I with cer- Carnitine should be supplemented lifelong. Published data tainty in diagnostically problematic cases. Glutaryl-CoA suggests that most, but not all, patients developing an ence- dehydrogenase activity can be determined in tissues, cul- phalopathic crisis had no carnitine supplementation. Ribo- tured fibroblasts, peripheral leukocytes, amniocytes and flavin responsiveness has never been demonstrated in any chorionic villi cells [30]. This procedure is justified in family patient with glutaric aciduria type I. If riboflavin is tried, studies or whenever there is strong clinical suspicion. responsiveness should be investigated by giving riboflavin Carrier detection is possible by enzyme assay, though in increasing doses from 50 to 300 mg and monitoring the results are not always unequivocal [30] and by mole- total glutaric acid in 24-hour-urine samples. In evaluating cular means in families in which the mutations are already the response unrelated high daily variations of the urinary known. Reliable prenatal diagnosis can be offered by enzyme excretion of glutarate must be taken into account. assay [30], determination of glutaric acid by stable isotope dilution gas chromatography–mass spectrometry (GC-MS) (3) Dietary Treatment assay in amniotic fluid [25], and by molecular analysis Most patients with glutaric aciduria type I are treated by [31]. restriction of natural protein in general or of lysine in par- ticular, supplemented with a lysine free amino acid mixture (. Table 23.1). Application of lysine-free amino acid mix- 23.5.5 Treatment and Prognosis tures minimizes the risk for malnutrition, allows a reliable control of protein and lysine intake and, most importantly, Three decades after the first description of glutaric aciduria has proven the best long-term results. It should therefore be type I, approximately 350–400 patients have been identified followed during the vulnerable period for acute encephalo- world-wide and major progress has been achieved in the pathic crises, i.e. the first 6 years of life [17a]. Tryptophan prevention of acute striatal necrosis and neurologic se quelae, contributes only ≤20% to total body glutarate pro d uction. if diagnosis is made early and treatment is started before The intake of tryptophan should only be reduced, if conse- manifestation of acute encephalopathic crises. Early diag- quently and reliably monitored, which is not possible by nosis and treatment of the asymptomatic child is essential regular amino acid analysis. Concentrations of tryptophan as current therapy has little effect upon the brain injured directly modulate production of in the CNS. Us- child. If an encephalopathic crisis occurred, only 5% of ing diets low in tryptophan we observed side effects such as patients recovered completely, 75% remained handicapped sleeplessness, ill temper, irritability, and loss of appetite, of whom 40% died early. However, all concepts for diag- which could be improved by isolated tryptophan supple- nostic work-up, monitoring, and treatment are solely ex- mentation [14]. There are only anecdotal data about the perience-based, and even with early diagnosis 10–30% of value of protein restriction beyond six years of age. How- patients do not or only incompletely benefit from the cur- ever, protein excesses should be avoided. rent management [14, 16, 17]. Special efforts to supply adequate calories are often Five different therapeutic measures are generally em- necessary in patients with motor dysfunction and swallow- ployed: ing difficulties. This may require nasogastric or gastrostomy feeding. We have also observed that an improved nutritional (1) Emergency Treatment status is paralleled by a reduction of the dystonic/dyskinetic Emergency treatment must start before onset of severe syndrome. neurological signs, which already indicate the manifesta- tion of neuronal damage. During intercurrent illnesses, (4) Neuropharmacological Agents especially gastrointestinal infections, treatment should Several of these have been tried to ameliorate neurological consist of frequent high carbohydrates feeds and increased symptoms in patients with glutaric aciduria type I. Clome- carnitine supplementation, followed by high-dose intra- thiazole was found useful in severe cases of hyperpyrexia. venous glucose and carnitine, if necessary [11, 21]. If mix- In our experience, baclofen (Lioresal, 1-2 mg/kg daily) or tures of free amino acids devoid of lysine are used, these are benzodiazepines (diazepam, 0.1–1 mg/kg daily) reduce offered orally, in addition. If the temperature rises >38.5 °C involuntary movements and improve motor function, prob- (101 F), antipyretics must be administered, e.g. ibuprofen ably mostly through muscle relaxation. In some patients (10–15 mg/kg body wt per dose, 3-4 doses daily). All pa- their use and dosage are limited by worsening of truncal tients with glutaric aciduria type I should be supplied with hypotonia. The patient’s head should be kept in the midline an emergency card. Frequent visits and regular information position, as this allows maximum mobility and minimizes and training of parents may help to prevent lapses or mis- dystonia. takes. This concept must be strictly followed for the first In patients with residual motor function anticholin- 6 years of life. After this age emergency treatment is indi- ergics, such as trihexyphenidyl, may improve choreoathe- vidually adjusted. tosis [17]. Valproic acid is contraindicated as it effectively 302 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

