POLG mutations presenting as Charcot-Marie-Tooth disease

Area of Science:

• Genetics and Neurology
• Mitochondrial DNA Maintenance
• Neuromuscular Disorders

Background:

• The POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase.
• Mutations in POLG are associated with a spectrum of mitochondrial disorders.
• Axonal neuropathy is a common neurological manifestation in mitochondrial diseases.

Observation:

• Two patients presented with distinct clinical phenotypes dominated by axonal neuropathy.
• Patient 1: Late-onset sensory axonal neuropathy due to a homozygous POLG mutation (c.2243G>C) linked to uniparental disomy of chromosome 15.
• Patient 2: Early-onset axonal Charcot-Marie-Tooth disease (CMT) caused by compound heterozygous POLG mutations (c.926G>A and c.2209G>C).

Findings:

• Identified novel POLG mutations and their association with specific axonal neuropathy presentations.
• Demonstrated the role of genetic background, including uniparental disomy, in disease manifestation.
• Correlated specific POLG genotypes with distinct clinical outcomes: sensory neuropathy vs. CMT.

Implications:

• Expands the known spectrum of POLG-related disorders.
• Highlights the importance of genetic testing for POLG in patients with unexplained axonal neuropathies.
• Suggests potential genotype-phenotype correlations for targeted diagnosis and management of POLG-associated neuropathies.