Isolated Distal Myopathy of the Upper Limbs Associated With Mitochondrial DNA Depletion and Polymerase γ Mutations

Abstract

Setting: University-based outpatient neurology clinic and pathology and genetics laboratory.Patient: A 27-year-old man presenting with isolated distal myopathy of the upper extremities in the absence of sensory disturbances.Results: Histochemical analysis of a muscle biopsy specimen showed numerous cytochrome c oxidase-deficient fibers. Molecular analysis revealed marked depletion of muscle mitochondrial DNA in the absence of multiple mitochondrial DNA deletions. Sequence analysis of the POLG gene revealed heterozygous sequence variants in compound c.1156CϾT (p.R386C) and c.2794CϾT (p.H932Y) segregating with clinical disease in the family. The p.R386C change appears to be a novel mutation. Conclusion:Our case broadens the phenotypic spectrum of disorders associated with POLG mutations and highlights the complex relationship between genotype and phenotype in POLG-related disease.

POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria

“…Although distal myopathy has been previously described in POLG-related diseases (Giordano et al, 2010), it had an adult-onset. Skeletal muscle weakness and exercise intolerance can accompany PEO (Luoma et al, 2004); however, most of the previous reports with either neuropathy or myopathy caused by a heterozygous POLG mutation have been reported in older subjects (Milone and Massie, 2010;Wong et al, 2008).…”

The unfolding spectrum of inherited distal myopathies

“…It is caused by mutations in the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ gene ( POLG ). POLG dominant and recessive mutations can also lead to distal myopathy, predominantly affecting upper limb muscles, and characterized by histological signs of mitochondrial dysfunction (ragged‐red, ragged‐blue, and/or cytochrome c oxidase‐negative fibers) and muscle mtDNA depletion or deletions …”

Diagnosis and treatment of mitochondrial myopathies

“…Many features of MM are uncommon, or recently described (such as distal myopathy from certain POLG mutations (17)). These ill-defined syndromes may have a novel or unique molecular basis, or they may be due to mutations previously described to cause specific syndromes.…”