Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine-dependent seizures (?glutamic acid decarboxylase deficiency) (> 50 patients); (2) GABA-transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain-specific dipeptide of GABA and L-histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA-transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.

4-Aminobutyrate Transaminase↗

PubMed1993

L-2-hydroxyglutaric acidaemia: clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase.

L-2-Hydroxyglutaric acidaemia represents a newly defined inborn error of metabolism, with increased levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. The concentration in cerebrospinal fluid is higher than in plasma. The other consistent biochemical finding is an increase of lysine in blood and cerebrospinal fluid, but lysine loading does not increase L-2-hydroxyglutaric acid concentration in plasma. This autosomal recessively inherited disease is expressed as progressive ataxia, mental deficiency with subcortical leukoencephalopathy and cerebellar atrophy on magnetic resonance imaging. Since these features were described in 8 patients by Barth and co-workers in 1992, 4 more patients with similar findings have been diagnosed and added to the present series. L-2-Hydroxyglutaric acid is found in only trace amounts on routine gas chromatographic screening in normal persons, and its origin, its fate and even its relevance to normal metabolism are unknown. Therefore its catabolism was studied in normal liver. Incubation of rat liver with L-2-hydroxyglutaric acid did not produce H2O2, which excluded (peroxisomal) L-2-hydroxyacid oxidase as the main route of catabolism. However, L-2-hydroxyglutaric acid is rapidly dehydrogenated if NAD+ is added as a co-factor to the standard reaction medium. This could also be demonstrated in human liver. The preliminary evidence for this enzyme activity in rats and humans, L-2-hydroxyglutaric acid dehydrogenase, is given. Further investigations are required to clarify the possible relevance to the metabolic defect in L-2-hydroxyglutaric acidaemia.

Adolescent↗

PubMed1993

Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis.

Prenatal diagnosis has been undertaken in 17 pregnancies in 15 families at risk for aspartoacylase deficiency. Amniocentesis was at 14-18 weeks gestation followed by measurement of amniotic fluid N-acetyl-L-aspartate (NAA) levels in all pregnancies and amniocyte aspartoacylase activity in most pregnancies. In one case amniocentesis was performed at 11 weeks gestation in conjunction with chorionic villus sampling. At 14-18 weeks of gestation, control levels of NAA were 0.30-2.55 mumol/L. The fetus was predicted to be affected in 8 of the pregnancies, 4 of which were confirmed by enzyme analysis on fetal tissue and 2 by the clinical and metabolic expression of Canavan disease in a newborn. In two cases there was no fetal tissue available for enzyme confirmation. One of these had the highest amniotic fluid NAA level (8.68 mumol/L) and in the other pregnancy there were two amniocenteses, both with markedly elevated levels. Of 9 fetuses predicted to be normal, 8 newborns were clinically and biochemically normal. A single case with amniotic fluid NAA in the normal range (1.56 mumol/L, measured in one laboratory only) resulted in an aborted fetus in whom aspartoacylase was deficient in cultured skin fibroblasts. We propose that amniotic fluid NAA levels remain the best predictor of an affected fetus and recommend that the assay be performed in multiple laboratories.

Amniotic Fluid↗

PubMed1993

Familial encephalopathy and L-2-hydroxyglutaric aciduria.

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Adolescent↗

PubMed1993

Long-term outcome in 134 patients with galactosaemia.

