Distal weakness with respiratory insufficiency caused by the m.8344A > G "MERRF" mutation

Area of Science:

• Mitochondrial genetics
• Neuromuscular disorders
• Molecular diagnostics

Background:

• The m.8344A>G mutation in the mt-tRNA(Lys) gene is the most common cause of myoclonic epilepsy and ragged red fibers (MERRF) syndrome.
• While classically associated with myoclonus, ataxia, and epilepsy, this mutation exhibits significant phenotypic variability.

Observation:

• This study details an unusual case of a middle-aged woman with the m.8344A>G mutation presenting with childhood-onset distal weakness, ptosis, facial weakness, and later respiratory insufficiency.
• Diagnostic investigations, including neurophysiology and genetic testing, ruled out myasthenia gravis and myotonic dystrophy.
• Muscle biopsy revealed significant mitochondrial abnormalities, including ragged-red fibers and COX-deficient fibers, prompting mitochondrial genome sequencing.

Findings:

• Mitochondrial genome sequencing confirmed the presence of the m.8344A>G mutation.
• The patient's presentation expands the known phenotypic spectrum of this mutation, demonstrating its capacity to cause indolent distal weakness and respiratory compromise.
• Marked histochemical defects were observed in muscle tissue.

Implications:

• This case underscores the phenotypic heterogeneity of the m.8344A>G mutation.
• It suggests considering screening for this mutation in patients with unexplained indolent myopathy, particularly those mimicking distal limb-girdle muscular dystrophy, especially when common gene panels are negative.
• The findings emphasize the importance of comprehensive genetic analysis in diagnosing complex neuromuscular disorders.