关键词: COX20, 基因型, 周围神经病, 复合物IV缺乏症, 线粒体病

Abstract: Background: Primary mitochondrial diseases have high clinical and genetic heterogeneity, and peripheral nervous system is one of the most commonly involved organ. Objective: To investigate the clinical and genetic characteristics of hereditary peripheral neuropathy caused by COX20 gene variants. Design: Case series report. Methods: Four patients with hereditary peripheral neuropathy caused by COX20 gene variants treated in the Children's Hospital of Fudan University from May 2018 to May 2020 were enrolled, and their clinical manifestations, molecular tests, data of treatment and followups were retrospectively reviewed. Also, we searched published articles using keyword of "COX20", and "Complex Ⅳ deficiency" in Chinese and English databases from the inception to December 2021. The relationship between COX20 gene variantion and clinical phenotypes was summarized. Main outcome measures: COX20 gene variantion sites and clinical phenotypes. Results: Four patients including 2 males and 2 females were enrolled. Three patients had delayed motor mile stones. All 4 patients presented with walking instability onset at early childhood, and nerve conduction study revealed polyperipheral neuropathy especially with sensory axonal damaged. Whole exome sequencing of 4 patients revealed compound heterozygous variants of COX20 gene, including 2 reported missense variants, 1 reported nonsense variant and 1 novel variant—c.262delG(p.E88kfs*35) which has never been reported before. Literature review showed 22 patients from 18 families (including our cases) have been reported till now, with the median age of onset at 5 years old (1.017 years old). All patients presented with walking difficulty or unsteady gait at onset(22/22, 100%). Common clinical manifestations included developmental retardation(11/22, 50.0%), dysarthria(14/22, 63.6%), muscle weakness with or without foot deformity(14/22, 63.6%), ataxia(8/22, 36.4%), dystonia(6/22, 27.3%), and cognitive regression(5/22, 22.7%). Nerve conduction and electromyography tests revealed polyperipheral neuropathy in most patients (19/21, 90.5%). Magnetic resonance imaging revealed spinal cord atrophy in 4 patients (4/10, 40%) and cerebellum atrophy in 4 patients (4/18, 22.2%). Nine patients lost the ability of independent walking at a median age of 10(721) years. A total of 9 pathogenic variants in four types were reported, including five missense variants, two splice site mutations, one nonsense variant and one frameshift variant. Conclusion: COX20related patients always present with peripheral axonal neuropathy at an early childhood onset. The disease progresses gradually with a high disability rate. Some patients also have dysphagia, ataxia, dystonia, and cognitive regression. Among all the COX20 variants reported now, missense variants are the most common.

Key words: COX20, Genotype, Hereditary peripheral neuropathy, Complex IV deficiency, Mitochondrial disorder