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Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3
  1. Rita Horvath*,1,2,
  2. Birgit Czermin*,2,
  3. Sweena Gulati1,
  4. Stephanie Demuth3,
  5. Gunnar Houge4,
  6. Angela Pyle1,
  7. Christine Dineiger2,
  8. Emma L Blakely5,
  9. Adam Hassani1,
  10. Charlotte Foley1,
  11. Michael Brodhun6,
  12. Karin Storm7,
  13. Janbernd Kirschner7,
  14. Grainne S Gorman5,
  15. Hanns Lochmüller1,
  16. Elke Holinski-Feder2,
  17. Robert W Taylor5,
  18. Patrick F Chinnery1
  1. 1Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  2. 2Medical Genetic Center, Munich, Germany
  3. 3Human Genetic Laboratory, Erfurt, Germany
  4. 4Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  5. 5Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle, UK
  6. 6Institute of Pathology, Helios-Klinikum, Erfurt, Germany
  7. 7Department of Pediatrics, University of Freiburg, Freiburg, Germany
  1. Correspondence to Dr Rita Horvath, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; rita.horvath{at}ncl.ac.uk

Abstract

Objective Inherited ataxias are heterogeneous disorders affecting both children and adults. The primary cause can be identified in about half of the patients and only very few can receive causative therapy.

Methods The authors performed sequencing of known Coenzyme Q10 (CoQ10) deficiency genes in 22 patients with unexplained recessive or sporadic ataxia.

Results CABC1/ADCK3 mutations were detected in four patients and two siblings presenting with cerebellar ataxia, epilepsy and muscle symptoms. Spasticity, dystonia, tremor and migraine were variably present; cognitive impairment was severe in early childhood cases, but was absent in adults. In contrast to previous reports, two of the patients had a later-onset, very mild phenotype and remained ambulatory in their late forties. Muscle biopsy revealed lipid accumulation, mitochondrial proliferation and cytochrome c oxidase-deficient fibres, but no typical ragged red fibres. Respiratory-chain enzyme activities and CoQ10 were decreased in severely affected patients but remained normal in a mildly affected patient at 46 years of age.

Conclusions These observations highlight the importance of screening for a potentially treatable cause, CABC1/ADCK3 mutations, not only in severe childhood-onset ataxia, but also in patients with mild cerebellar ataxia in adult life.

  • Autosomal recessive ataxia
  • mitochondrial
  • coenzyme Q10 (CoQ10) deficiency
  • CABC1/ADCK3
  • neurogenetics
  • mitochondrial disorders
  • muscle
  • paediatric neurology
  • neuromuscular
  • HMSN (Charcot–Marie–Tooth)
  • muscle disease
  • dystrophin
  • incl body myositis
  • myotonic dystrophy
  • muscular dystrophy
  • neuropathology
  • myasthenia
  • myopathy
  • biochemistry
  • molecular biology
  • non-clinician
  • metabolic disease
  • mitochondrial disorders
  • muscle disease

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Footnotes

  • * RH and BC contributed equally to the study.

  • Funding This study receives funding from the Parkinson's Disease Society (UK), the Medical Research Council (MRC) Translational Muscle Centre, and the UK NIHR Biomedical Research Centre in Ageing and Age-related disease. RH is supported by the Academy of Medical Sciences (UK, BH090164) and by the MRC (UK, G1000848) as part of the MRC Centre for Neuromuscular Diseases.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by County Durham & Tees Valley 1 Research Ethics Committee (REC 08/H0905/106).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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