Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy

Ian C Smith; Chantal A Pileggi; Ying Wang; Kristin Kernohan; Taila Hartley; Hugh J McMillan; Marcos Loreto Sampaio; Gerd Melkus; John Woulfe; Gaganvir Parmar; Pierre R Bourque; Ari Breiner; Jocelyn Zwicker; C Elizabeth Pringle; Olga Jarinova; Hanns Lochmüller; David A Dyment; Bernard Brais; Kym M Boycott; Care4Rare Canada Consortium,; Siegfried Hekimi; Mary-Ellen Harper; Jodi Warman-Chardon

doi:10.1212/NXG.0000000000200048

Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy

Neurol Genet. 2023 Jan 25;9(1):e200048. doi: 10.1212/NXG.0000000000200048. eCollection 2023 Feb.

Authors

Ian C Smith¹, Chantal A Pileggi¹, Ying Wang¹, Kristin Kernohan¹, Taila Hartley¹, Hugh J McMillan¹, Marcos Loreto Sampaio¹, Gerd Melkus¹, John Woulfe¹, Gaganvir Parmar¹, Pierre R Bourque¹, Ari Breiner¹, Jocelyn Zwicker¹, C Elizabeth Pringle¹, Olga Jarinova¹, Hanns Lochmüller¹, David A Dyment¹, Bernard Brais¹, Kym M Boycott¹; Care4Rare Canada Consortium,; Siegfried Hekimi¹, Mary-Ellen Harper¹, Jodi Warman-Chardon¹

Affiliation

¹ The Ottawa Hospital Research Institute (I.C.S., M.L.S., G.M., A.B., J.Z., H.L., J.W.-C.), Ottawa; Department of Biochemistry, Microbiology and Immunology (C.A.P., G.P., M.-E.H.), Faculty of Medicine, University of Ottawa, Ontario; Ottawa Institute of Systems Biology (C.A.P., G.P., M.-E.H.), University of Ottawa, Ontario; Department of Biology (Y.W., S.H.), McGill University, Montreal, Quebec; Children's Hospital of Eastern Ontario Research Institute (K.K., T.H., O.J., H.L., D.A.D., K.M.B., J.W.-C.), University of Ottawa, Ontario; Newborn Screening Ontario (K.K.), Ottawa; Departments of Pediatrics, Neurology, & Neurosurgery (H.J.M.), Montreal Children's Hospital, McGill University, Montreal, Quebec; Department of Radiology, Radiation Oncology and Medical Physics (M.L.S., G.M.), University of Ottawa, Ontario; Department of Laboratory Medicine (J.W.), The Ottawa Hospital, Ontario; Department of Medicine (Neurology) (P.R.B., A.B., J.Z., E.P., C.E.P., H.L., J.W.-C.), The Ottawa Hospital, Ontario; Faculty of Medicine/Brain and Mind Research Institute (A.B., H.L., D.A.D., K.M.B., J.W.-C.), University of Ottawa, Ontario; and Department of Neurology and Neurosurgery (B.B.), Montreal Neurological Institute and Hospital, McGill University, Quebec, Canada.

Abstract

Background and objectives: Coenzyme Q₁₀ (CoQ₁₀) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ₁₀), the second-to-last step in the CoQ₁₀ biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ₁₀ biosynthesis.

Methods: Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.

Results: Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ₁₀ levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ₁₀, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.

Discussion: This report describes a new neurologic phenotype of COQ7-related primary CoQ₁₀ deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ₁₀ deficiency previously reported in the literature.