Abstract
Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.
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Acknowledgements
We would like to thank Kristine Boxen at the Auckland Science Analytical Services for Sanger sequencing services and the New Zealand eScience Infrastructure for high-performance computing support.
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Communicated by: Johan Lodewijk Karel Van Hove, MD, PhD
Electronic Supplementary Material
Supplementary Figure 1
Evolutionary conservation of the locus affected by the missense (PDF 731 kb)
Supplementary Tables 1–3
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Supplementary Table 4
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Supplementary Methods
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Appendices
Take-Home Message
Compound heterozygous COQ8A mutations cause treatment-responsive CoQ10 deficiency ataxia.
Contributions of Individual Authors
JCJ, KL and RGS designed and conducted experiments and wrote the manuscript; WW and BS conducted experiments; JT, DRL and RH clinically confirmed research results; SPR clinically evaluated patients and conducted the trial of CoQ10 treatment; SM, PMG and RM performed muscle and plasma CoQ10 analysis.
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Professor Russell Snell.
Competing Interest Statement
JCJ, WW, BS, JT, DRL, RH, SM, PMG, RM, SPR, RGS and KL declare they have no conflict of interest.
Details of Funding
JCJ is supported by a Rutherford Discovery Fellowship from the New Zealand Government and administered by the Royal Society of New Zealand; SPR is supported by Curekids NZ. The research was funded by the Neurological Foundation of New Zealand, the University of Auckland and the Minds for Minds Charitable Trust.
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The study was approved by the New Zealand Northern B Health and Disability Ethics Committee (ref 12/NTB/59), and parents provided written informed consent.
Patient Consent Statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
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Jacobsen, J.C. et al. (2017). Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 42. JIMD Reports, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_73
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DOI: https://doi.org/10.1007/8904_2017_73
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