Ataxia telangiectasia presenting as dopa-responsive cervical dystonia

Neurology. 2013 Sep 24;81(13):1148-51. doi: 10.1212/WNL.0b013e3182a55fa2. Epub 2013 Aug 14.

Abstract

Objective: To identify the cause of cervical dopa-responsive dystonia (DRD) in a Muslim Indian family inherited in an apparently autosomal recessive fashion, as previously described in this journal.

Methods: Previous testing for mutations in the genes known to cause DRD (GCH1, TH, and SPR) had been negative. Whole exome sequencing was performed on all 3 affected individuals for whom DNA was available to identify potentially pathogenic shared variants. Genotyping data obtained for all 3 affected individuals using the OmniExpress single nucleotide polymorphism chip (Illumina, San Diego, CA) were used to perform linkage analysis, autozygosity mapping, and copy number variation analysis. Sanger sequencing was used to confirm all variants.

Results: After filtering of the variants, exome sequencing revealed 2 genes harboring potentially pathogenic compound heterozygous variants (ATM and LRRC16A). Of these, the variants in ATM segregated perfectly with the cervical DRD. Both mutations detected in ATM have been shown to be pathogenic, and α-fetoprotein, a marker of ataxia telangiectasia, was increased in all affected individuals.

Conclusion: Biallelic mutations in ATM can cause DRD, and mutations in this gene should be considered in the differential diagnosis of unexplained DRD, particularly if the dystonia is cervical and if there is a recessive family history. ATM has previously been reported to cause isolated cervical dystonia, but never, to our knowledge, DRD. Individuals with dystonia related to ataxia telangiectasia may benefit from a trial of levodopa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Carrier Proteins / genetics
  • Cell Cycle Proteins / genetics*
  • Child
  • DNA-Binding Proteins / genetics*
  • Diagnosis, Differential
  • Dystonic Disorders / diagnosis
  • Dystonic Disorders / genetics*
  • Family Health*
  • Female
  • Genetic Linkage
  • Genotype
  • Humans
  • India
  • Islam
  • Male
  • Microfilament Proteins
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Serine-Threonine Kinases / genetics*
  • Tumor Suppressor Proteins / genetics*
  • alpha-Fetoproteins / metabolism

Substances

  • CARMIL1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Microfilament Proteins
  • Tumor Suppressor Proteins
  • alpha-Fetoproteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Dystonia, Dopa-responsive