Advertisement

Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair

  • Jessie C. Jacobsen
  • Whitney Whitford
  • Brendan Swan
  • Juliet Taylor
  • Donald R. Love
  • Rosamund Hill
  • Sarah Molyneux
  • Peter M. George
  • Richard Mackay
  • Stephen P. Robertson
  • Russell G. SnellEmail author
  • Klaus Lehnert
Research Report
Part of the JIMD Reports book series (JIMD, volume 42)

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.

Keywords

Autosomal recessive cerebellar ataxia CoQ10 COQ8A 

Notes

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.

Supplementary material

475347_1_En_73_MOESM1_ESM.pdf (731 kb)
Supplementary Figure 1 Evolutionary conservation of the locus affected by the missense (PDF 731 kb)
475347_1_En_73_MOESM2_ESM.pdf (85 kb)
Supplementary Tables 1–3 ■■■■ (PDF 85 kb)
475347_1_En_73_MOESM3_ESM.xlsx (24 kb)
Supplementary Table 4 ■■■■ (XLSX 24 kb)
475347_1_En_73_MOESM4_ESM.pdf (65 kb)
Supplementary Methods ■■■■ (PDF 65 kb)

References

  1. Anheim M, Fleury M, Monga B et al (2010) Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics 11:1–12CrossRefGoogle Scholar
  2. Aure K, Benoist JF, Ogier de Baulny H, Romero NB, Rigal O, Lombes A (2004) Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 63:727–729CrossRefGoogle Scholar
  3. Barca E, Musumeci O, Montagnese F et al (2016) Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. Clin Genet 90:156–160CrossRefGoogle Scholar
  4. Blumkin L, Leshinsky-Silver E, Zerem A, Yosovich K, Lerman-Sagie T, Lev D (2014) Heterozygous mutations in the ADCK3 gene in siblings with cerebellar atrophy and extreme phenotypic variability. JIMD Rep 12:103–107CrossRefGoogle Scholar
  5. Crane FL, Sun IL, Sun EE (1993) The essential functions of coenzyme Q. Clin Investig 71:S55–S59CrossRefGoogle Scholar
  6. Cullen JK, Abdul Murad N, Yeo A et al (2016) AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation. PLoS One 11:e0148213CrossRefGoogle Scholar
  7. Desbats M, Lunardi G, Doimo M, Trevisson E, Salviati L (2015) Genetic bases and clinical manifestations of coenzyme Q10 (CoQ10) deficiency. J Inherit Metab Dis 38:145–156CrossRefGoogle Scholar
  8. Do TQ, Hsu AY, Jonassen T, Lee PT, Clarke CF (2001) A defect in coenzyme Q biosynthesis is responsible for the respiratory deficiency in Saccharomyces cerevisiae abc1 mutants. J Biol Chem 276:18161–18168CrossRefGoogle Scholar
  9. Gerards M, van den Bosch B, Calis C et al (2010) Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10:510–515CrossRefGoogle Scholar
  10. Hikmat O, Tzoulis C, Knappskog PM et al (2016) ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic? Eur J Neurol 23:1188–1194CrossRefGoogle Scholar
  11. Horvath R, Czermin B, Gulati S et al (2012) Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry 83:174–178CrossRefGoogle Scholar
  12. Kent WJ, Sugnet CW, Furey TS et al (2002) The human genome browser at UCSC. Genome Res 12:996–1006CrossRefGoogle Scholar
  13. Khadria AS, Mueller BK, Stefely JA, Tan CH, Pagliarini DJ, Senes A (2014) A Gly-zipper motif mediates homodimerization of the transmembrane domain of the mitochondrial kinase ADCK3. J Am Chem Soc 136:14068–14077CrossRefGoogle Scholar
  14. Khan S, Vihinen M (2007) Spectrum of disease-causing mutations in protein secondary structures. BMC Struct Biol 7:56CrossRefGoogle Scholar
  15. Lagier-Tourenne C, Tazir M, López LC et al (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 82:661–672CrossRefGoogle Scholar
  16. Lamperti C, Naini A, Hirano M et al (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60:1206–1208CrossRefGoogle Scholar
  17. Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRefGoogle Scholar
