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
Authors: Lynex Clare N , Carr Ian M , Leek Jack P , Achuthan Rajgopal , Mitchell Simon , Maher Eamonn R , Woods C Geoffrey , Bonthon David T , Markham Alex F 
Published: January 2005

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