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

Neurochemical Research volume 44, pages 2372–2384 (2019)Cite this article

Abstract

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.

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Acknowledgements

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.

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Author notes

  1. Adel Shalata and Michael Edery contributed equally to this work.

Affiliations

  1. Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, P.O.B. 4940, 31048, Haifa, Israel

    Adel Shalata, Clair Habib, Mohammad Mahroum, Lama Khalaily & Hana Shapira

  2. Clalit Health Care-Haifa and West Galilee District, Haifa, Israel

    Adel Shalata

  3. Ginatuna Association, Sakhnin, Israel

    Adel Shalata & Mohammad Mahroum

  4. Department of Genetic and Metabolic Diseases, Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, 9112001, Jerusalem, Israel

    Michael Edery, Liza Douiev & Ann Saada

  5. Department of Pediatrics, Bnai Zion Medical Center, Haifa, Israel

    Clair Habib, Jacob Genizi, Nurit Assaf & Idan Segal

  6. Pediatric Neurology Unit, Bnai Zion Medical Center, Haifa, Israel

    Jacob Genizi, Nurit Assaf & Idan Segal

  7. Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel

    Jacob Genizi & Nurit Assaf

  8. Child Development Center, Clalit Health Care, Carmiel, Israel

    Hoda Abed El Rahim & Danielle Urian

  9. Neurology Department, Schneider Children Hospital, Petah Tikva, Israel

    Hoda Abed El Rahim

  10. Laboratory of Molecular Medicine, Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel

    Shay Tzur

  11. Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel

    Shay Tzur

  12. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Liza Douiev & Ann Saada

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  1. Adel Shalata
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  2. Michael Edery
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  13. Liza Douiev
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  14. Ann Saada
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Correspondence to Adel Shalata or Ann Saada.

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Shalata, A., Edery, M., Habib, C. et al. Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature. Neurochem Res 44, 2372–2384 (2019). https://doi.org/10.1007/s11064-019-02786-5

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  • DOI: https://doi.org/10.1007/s11064-019-02786-5

Keywords

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