competes with glutaric acid for esterification with L-carni- muscular tension and sweating, common findings in glu- tine and may promote disturbances in the mitochondrial taric aciduria type I, require a high intake of calories and acetyl-CoA/CoA ratio. Vigabatrine has been commonly water. Percutaneous gastrostomy can lead to a dramatic used in the past. It showed little to no effect [15] but is still improvement in nutritional status, a marked decrease in used by a number of patients, which in view of the severe psychological tension associated with feeding, a reduction side effects should be carefully re-evaluated on an individual in the burden of care for families and even a reduction in basis. There are anecdotal reports of sustained improve- the dystonia/dyskinesia. As a final remark, neurosurgical ment with experimental therapies including botulinum interventions of subdural hygromas and hematomas in toxin injections and a baclofen pump [32]. Considering the infants and toddlers with glutaric aciduria type I should be IV severe neurological disease surprisingly little information avoided, if at all possible (. Fig. 23.2d). is available on the effects of other neuropharmacological As the risk for encephalopathic crises subsides after 4 to agents; medications listed in . Table 23.1 could be empiri- 5 years of age, the rationale of dietary treatment using lysine cally employed. free amino acid mixtures beyond 6 years of age is uncertain. In some symptomatic patients, movement disorders were (5) Nonspecific Multiprofessional Support aggravated by excessive intake of protein and could be re- This is of utmost importance since despite the severe motor versed after reduction of protein intake. Furthermore, five handicap, intellectual functions are preserved until late into undiagnosed and untreated patients, have presented with the course of the disease. Affected patients require the full leukoencephalopathy as late-onset disease in adolescence recourses of a multidisciplinary specialist institution. The or adulthood [20]. However, it is not yet known whether social integration of patients can be greatly improved using dietary treatment can prevent chronic neurodegenerative Bliss boards and, in particular, language computers. As in- changes. Emergency measures during intercurrent illnesses voluntary movements of orofacial muscles may be severe, may also be partially relaxed in older children. Carnitine feeding difficulties can become a major problem. Increased supplementation must be followed for life.

23.6 L-2-Hydroxyglutaric Aciduria . Table 23.1. Maintenance therapy in patients with glutaric aciduria type I 23.6.1 Clinical Presentation Measures Infants Children Children Adults <6 years >6 years The initial description of L-2-hydroxyglutaric aciduria Diet was followed by a number of reports from all over the world Natural 1.8–1.0 1.4–1.11.5–1.11.0 illustrating previous mis- and under diagnosis. Most pa- Protein tients with L-2-hydroxyglutaric aciduria follow a character- (g/kg b.w./day) istic disease courses [33–36]. In infancy and early child- Amino Acid 1.0–0.8 1.0–0.8 n.a. n.a. hood mental and psychomotor development appears nor- Mixture mal or only slightly retarded. Thereafter seizures, progressive (g/kg b.w./day) ataxia, pyramidal tract signs, slight extrapyramidal signs

Lysine 100–90 80–50 n.a. n.a. and progressive mental retardation become the most ob- (mg/kg b.w./day) vious clinical findings. Progressive macrocephaly is present in about half of the patients. The IQ in teenagers is ≈40–50. Tryptophan ≥20–17 ≥17–13 n.a. n.a. Sometimes mental deterioration is rapidly progressive, and (mg/kg b.w./day) a single patient with fatal neonatal outcome has been de- Energy 120 95–80 70-60 50–40 scribed [37]. (kcal/kg b.w./day) In L-2-hydroxyglutaric aciduria the neuroimaging Supplementations findings are very specific [33, 38]. The subcortical white matter appears mildly swollen with some effacement of L-Carnitine 100 50–100 50–100 50 (mg/kg b.w./day) gyri. The progressive loss of arcuate fibers is combined with a severe cerebellar atrophy and increased signal den- Neuropharmaceuticals (Patients with neurological disease): sities of dentate nuclei, globi pallidi and less frequently Baclofen, Clonazepam, Diazepam, Triheyphenidyl, Memantine, the nuclei caudati and putamina (. Figs. 23.2e and f) on Haloperidol, L-Dopa/Levodopa, . Do not Use Valproic Acid or Vigabatrin. T2-weighted images, while the thalamus shows decreased signal densities. Multiprofessional Support of Patient and Family

