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.
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 gamma-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.
%0 Journal Article
%1 Lynex2004
%A Lynex, Clare N
%A Carr, Ian M
%A Leek, Jack P
%A Achuthan, Rajgopal
%A Mitchell, Simon
%A Maher, Eamonn R
%A Woods, C. Geoffrey
%A Bonthon, David T
%A Markham, Alex F
%D 2004
%J BMC Neurol
%K Cerebral Palsy; Chromosome Mapping; Contig Female; Glutamate Decarboxylase; Homozygote; Humans; Male; Microsatellite Repeats; Mutation, Missense; Pedigree; Plant Viral Movement Proteins; Sequence Analysis, Protein; Stiff-Person Syndrome; Proteins
%N 1
%P 20
%R 10.1186/1471-2377-4-20
%T 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.
%U http://dx.doi.org/10.1186/1471-2377-4-20
%V 4
%X 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 gamma-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.
@article{Lynex2004,
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 gamma-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.},
added-at = {2014-07-19T20:43:34.000+0200},
author = {Lynex, Clare N and Carr, Ian M and Leek, Jack P and Achuthan, Rajgopal and Mitchell, Simon and Maher, Eamonn R and Woods, C. Geoffrey and Bonthon, David T and Markham, Alex F},
biburl = {https://www.bibsonomy.org/bibtex/2171b7b5bdff74a7d9537882e02d6f358/ar0berts},
doi = {10.1186/1471-2377-4-20},
groups = {public},
interhash = {34d4bff03a8d682ec1a47f07a2b1dd5a},
intrahash = {171b7b5bdff74a7d9537882e02d6f358},
journal = {BMC Neurol},
keywords = {Cerebral Palsy; Chromosome Mapping; Contig Female; Glutamate Decarboxylase; Homozygote; Humans; Male; Microsatellite Repeats; Mutation, Missense; Pedigree; Plant Viral Movement Proteins; Sequence Analysis, Protein; Stiff-Person Syndrome; Proteins},
month = Nov,
number = 1,
pages = 20,
pii = {1471-2377-4-20},
pmid = {15571623},
timestamp = {2014-07-19T20:43:34.000+0200},
title = {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.},
url = {http://dx.doi.org/10.1186/1471-2377-4-20},
username = {ar0berts},
volume = 4,
year = 2004
}