BACKGROUND: Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5cM chromosomal region located at 2q24-31.1, in rare consanguineous families. METHODS: Here we present data that refine this locus to a 0.5cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter -aminobutyric acid (GABA). RESULTS: A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. CONCLUSIONS: Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the neurological sequelae of circulating anti-GAD antibodies and the recognised excitotoxicity of glutamate in various contexts.
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