Purpose of review: There has been increased recognition of the pediatric neurotransmitter disorders. This review focuses on the clinical disorders of GABA metabolism.
Recent findings: The known clinical disorders of GABA metabolism are pyridoxine dependent epilepsy, GABA-transaminase deficiency, SSADH deficiency, and homocarnosinosis. Pyridoxine dependent epilepsy is diagnosed clinically but potentially more common presentations, with later and atypical features, widen the spectrum. No gene locus has been confirmed; the pathophysiology may involve alterations in PLP transport, binding to GAD, or other PLP-dependent pathways. SSADH deficiency is associated with developmental delay, prominent language deficits, hypotonia, ataxia, hyporeflexia, and seizures. Increased detection is reported when specific ion monitoring is used for GHB on urine organic acids. The most consistent MRI abnormality is increased signal in the globus pallidus. MR spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare but require CSF for detection, thus allowing for the possibility that these entities, as in the other pediatric neurotransmitter disorders, are underrecognized.
Summary: The disorders of GABA metabolism require an increased index of clinical suspicion. Pyridoxine dependent epilepsy is a treatable condition with a potentially widening clinical spectrum, but with a prognosis dependent on early intervention. SSADH deficiency has a heterogeneous spectrum and requires careful urine organic acid testing for screening, followed by enzymatic confirmation allowing appropriate prognostic and genetic counseling.