Gamma-Aminobutyric Acid (GABA) Disorders
Two disorders affect the catabolism of GABA: GABA transaminase deficiency and succinic semialdehyde dehydrogenase deficiency. GABA transaminase defi ciency . Two families have been reported with GABA transaminase deficiency (Jaeken et al. 1984; Tsuji et al. 2010). The patients had axial hypotonia, spasticity, severe convulsions, and feeding problems necessitating tube feeding. Patients in the first family had accelerated growth and increased growth hormone secretion. In the second family, MRI showed diffusion restriction in the internal and external capsule and subcortical white matter areas (Tsuji et al. 2010). Biochemically, patients have elevation of free GABA in cerebrospinal fl uid but also elevation of homocarnosine and β-alanine. Elevated GABA can be recognized on magnetic resonance spectroscopy (Tsuji et al. 2010). The enzyme activity was deficient in liver and lymphocytes, and mutations were identifi ed in the ABAT gene.
Succinic semialdehyde dehydrogenase defi ciency (SSADH) or 4-hydroxybutyric aciduria. Patients with succinic semialdehyde dehydrogenase defi ciency accumulate succinic semialdehyde derived from GABA transamination, which is converted by succinic semialdehyde reductase into 4-hydrobybutyric acid and excreted in urine. Most patients present in the first 2 years of life, and whereas 26 % of patients have problems in the neonatal period, an equal number have normal early development (Gibson et al. 1997). These patients present with a static neurological picture of developmental delay and intellectual disability with prominent defi cits in expressive language, motor delay, hypotonia, and nonprogressive ataxia, each present in more than 70 % of patients (Gibson et al 1997; Pearl et al. 2003). Neuropsychiatric symptoms are frequent and include hyperactivity, inattention, and anxiety. Sleep disorders are very common and include excessive daytime sleepiness, prolonged REM latency, and reduced REM sleep (Pearl et al. 2009). Seizures are present in 48 % of patients consisting mostly of generalized tonic-clonic and atypical absence seizures and myoclonic seizures in a minority. EEG abnormalities were noted in 26 % of patients. About 10 % of patients have a degenerative course with myoclonus and extrapyramidal movements of chorea and dystonia (Pearl et al. 2009). Neuroimaging shows increased T2 signal intensity in the globus pallidus, cerebellar dentate nucleus and brain stem, and subcortical white matter (Gibson et al. 1997; Pearl et al. 2003). There may also be cerebellar and cerebral atrophy. NMR spectroscopy is usually normal, unless special edited sequences for GABA and GABA metabolites are done, which show increases in these compounds (Pearl et al. 2003).
This text is an extract from “Physician´s Guide to the Diagnosis, Treatment and Follow-Up of Inherited Metabolic Diseases”, Editors: Nenad Blau, Marinus Duran, K. Michael Gibson, Carlos Dionisi-Vici, Publisher: Springer
Jaeken J, Casaer P, De Cock P et al (1984) Gamma-aminobutyric acid transaminase defi ciency: a newly recognized inborn error of neurotransmitter metabolism. Neuropediatrics 15:165–169
Tsuji M, Aida N, Obata T et al (2010) A new case of GABA transaminase defi ciency facilitated by proton MR spectroscopy. J Inherit Metab Dis 33:85–90
Gibson KM, Christensen E, Jakobs C et al (1997) The clinical phenotype of succinic semialdehyde dehydrogenase defi ciency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics 99:567–574
Pearl PL, Novotny EJ, Acosta MT et al (2003) Succinic semialdehyde dehydrogenase defi ciency in children and adults. Ann Neurol 54(Suppl 6):S73–S80
Pearl PL, Gibson KM, Cortez MA et al (2009) Succinic semialdehyde dehydrogenase defi ciency: lessons from mice and men. J Inherit Metab Dis 32:343–352