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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 (GAD 67 ), 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 GAD 67  was detected, which segregated with CP in affected individuals.    Conclusions  This result is interesting because auto-antibodies to GAD 67  and the more widely studied GAD 65  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

bmc neurology

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