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 Neurol. 2004 Nov 30;4(1):20. doi: 10.1186/1471-2377-4-20.


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.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebral Palsy / genetics*
  • Chromosome Mapping
  • Contig Mapping
  • Female
  • Glutamate Decarboxylase / genetics*
  • Homozygote
  • Humans
  • Male
  • Microsatellite Repeats
  • Mutation, Missense / genetics*
  • Pedigree
  • Plant Viral Movement Proteins
  • Sequence Analysis, Protein
  • Stiff-Person Syndrome / genetics*
  • Viral Proteins / genetics*


  • Plant Viral Movement Proteins
  • Viral Proteins
  • Glutamate Decarboxylase

Associated data

  • OMIM/603513
  • OMIM/605388