Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

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Abstract
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 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods: Here we present data that refine this locus to a 0.5 cM 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 amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results: A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions: This result is interesting because 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. 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 presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts. Table 4 GAD1 single nucleotide substitutions detected on mutation analysis and occurring in sequences submitted to NCBI SNP database and in the literature. This is not a definitive list, but includes those described at the time of the mutational analysis. *Nucleotide positions were not provided by Maestrini et al. [47]. Source SNP position in mRNA, from the translational start site (bp) Gene position of SNP(bp) Amino acid change (A)Lappalainen et al. (2002) A(-478)Del Exon 0 (73) No substitution (B)Lappalainen et al. (2002) G(-147)A Exon 0 (404) No substitution (C)Lappalainen et al. (2002) A(-39)C Exon 1 (25) No substitution (D)Spastic CP patients family B G(36)C Exon 1 (97) Ser(12)Cys (E)NCBI collated resource G(48)C Exon 1 (104) Pro(17)Ala (F)Control samples & family A NCBI collated resource T(110)C Exon 2 (29) No substitution (G)Kure et al. (1998) T(315)C Exon 4 (14) No substitution (H)Bu and Tobin (1994) Kure et al. (1998) A(407)G Exon 4 (105) No substitution (I)Maestrini et al. (2002)* G/C Intron 4 No substitution (J)NCBI collated resource C(696)T Exon 6 (56) No substitution (K)Lappalainen et al. (2002) T/Del Intron 7 (35) No substitution (L)In control samples Lappalainen et al. (2002) T/C Intron 8 (185) No substitution (M)Maestrini et al. (2002)* C/T Intron 9 No substitution