Ataxia telangiectasia presenting as dopa-responsive cervical dystonia.
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.


CONCLUSIONS
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.
From the Department of Molecular Neuroscience (G.C., N.W.W.), and Sobell Department of Motor Neuroscience and Movement Disorders (M.S., K.P.B.), UCL Institute of Neurology, Queen Square, London, UK; Neurology Centre and Research (M.D.M.), Kolhapur, India; Department of Neurology (S.A.S.), University of Kiel, Germany; Movement Disorders Clinic (M.S.), Second Department of Neurology, Attiko Hospital, University of Athens, Greece; and Neurology Clinic (M.S.), Philipps University, Marburg, Germany.
Gavin
G
Charlesworth
Mahavir D
MD
Mohire
Susanne A
SA
Schneider
Maria
M
Stamelou
Nicholas W
NW
Wood
Kailash P
KP
Bhatia
D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D020821:Dystonic Disorders / Q000175:diagnosis / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007194:India; D007514:Islam; D008297:Male; D008840:Microfilament Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000509:alpha-Fetoproteins / Q000378:metabolism
C547525:CARMIL1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D025521:Tumor Suppressor Proteins; D000509:alpha-Fetoproteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases