Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation
- Yo-Tsen Liu1,2,3,4,
- Joshua Hersheson2,
- Vincent Plagnol5,
- Katherine Fawcett2,
- Kate E C Duberley2,
- Elisavet Preza2,
- Iain P Hargreaves6,
- Annapurna Chalasani6,
- Matilde Laurá1,2,
- Nick W Wood2,
- Mary M Reilly1,2,
- Henry Houlden1,2
- 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
- 2Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
- 3Section of Epilepsy, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- 4National Yang-Ming University School of Medicine, Taipei, Taiwan
- 5University College London, Genetics Institute, London, UK
- 6Neurometabolic Unit, National Hospital of Neurology and Neurosurgery, London, UK
- Correspondence to Professor Henry Houlden, Department of Molecular Neuroscience and MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square House, Queen Square, London WC1N 3BG, UK;
- Received 8 August 2013
- Revised 7 October 2013
- Accepted 14 October 2013
- Published Online First 11 November 2013
Background The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene (ADCK3) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC).
Methods We report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient.
Results A novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient's fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment.
Conclusion This study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/