Novel Mutation m.10372A>G in MT-ND3 Causing Sensorimotor Axonal Polyneuropathy

Area of Science:

• * Mitochondrial genetics
• * Neuromuscular disorders

Background:

• * Adult-onset sensorimotor axonal polyneuropathy is often idiopathic.
• * Mitochondrial DNA (mtDNA) mutations can cause complex multisystem disorders.
• * The MT-ND3 gene encodes a subunit of mitochondrial respiratory chain complex I (CI).

Purpose of the Study:

• * Investigate the pathogenicity of a novel MT-ND3 mutation in a patient with adult-onset sensorimotor axonal polyneuropathy.
• * Characterize the clinical, morphologic, and biochemical features associated with the mutation.

Main Methods:

• * Performed clinical assessments, skeletal muscle biopsy, and myoblast cultures.
• * Utilized whole-genome sequencing (WGS) and Sanger sequencing for mtDNA analysis.
• * Quantified heteroplasmic levels of mutated mtDNA using real-time PCR.

Main Results:

• * Muscle biopsy revealed ragged red fibers, paracrystalline inclusions, reduced CI respiratory chain activity, and decreased ATP production.
• * Identified a novel heteroplasmic MT-ND3 mutation in the patient's skeletal muscle mtDNA.
• * WGS confirmed the mtDNA mutation; cultured myoblasts lacked the mutation and showed normal respiratory chain activity.

Conclusions:

• * A novel MT-ND3 mutation is pathogenic and causes adult-onset sensorimotor axonal polyneuropathy.
• * Loss of heteroplasmy in blood and cultured cells, alongside normal myoblast respiratory function, supports pathogenicity.
• * Highlights the importance of mitochondrial investigations in idiopathic polyneuropathy, especially with muscle involvement.