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

Ataxia Telangiectasia Presenting as Dopa-Responsive Cervical Dystonia

Free PMC article

Ataxia Telangiectasia Presenting as Dopa-Responsive Cervical Dystonia

Gavin Charlesworth et al. Neurology. .
Free PMC article


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.


Figure 1
Figure 1. Original and updated genetic pedigree
(A) Genetic pedigree as previously published. Individuals affected by cervical dopa-responsive dystonia are indicated by shaded symbols and those for whom DNA was available by “DNA.” (B) Updated genetic pedigree in light of the initial exome sequencing results. The individuals marked with a cross (III:6 and III:8) have clinically typical ataxia telangiectasia. Mutational status for ATM is marked below the relevant individuals as follows: wt = wild-type allele; fs = frameshift deletion (c.7886_7890del); and m = missense mutation (c.6154G>A). DNA availability is marked as previously. The marriage between individuals II:5 and II:6 is possibly consanguineous.
Figure 2
Figure 2. Filtering of exome sequencing data
Graphic illustration of the filtering process applied to the exome datasets in order to select out likely candidate causal variants for this ostensibly autosomal recessive condition. Other databases = 1000 Genomes, NCHLBI Exome Sequencing Project, and the Complete Genomic 69 database. dbSNP = database of single nucleotide polymorphisms; MAF = minor allele frequency.

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