Phenotypic Heterogeneity of the m.14459G>A Mutation

The authors read with interest the article by Kurt et al about 2 unrelated, pediatric patients carrying the mutation m.14459G>A in the ND6 gene, which manifested clinically as Leigh-like syndrome with generalized dystonia. The authors have the following comments and concerns. The authors do not agree with the statement in the Introduction that most of the mutations affecting subunits of complex I of the respiratory chain are maternally inherited. Only 7 of the 44 subunits of complex I are mtDNA-encoded. Thus, it is much more likely that genes located on the nDNA are mutated in case of complex I defects. Were reduced tendon reflexes in patient 2 attributable to myopathy or neuropathy? Since myopathy is more frequent than neuropathy in mitochondrial disorders and since bilateral ptosis was present, myopathy is much more likely. Were there other indications for myopathy, such as myalgia, cramps, fasciculations, easy fatigability, exercise intolerance, or creatine kinase elevation? The readers should be informed about the results of nerve conduction studies and electromyography in this patient. Mitochondrial disorders frequently present with elevated cerebral lactate. Did the 2 patients undergo magnetic resonance spectroscopy or lumbar puncture to see whether lactate in the cerebrospinal fluid was elevated or not? Was lactate elevated in the serum or was the lactate stress test abnormal? The authors mention “stroke” as clinical manifestation of a m.14458G>A mutation. Do they mean ischemic stroke or a stroke-like episode, frequently found in mitochondrial disorders? Were cardiovascular risk factors, such diabetes, arterial hypertension, hyperlipidemia, smoking, or atrial fibrillation, positive in this particular patient? Were imaging findings indicative of an ischemic stroke or a stroke-like lesion? Which therapy did this patient receive for the “stroke”? Leber’s hereditary optic neuropathy is more frequently due to homoplasmic than heteroplasmic mtDNA mutations. The authors describe 3 patients with Leber’s hereditary optic neuropathy in Table 1 in whom the mutation was heteroplasmic. How to explain heteroplasmy in these 3 Leber’s hereditary optic neuropathy patients? Did visual impairment recover in these 3 patients? Due to marked phenotypic heterogeneity of heteroplasmic mtDNA mutations and high intrafamilial heterogeneity, family members of both index cases should be extensively investigated for subclinical involvement of organs frequently affected in mitochondrial disorders, such as the brain, endocrine, organs, muscle, nerve, heart, intestines, or the kidney. Heteroplasmy rate in the mothers may go undetected if very low. Overall, this interesting case study could be more meaningful by providing more clinical data, by providing explanations for some unusual findings, and by a more extensive investigation of first-degree family members.