n.a., not applicable. 303 23 23.7 · D-2-Hydroxyglutaric Aciduria

23.6.2 Metabolic Derangement severe seizures, lack of psychomotor development and early death [43] to mild developmental delay and no symptoms Quantitative analysis of organic acids revealed higher ele- at all [44]. An international survey of 17 patients revealed a vations of L-2-hydroxyglutaric acid in CSF than in plasma continuous spectrum between these extremes with most [39]. In addition a number of hydroxydicarboxylic acids patients suffering from a severe early onset epileptic ence- (glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and phalopathy, while a substantial subgroup showed mild isocitrate) were only found elevated in CSF, pointing to a symptoms or were even asymptomatic [45]. Clinical and specific disturbance of brain metabolism. Another consis- neuroradiological symptoms of the severely affected pa- tent biochemical finding is an increase of lysine in blood tients were quite uniform. Severe, often intractable seizures and CSF. started in early infancy. The babies were severely hypotonic. A gene encoding a putative FAD-dependent L-2-hy- Conscious levels varied from irritability to stupor. Cerebral droxyglutarate dehydrogenase, first tentatively identified visual failure was uniformly present. Psychomotor develop- in human liver [33], has been recently found defective in ment appeared almost absent. A third of the severely af- L-2-hydroxyglutaric aciduria and its gene identified and fected patients suffered from cardiomyopathy. Less severely mutations demonstrated [40, 41]. It was concluded that affected patients exhibited mostly mild neurological symp- L-2-hydroxyglutaric acid is normally converted into 2-oxo- toms including slight developmental delay, delayed speech glutarate, while the origin of L-2-hydroxyglutaric acid re- and febrile convulsions. mains uncertain. In the severely affected patients neuroimaging uni formly revealed disturbed and delayed gyration, myelination and opercularization, ventriculomegaly, more pronounced of 23.6.3 Genetics the occipital horns, and cysts over the head of the caudate nucleus (. Fig. 23.2g). Enlarged prefrontal spaces and sub- L-2-hydroxyglutaric aciduria is an autosomal recessive dural effusions in some patients were further reminiscent of disorder. Heterozygotes display no detectable clinical or the neuroimaging findings in glutaric aciduria type I. biochemical abnormalities, but can now be ascertained by molecular diagnosis in informative families. 23.7.2 Metabolic Derangement

23.6.4 Diagnostic Tests Patients show highly elevated levels of D-2-hydroxyglutaric acid in all body fluids with no apparent correlation to the L-2-hydroxyglutarate is found elevated in all body fluids clinical phenotype. In addition Krebs cycle intermediates [33, 42]. In addition, lysine is slightly elevated in cerebro- are found elevated in the urine of some patients, as well as spinal fluid as well as protein in the absence of pleocytosis. GABA in CSF [45]. The disorder has recently been shown Differentiation between the two isomers of 2-hydroxy- to be due to a deficiency of D-2-hydroxyglutaric acid dehy- glutarate is indispensable for diagnosis. Prenatal diagnosis drogenase, an enzyme that converts D-2-hydroxyglutaric is possible utilizing accurate determination of L-2-hydroxy- acid to 2-oxoglutaric acid [46, 47, 47a]. The enzyme is homo- glutarate by stable isotope dilution GC-MS assay in amniotic logous to FAD-dependent D-lactate dehydrogenase. The fluid [42, 36] as well as molecular diagnosis. origin of D-2-hydroxyglutaric acid is still not completely resolved. It might be formed from 2-oxoglutaric acid as part of a metabolic cycle, yet to be described, or arise as an 23.6.5 Treatment and Prognosis intermediate in the conversion of 5-aminolevulinic acid to 2-oxoglutaric acid [43, 44]. The neurodegeneration in To date there is no rational therapy for L-2-hydroxyglutaric D-2-hydroxyglutaric aciduria could be linked to an excito- aciduria. Epilepsy can generally be controlled by standard toxic sequence. D-2-hydroxyglutaric acid directly activates medications. The oldest known patients are over 30 years of N-methyl-D-aspartate (NMDA) receptors, and in addition age. They are bedridden and severely retarded. significantly increased cellular calcium levels and inhibited ATP synthesis, but without affecting the electron-trans- ferring complexes I–IV [21]. 23.7 D-2-Hydroxyglutaric Aciduria

