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

Area of Science:

• Genetics
• Neurology
• Mitochondrial Biology

Background:

• Cytochrome c oxidase assembly factor 7 (COA7) variants are a rare cause of mitochondrial disease.
• Clinical descriptions of COA7-related disorders are limited, showing significant phenotypic variability.
• Understanding COA7 variants is crucial for diagnosing and managing mitochondrial disorders.

Purpose of the Study:

• To describe the clinical presentation and genetic findings in two siblings with compound heterozygous COA7 variants.
• To expand the known clinical spectrum of COA7-related mitochondrial disease.
• To investigate intrafamilial phenotypic variability in response to COA7 variants.

Main Methods:

• Longitudinal assessment of two siblings with clinical presentation suggestive of mitochondrial disease.
• Neurologic, neurophysiologic, genetic, biochemical (skin biopsy for mitochondrial complex IV activity), and neuroimaging (brain MRI) evaluations.
• Identification and characterization of compound heterozygous COA7 variants, including a novel variant (c.457C>T; p.Leu153Phe).

Main Results:

• Both siblings presented with early-onset, slowly progressive axonal sensorimotor neuropathy.
• Shared features included distal weakness, gait impairment, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties.
• Differences in severity and associated features (e.g., cerebellar involvement) were observed, highlighting intrafamilial variability. Reduced mitochondrial complex IV activity was detected.

Conclusions:

• These cases expand the clinical spectrum of COA7-related disorders.
• Intrafamilial phenotypic variability is a significant feature of COA7-related mitochondrial disease.
• The identification of a novel COA7 variant and extended follow-up provide valuable insights into disease presentation and progression.