Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.

OBJECTIVES

Variants in COA7 (cytochrome c oxidase assembly factor 7) are a rare cause of mitochondrial disease, with limited clinical descriptions and phenotypic variability. We describe 2 siblings carrying compound heterozygous COA7 variants, one of which (c.457C>T; p.Leu153Phe) is novel. Both presented with early-onset, slowly progressive axonal sensorimotor neuropathy, with differences in severity and associated features.

METHODS

Patients were identified based on clinical presentation and evaluated through longitudinal neurologic, neurophysiologic, genetic, biochemical, and neuroimaging assessments.

RESULTS

The elder brother developed symptoms at age 12, including muscle cramps, tremors, and falls, whereas the sister showed motor impairment with difficulty walking and running from age 5, along with more prominent cerebellar involvement. Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother. Nerve conduction studies demonstrated axonal sensorimotor polyneuropathy. Genetic analysis identified 2 compound heterozygous COA7 variants. Skin biopsy revealed reduced mitochondrial complex IV activity. Brain MRI findings were unremarkable in both siblings.

DISCUSSION: These cases expand the clinical spectrum of COA7-related disorders and illustrate the potential for intrafamilial phenotypic variability. The identification of a novel variant and extended clinical follow-up provide further insight into the features associated with COA7 variants.