In a retrospective study 134 galactosaemic patients, born between 1955 and 1989 in the Federal Republic of Germany were traced and their long-term outcome evaluated. We investigated 83 galactosaemic patients (78 homozygotes, 5 compound heterozygotes) by clinical, psychometric and laboratory testing; 31 patients were evaluated by medical history, the remaining 20 patients had died due to sequelae of the underlying disease. In 48 out of 78 classical galactosaemia patients galactose-free therapy had been started before the 15th day, in 19 between days 15 and 56 and in 11 patients after the 56th day. Physical findings revealed that puberty was delayed in 1 out of 18 males and 6 out of 11 females. Neurological abnormalities included ataxia (n = 6), intention tremor (n = 11) and microcephaly (n = 10). Speech abnormalities were found in 43 out of 66 patients over 3 years of age and disturbance of visual perception and/or arithmetic deficits in 29. Intelligence declined with age, i.e., a DQ or IQ less than 85 was found in 4 out of 34 patients less than 6 years of age (12%), in 10 out of 18 between 7 and 12 years (56%) and in 20 out of 24 older than 12 years (83%). Metabolite patterns (RBC galactose-1-phosphate and UDP-galactose, plasma and urinary galactitol) did not correlate with DQ or IQ. Dietary compliance was good in almost all patients. Compound heterozygotes (n = 5) had normal mental and growth development and all laboratory parameters were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias.

A stable-isotope dilution assay has been developed for quantitation of D- and L-2-hydroxyglutaric acids in physiologic fluids. D- and L-2-hydroxyglutaric acids are separated as the O-acetyl-di-(D)-2-butyl esters. The method uses D,L-[3,3,4,4-2H4]-2-hydroxyglutaric acid as internal standard with ammonia chemical ionization, selected ion monitoring gas chromatography-mass spectrometry. For 13 patients with L-2-hydroxyglutaric aciduria, the concentrations of L-2-hydroxyglutaric acid were urine, 1283 +/- 676 mmol/mol creatinine (range, 332-2742; n = 12 patients); plasma, 47 +/- 13 mumol/L (range, 27-62; n = 8); cerebrospinal fluid, 62 +/- 30 mumol/L (range, 34-100; n = 6). In a child with D-2-hydroxyglutaric aciduria, the levels of D-2-hydroxyglutaric acid were urine, 1565 +/- 847 mmol/mol creatinine (range, 729-2668; n = 4); plasma, 61 +/- 14 mumol/L (range, 46-73; n = 3); cerebrospinal fluid, 15 and 25 mumol/L (n = 2). Control concentrations of D- and L-2-hydroxyglutaric acids were (D:L): urine (n = 18), 6.0 +/- 3.6 mmol/mol creatinine (range, 2.8-17): 6.0 +/- 5.4 (range, 1.3-19); plasma (n = 10), 0.7 +/- 0.2 mumol/L (range, 0.3-0.9): 0.6 +/- 0.2 (range, 0.5-1.0); cerebrospinal fluid (n = 10), 0.1 +/- 0.1 mumol/L (range, 0.07-0.3): 0.7 +/- 0.6 (range, 0.3-2.3). Investigation of control amniotic fluid (n = 10) revealed the following values (D:L): 1.2 +/- 0.4 mumol/L (range, 0.6-1.8): 4.0 +/- 0.7 (range, 3.1-5.2), suggesting the feasibility of prenatal diagnosis in families at risk.

Acyl-CoA Dehydrogenase↗

PubMed1993

Diagnosis of peroxisomal disorders by analysis of phytanic and pristanic acids in stored blood spots collected at neonatal screening.

Concentrations of phytanic acid and pristanic acid were measured in stored dried blood spots collected at neonatal screening from patients with peroxisomal disorders, and compared with concentrations in control blood spots. In blood spots from two patients with Zellweger syndrome both phytanic acid and pristanic acid concentrations were increased but their concentration ratio was normal. In the blood spot from a patient with rhizomelic chondrodysplasia punctata, the concentration of phytanic acid was increased, whereas pristanic acid was within the control range, resulting in a low pristanic acid/phytanic acid ratio. In the blood spot from a patient with X-linked adrenoleukodystrophy, the concentrations of the acids and their ratio were normal. These findings are consistent with results for these acids in plasma from such patients. Measurement of phytanic acid and pristanic acid and their ratios in stored dried blood collected at neonatal screening can therefore be used in the diagnosis of peroxisomal disorders, especially for those cases in which, owing to early death of the patient, no other material is available for biochemical investigations.

Fatty Acids↗