Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

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The inherited disorders of γ-amino butyric acid (GABA) metabolism require an increased index of clinical suspicion. The known genetic disorders are GABA-transaminase deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency and homocarnosinosis. A recent link has also been made between impaired GABA synthesis and nonsyndromic cleft lip, with or without cleft palate. SSADH deficiency is the most commonly occurring of the inherited disorders of neurotransmitters. The disorder has a nonspecific phenotype with myriad neurological and psychiatric manifestations, and usually has a nonprogressive temporal course. Diagnosis is made by the detection of γ-hydroxybutyrate excretion on urine organic acid testing. The most consistent magnetic resonance imaging abnormality is an increased signal in the globus pallidus. Magnetic resonance 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 cerebrospinal fluid for detection, thus allowing for the possibility that these entities, as in the other inherited neurotransmitter disorders, are underrecognized. Up to a third of cerebral synapses employ γ-amino butyric acid (GABA), the major inhibitory neurotransmitter of the brain. Its major precursor is L-glutamate, which is converted to GABA via the enzyme glutamate decarboxylase (GAD). GAD has two active isoforms, GAD65 and GAD67. Pyridoxal-5-phosphate is a coenzyme for GAD. GABA is metabolized by the enzyme GABA-transaminase (GABA-T), to succinic semialdehyde. This unstable intermediate compound is metabolized rapidly to succinic acid, which enters the tricarboxylic acid cycle. The so-called GABA shunt is a closed loop that involves the transamination of α-ketoglutarate to glutamate, which is then converted via GAD to GABA (Figure 1). The subsequent transamination of GABA to succinic semialdehyde requires the presence of α-ketoglutarate to accept the amine group. Thus, this restores glutamate and a molecule of the GABA precursor is formed as a molecule of GABA is catabolized. This enables constant replenishment of this vital neurotransmitter pool. There is an ancillary loop, known as the glutamine-glutamate shuttle. Released GABA is taken up by glial cells, where glutamate can be formed, but not converted to GABA, owing to an absence of GAD. Instead, GABA is converted via glutamine synthetase to glutamine, which is returned to the neuron and is converted via glutaminase back to glutamate. Thus, the loop is completed and the supply of GABA precursor is conserved. KeywordsDisorders involving the GABA catabolic pathway are GABA-T deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency and homocarnosinosis; all of these entities invoke neurological dysfunction. SSADH deficiency is the most common, but has a heterogeneous, nonspecific phenotype. Enzymatic deficiency can be documented in SSADH and GABA-T deficiency. Homocarnosine is a dipeptide compound consi...