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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

Lynex, C.N., Carr, I.M., Leek, J.P., Achuthan, R., Mitchell, S., Maher, E.R., Woods, C.G., Bonthon, D.T. and Markham, A.F. (2004) 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. BMC Neurology, 4 (20). ISSN 1471-2377

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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.

Item Type: Article
Copyright, Publisher and Additional Information: © 2004 Lynex et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Institution: The University of Leeds
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Genetics (Leeds)
Depositing User: Repository Officer
Date Deposited: 13 Mar 2006
Last Modified: 09 Jun 2014 05:40
Published Version: http://www.biomedcentral.com/1471-2377/4/20
Status: Published
Refereed: Yes
Identification Number: 10.1186/1471-2377-4-20
URI: http://eprints.whiterose.ac.uk/id/eprint/1057

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