Gamma Aminobutyric Acid Transminase Deficiency

Gamma aminobutyric acid transminase deficiency was first reported in 1984 in a brother and sister from a Flemish family. No other patients seem to have been described since.

Clinical Presentation Gamma Aminobutyric Acid Transminase Deficiency

Both patients showed feeding difficulties from birth, often necessitating gavage feeding. They had a pronounced axial hypotonia and generalized convulsions. A high-pitched cry and hyperreflexia were present during the first 6-8 months. Furgher evolution was characterized by leghargy and psychomotor retardation (the developmental level of 4 weeks was never attained). Corneal reflexes and reaction of the pupils to light remained normal. A remarkable, continued acceleration of length-growth was noted from birth to death. This was explained by increased fasting plasma growth hormone levels (8-39 ng/ml;normal, <5); these could be suppressed by oral glucose. In one of the patients, head circumference showed a rapid increase during the last 6 weeks (from the 50th to the 97th percentiles). Postmortem examination of the brain showed a spongiform leukodystrophy.

Metabolic Derangement Gamma Aminobutyric Acid Transminase Deficiency

The CSF and plasma concentrations of GABA, GABA conjugates, β-alanine. Liver GABA and β-alanine concentration were normal. This metabolite pattern could be explained by a decrease in GABA transaminase activity in the liver (and lymphocytes). Intermediate levels were found in the healthy sibling, the father, and the mother. It can be assumed that the same enzymatic defect exists in the brain, since GABA transaminases of human brain and of peripheral tissues have the same kinetic and molecular properties. β-alanine seems to be an alternative substrate for GABA transaminase , hence its increase in this disease.

In this context it can be mentioned that the antiepileptic drug γ-vinyl GABAGABA transaminase (vigabratin) causes an irreversible inhibition of , leading to two-to threefold increases in CSF free GABA. Interestingly, we have noted that this drug also constantly and
significantly but not glutamic oxaloacetic transaminase activity.

Disorders of Neurotransmitters Diseases

Diagnostic Test Gamma Aminobutyric Acid Transminase Deficiency

The diagnosis requires amino acid analysis of the CSF. Due to enzymatic homocarnosine degradation, free GABA levels in the CSF show artifactual increases unless samples are deep-frozen (at-200C) within a few minutes if analysis is performed within a few weeks and at-700C if time until analysis is longer. Control CSF free GABA levels range from about 40 to 150 nmol/l after the age of 1 year and are lower in younger children. Because of these low levels, sensitive techniques have to be used such as ion-exchange chromatography and fluorescence detection or a stable isotope dilution technique.

Enzymatic confirmation can be obtained on lymphocytes, lymphoblasts, and liver. As for prenatal diagnosis, GABA transaminase activity is not expressed in fibroblasts, but activity is present in chorionic villus tissue.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Gamma Aminobutyric Acid Transminase Deficiency

We obtained no clinical or biochemical response after administration of pharmacological doses of pyridoxine, the precursor of the coenzyme of GABA transaminase, nor with picrotoxin, a potent noncompetitive GABA antagonist. Both children died at the ages of 1 year and 2 year and 7 months, respectively.

Disorders of Neurotransmitters Diseases

Genetics Gamma Aminobutyric Acid Transminase Deficiency

Inheritance is autosomal recessive.

Disorders of Neurotransmitters Diseases

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