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.
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.
authors.affiliation: Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James's University Hospital, Leeds, UK. clare.email@tiscali.co.uk
authors.forename: Clare N
authors.initials: CN
authors.lastname: Lynex
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Jack P
authors.initials: JP
authors.lastname: Leek
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Achuthan
authors.forename: Simon
authors.initials: S
authors.lastname: Mitchell
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthon
authors.forename: Alex F
authors.initials: AF
authors.lastname: Markham
mesh_terms: D002547:Cerebral Palsy / Q000235:genetics*; D002874:Chromosome Mapping; D020451:Contig Mapping; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D053830:Plant Viral Movement Proteins; D020539:Sequence Analysis, Protein; D016750:Stiff-Person Syndrome / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D053830:Plant Viral Movement Proteins; D014764:Viral Proteins; D005968:Glutamate Decarboxylase