23.7.1 Clinical Presentation 23.7.3 Genetics

Patients with D-2-hydroxyglutaric aciduria exhibit a more D-2-hydroxyglutaric aciduria is an autosomal recessive variable phenotype than patients with L-2-hydroxyglutaric disorder. Pathogenic mutations have been found in mildly aciduria. The clinical spectrum varies from neonatal onset, as well as in severely affected patients. Heterozygotes dis- 304 Chapter 23 · Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism

play no detectable clinical or biochemical abnormalities, remarkably increased; however, in the majority of cases but can now be ascertained by molecular diagnosis in it increases pathologically after six months of age crossing families known to be at risk [47]. the percentiles with obvious macrocephaly by 1 year. In the second year of life seizures often develop together with irritability and sleep disturbance. Hypotonicity gives way to 23.7.4 Diagnostic Tests spasticity reminiscent of cerebral palsy. Impaired chewing and swallowing, problems with gastroesophageal reflux, D-2-hydroxyglutaric acid is found elevated from 120– vomiting and aspiration can result in recurrent infections 26 000 mmol/mol of creatinine (controls <17) in urine, and failure to thrive. Death usually occurs in a few years IV from 3–660 µmol/l (controls <0.9) in plasma, and from 3– although survival in a vegetative state or near vegetative 320 µmol/l (controls <0.34) in cerebrospinal fluid [42, 45]. state may extend to the second decade. In addition, GABA was found elevated in CSF and inter- The most consistent findings on magnetic resonance mediates of energy metabolism in urine (lactic, succinic, imaging (MRI) studies are diffuse abnormalities of white malic, and 2-oxoglutaric acids) in some patients. Differen- matter. Although not always present and not uniform [51], tiation between the two isomers of 2-hydroxyglutarate is MRI usually shows symmetric diffuse low signal intensity essential for diagnosis. Prenatal diagnosis has been success- on T1-weighed images and high signal intensity on T2- fully performed by accurate determination of D-2-hydro- weighed images (. Fig. 23.2h). xyglutarate by stable isotope dilution GC-MS assay in Like in L-2-hydroxyglutaric aciduria, the neuropatho- amniotic fluid ([42], C. Jacobs and M.H. Rhead, personal logy of Canavan disease is characterized by a progressive communication) as well as by molecular diagnosis. loss of myelinated arcuate fibers [52]. Detailed histopatho- A few patients with combined D- and L-2-hydroxy- logical descriptions at autopsy are available. White matter glutaric aciduria have been described [49]. It is unclear if is characteristically soft and gelatinous. The spongy or they represent a third clinical and/or biochemical entity. vacuolization changes are clearly seen in the lower layers However, in these patients prenatal diagnosis is not reliable of the gray matter and in the subcortical white matter, with using metabolite determination by stable isotope dilution the more central white matter relatively spared. GC-MS assay in amniotic fluid ([42], C. Jakobs, personal Most patient follow the described disease course, which communication). is also termed the infantile form. Rare clinical variants D-2-Hydroxyglutaric acid can also be elevated in mul- with different disease courses were described as congenital, tiple acyl-CoA dehydrogenase deficiency (glutaric aciduria i.e. presenting at or shortly after birth, or as juvenile forms, type II), but which can be distinguished by the classical i.e. presenting after 5 years of age [51]. urine organic acid profile found in the latter disorder (7 Chap. 13). 23.8.2 Metabolic Derangement

23.7.5 Treatment and Prognosis The disease is caused by aspartoacylase deficiency leading to the accumulation of N-acetylaspartic acid in brain, CSF, To date there is no rational therapy for D-2-hydroxy glutaric plasma, and urine. aciduria. Attempts of riboflavine and L-carnitine supple- mentation had no benefits. Seizures can be very difficult to control, and patients have died early with profound devel- 23.8.3 Genetics opmental delay. In general the clinical course does not ap- pear progressive, if affected children do not develop an N-Acetylaspartic aciduria is transmitted in an autosomal early onset epileptic encephalopathy. recessive manner. It is a pan-ethnic disease with a higher frequency among Askenazi Jews, most of whom carry two specific mutations, a missense mutation, E285A, account- 23.8 N -Acetylaspartic Aciduria ing for 84%, and a nonsense mutation, Y231X, accounting (Canavan Disease) for 13.4% [54]; the frequency of these two mutations makes carrier screening possible [55]. In non-Jewish patients the 23.8.1 Clinical Presentation mutations are diverse and mostly private.

N-Acetylaspartic aciduria mostly manifests at 2–4 months of age with head lag, hypotonia and macrocephaly, pro- 23.8.4 Diagnostic Tests gressing to marked developmental delay, seizures, optic nerve atrophy, progressive spasticity and opisthotonic pos- The diagnosis is best established by determining N-acetyl- turing [50]. At birth the head circumference may not be in the urine by organic acid analysis. Hundred- 305 23 References

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