Hardy SA, Blakely EL, Purvis AI, Rocha MC, Ahmed S, Falkous G, Poulton J, Rose
MR, O'Mahony O, Bermingham N, Dougan CF, Ng YS, Horvath R, Turnbull DM, Gorman
GS, Taylor RW. Pathogenic mtDNA mutations causing mitochondrial myopathy: The
need for muscle biopsy. Neurol Genet. 2016 Jun 23;2(4):e82.
Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary mitochondrial DNA (mtDNA)-related disease despite accounting for only 5%-10% of the mitochondrial genome.(1,2) Although some common mt-tRNA mutations, such as the m.3243A>G mutation, exist, the majority are rare and have been reported in only a small number of cases.(3) The MT-TP gene, encoding mt-tRNA(Pro), is one of the less polymorphic mt-tRNA genes, and only 5 MT-TP mutations have been reported as a cause of mitochondrial muscle disease to date (table e-1 at Neurology.org/ng, P6-10). We report 5 patients with myopathic phenotypes, each harboring different pathogenic mutations in the MT-TP gene, highlighting the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.
From the article
We report 5 adult patients with mitochondrial disease due to different mutations in the MT-TP gene with a predominantly myopathic phenotype. Ptosis (+/− progressive external ophthalmoplegia), proximal myopathy, and marked perceived fatigue appear to be salient features. In each case, the marked degree of COX deficiency and downregulation of both complex I and complex IV subunits in muscle was strongly suggestive of a defect in mitochondrial translation and entirely in keeping with an mt-tRNA mutation. To date, only 5 patients have been reported, each with different MT-TP mutations, and variable clinical features have been observed including ataxia, deafness, dilated cardiomyopathy, myoclonic epilepsy with ragged-red fibers–like disease, and retinitis pigmentosa; a myopathic phenotype is reported in all cases (table e-1).
Patients 1, 2, and 3 showed restricted expression of their MT-TP mutations to muscle, strongly indicative of a de novo mutational event, whereas patients 4 and 5 showed a hierarchical segregation pattern as observed in many pathogenic mtDNA mutations. Screening of maternal samples was undertaken for patients 2, 4, and 5, with maternal inheritance being confirmed in patient 4 only. Of note, only one of the previous studies demonstrated maternal inheritance of the MT-TP mutation, with 4 of the remaining studies also reporting apparent or likely de novo mutational events.
Single muscle fiber segregation studies remain the gold standard test to confidently establish pathogenicity of novel mtDNA variants. Although the m.15975T>C5 and m.16002T>C6 mutations have been reported previously, functional studies were not undertaken to confirm pathogenicity. Subsequent studies in muscle biopsies of all 5 patients confirm that mutation loads segregated with the mitochondrial histochemical defects in muscle (figure 1C; table e-2), powerfully illustrating an ongoing requirement to access pathologically relevant tissue—skeletal muscle—to support the investigation and diagnosis of patients with mitochondrial myopathy, even in the current era of high-throughput next-generation sequencing technologies.