  18. Liu Y-T, Hersheson J, Plagnol V et al (2014) Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation. J Neurol Neurosurg Psychiatry 85:493–498CrossRefGoogle Scholar
  19. Lopez LC, Schuelke M, Quinzii CM et al (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79:1125–1129CrossRefGoogle Scholar
  20. Malgireddy K, Thompson R, Torres-Russotto D (2016) A novel CABC1/ADCK3 mutation in adult-onset cerebellar ataxia. Parkinsonism Relat Disord 33:151–152CrossRefGoogle Scholar
  21. Mignot C, Apartis E, Durr A et al (2013) Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression. Orphanet J Rare Dis 8:173CrossRefGoogle Scholar
  22. Mollet J, Delahodde A, Serre V et al (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630CrossRefGoogle Scholar
  23. Molyneux SL, Florkowski CM, Lever M, George PM (2005) Biological variation of coenzyme Q10. Clin Chem 51:455–457CrossRefGoogle Scholar
  24. Molyneux SL, Young JM, Florkowski CM, Lever M, George PM (2008) Coenzyme Q10: is there a clinical role and a case for measurement? Clin Biochem Rev 29:71–82PubMedPubMedCentralGoogle Scholar
  25. Montero R, Pineda M, Aracil A et al (2007) Clinical, biochemical and molecular aspects of cerebellar ataxia and coenzyme Q10 deficiency. Cerebellum 6:118–122CrossRefGoogle Scholar
  26. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010) Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20:110–121CrossRefGoogle Scholar
  27. Poon WW, Davis DE, Ha HT, Jonassen T, Rather PN, Clarke CF (2000) Identification of Escherichia coli ubiB, a gene required for the first monooxygenase step in ubiquinone biosynthesis. J Bacteriol 182:5139–5146CrossRefGoogle Scholar
  28. Stefely JA, Reidenbach Andrew G, Ulbrich A et al (2015) Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis. Mol Cell 57:83–94CrossRefGoogle Scholar
  29. Stefely JA, Licitra F, Laredj L et al (2016) Cerebellar ataxia and coenzyme Q deficiency through loss of unorthodox kinase activity. Mol Cell 63:608–620CrossRefGoogle Scholar
  30. Tang PH, Miles MV, DeGrauw A, Hershey A, Pesce A (2001) HPLC analysis of reduced and oxidized coenzyme Q10 in human plasma. Clin Chem 47:256–265PubMedGoogle Scholar
  31. Terracciano A, Renaldo F, Zanni G et al (2012) The use of muscle biopsy in the diagnosis of undefined ataxia with cerebellar atrophy in children. Eur J Paediatr Neurol 16:248–256CrossRefGoogle Scholar
  32. Trouillas P, Takayanagi T, Hallett M et al (1997) International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 145:205–211CrossRefGoogle Scholar
  33. Yubero D, Montero R, Artuch R, Land JM, Heales SJR, Hargreaves IP (2014) Biochemical diagnosis of coenzyme Q(10) deficiency. Mol Syndromol 5:147–155CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2017

Authors and Affiliations

  • Jessie C. Jacobsen
    • 1
  • Whitney Whitford
    • 1
  • Brendan Swan
    • 1
  • Juliet Taylor
    • 2
  • Donald R. Love
    • 3
  • Rosamund Hill
    • 4
  • Sarah Molyneux
    • 6
  • Peter M. George
    • 6
  • Richard Mackay
    • 6
  • Stephen P. Robertson
    • 5
  • Russell G. Snell
    • 1
    Email author
  • Klaus Lehnert
    • 1
  1. 1.Centre for Brain Research, School of Biological SciencesThe University of AucklandAucklandNew Zealand
  2. 2.Genetic Health Service New ZealandAuckland City HospitalAucklandNew Zealand
  3. 3.Diagnostic Genetics, LabPLUSAuckland City HospitalAucklandNew Zealand
  4. 4.Department of NeurologyAuckland City HospitalAucklandNew Zealand
  5. 5.Dunedin School of Medicine, University of OtagoDunedinNew Zealand
  6. 6.Canterbury Health LaboratoriesChristchurchNew Zealand

Personalised recommendations