COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

Carola Hedberg-Oldfors; Niklas Darin; Christer Thomsen; Christopher Lindberg; Anders Oldfors

doi:10.1212/NXG.0000000000000464

COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

Neurol Genet. 2020 Jun 16;6(4):e464. doi: 10.1212/NXG.0000000000000464. eCollection 2020 Aug.

Authors

Carola Hedberg-Oldfors¹, Niklas Darin¹, Christer Thomsen¹, Christopher Lindberg¹, Anders Oldfors¹

Affiliation

¹ Department of Pathology and Genetics (C.H.-O., C.T., A.O.) and Department of Pediatrics (N.D.), Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg; and Department of Neurology (C.L.), Neuromuscular Centre, Sahlgrenska University Hospital, Gothenburg, Sweden.

Abstract

Objective: To describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8.

Methods: The patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis.

Results: Clinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*).

Conclusions: We describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.