Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature

  • Adel ShalataEmail author
  • Michael Edery
  • Clair Habib
  • Jacob Genizi
  • Mohammad Mahroum
  • Lama Khalaily
  • Nurit Assaf
  • Idan Segal
  • Hoda Abed El Rahim
  • Hana Shapira
  • Danielle Urian
  • Shay Tzur
  • Liza Douiev
  • Ann SaadaEmail author
Original Paper


Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient’s cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.


Spinocerebellar ataxia Q10 deficiency-4 SCAR9 Coenzyme Q ADCK3 Mitochondrial disease 



AS is supported by the Pakula family, via the American Friends of the Hebrew University of Jerusalem. The molecular genetics evaluation is supported by Ginatuna Association, Sakhnin City, POB 1115, Israel.


  1. 1.
    Quinzii CM, DiMauro S, Hirano M (2007) Human coenzyme Q10 deficiency. Neurochem Res 32:723–727. CrossRefGoogle Scholar
  2. 2.
    Emmanuele V, López LC, Berardo A, Naini A, Tadesse S, Wen B, D’Agostino E, Solomon M, DiMauro S, Quinzii C, Hirano M (2012) Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 69:978–983. CrossRefGoogle Scholar
  3. 3.
    Laredj LN, Licitra F, Puccio HM (2014) The molecular genetics of coenzyme Q biosynthesis in health and disease. Biochimie 100:78–87. CrossRefGoogle Scholar
  4. 4.
    Quinzii CM, Emmanuele V, Hirano M (2014) Clinical presentations of coenzyme q10 deficiency syndrome. Mol Syndromol 5:141–146. CrossRefGoogle Scholar
  5. 5.
    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 82:661–672. CrossRefGoogle Scholar
  6. 6.
    Mollet J, Delahodde A, Serre V, Chretien D, Schlemmer D, Lombes A, Boddaert N, Desguerre I, de Lonlay P, de Baulny HO, Munnich A, Rötig A (2008) CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet 82:623–630. CrossRefGoogle Scholar
  7. 7.
    Stefely JA, Licitra F, Laredj L et al (2016) Cerebellar ataxia and coenzyme Q deficiency through loss of unorthodox kinase activity. Mol Cell 63:608–620. CrossRefGoogle Scholar
  8. 8.
    Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, de Coo R, van der Kooi A, Smeets H (2010) Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion 10:510–515. CrossRefGoogle Scholar
  9. 9.
    Horvath R, Czermin B, Gulati S, Demuth S, Houge G, Pyle A, Dineiger C, Blakely EL, Hassani A, Foley C, Brodhun M, Storm K, Kirschner J, Gorman GS, Lochmüller H, Holinski-Feder E, Taylor RW, Chinnery PF (2012) Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3. J Neurol Neurosurg Psychiatry 83:174–178. CrossRefGoogle Scholar
  10. 10.
    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 12:103–107. CrossRefGoogle Scholar
  11. 11.
    Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows–Wheeler transform. Bioinformatics 26:589–595. CrossRefGoogle Scholar
  12. 12.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079. CrossRefGoogle Scholar
  13. 13.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. CrossRefGoogle Scholar
  14. 14.
    McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F (2016) The ensembl variant effect predictor. Genome Biol 17:122. CrossRefGoogle Scholar
  15. 15.
    Ben-Meir A, Yahalomi S, Moshe B, Shufaro Y, Reubinoff B, Saada A (2015) Coenzyme Q-dependent mitochondrial respiratory chain activity in granulosa cells is reduced with aging. Fertil Steril 104:724–727. CrossRefGoogle Scholar
  16. 16.
    Reisch AS, Elpeleg O (2007) Biochemical assays for mitochondrial activity: assays of TCA cycle enzymes and PDHc. Methods Cell Biol 80:199–222. CrossRefGoogle Scholar
  17. 17.
    Golubitzky A, Dan P, Weissman S, Link G, Wikstrom JD, Saada A (2011) Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE 6:e26883. CrossRefGoogle Scholar
  18. 18.
    Douiev L, Soiferman D, Alban C, Saada A (2016) The effects of ascorbate, N-acetylcysteine, and resveratrol on fibroblasts from patients with mitochondrial disorders. J Clin Med. 6pii:E1. CrossRefGoogle Scholar
  19. 19.
    Yu-Wai-Man P, Soiferman D, Moore DG, Burté F, Saada A (2017) Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion 36:36–42. CrossRefGoogle Scholar
  20. 20.
    Hikmat O, Tzoulis C, Knappskog PM, Johansson S, Boman H, Sztromwasser P, Lien E, Brodtkorb E, Ghezzi D, Bindoff LA (2016) ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: A POLG mimic? Eur J Neurol 23:1188–1194. CrossRefGoogle Scholar
  21. 21.
    Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosińska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M, Płoski R (2016) New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre. J Transl Med 14:174. CrossRefGoogle Scholar
  22. 22.
    Yubero D, Allen G, Artuch R, Montero R (2017) The value of coenzyme Q10 determination in mitochondrial patients. J Clin Med 6pii:E37. CrossRefGoogle Scholar

Web Resources

  1. The Human Genome Mutation Database,
  2. The Clinical Variants database,
  3. The gene cards database,
  4. Online Mendelian Inheritance in Man (OMIM),
  5. UCSC Genome Browser,

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Simon Winter Institute for Human GeneticsBnai Zion Medical CenterHaifaIsrael
  2. 2.Clalit Health Care-Haifa and West Galilee DistrictHaifaIsrael
  3. 3.Ginatuna AssociationSakhninIsrael
  4. 4.Department of Genetic and Metabolic Diseases, Monique and Jacques Roboh Department of Genetic ResearchHadassah Medical CenterJerusalemIsrael
  5. 5.Department of PediatricsBnai Zion Medical CenterHaifaIsrael
  6. 6.Pediatric Neurology UnitBnai Zion Medical CenterHaifaIsrael
  7. 7.Bruce and Ruth Rappaport Faculty of MedicineTechnionHaifaIsrael
  8. 8.Child Development CenterClalit Health CareCarmielIsrael
  9. 9.Neurology DepartmentSchneider Children HospitalPetah TikvaIsrael
  10. 10.Laboratory of Molecular Medicine, Rappaport Faculty of Medicine and Research InstituteTechnion - Israel Institute of TechnologyHaifaIsrael
  11. 11.Genomic Research DepartmentEmedgene TechnologiesTel AvivIsrael
  12. 12.Faculty of MedicineHebrew University of JerusalemJerusalemIsrael

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