Pathogenic mtDNA mutations causing mitochondrial myopathy: The need for muscle biopsy

Abstract

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.

Figure 1.. Histopathologic and molecular genetic characterization of 5 pathogenic MT-TP (mt-tRNA^Pro) mutations

(A) Sequential COX-succinate dehydrogenase histochemistry demonstrating a mosaic pattern of COX deficiency in all patient muscle samples (COX-deficient fibers are blue, COX-positive fibers are brown); note the presence of COX-deficient ragged-red fibers in each of the 5 biopsies (scale bar = 100 μm). Sequence electropherograms showing the relevant MT-TP mutation for each patient are also included. (B) Schematic representation of the cloverleaf structure of the mt-tRNA^Pro molecule and the corresponding location of the 5 pathogenic mutations. Each mutation occurs in a different stem of the mt-tRNA^Pro molecule. The affected position and the substitution that occurs are highlighted in bold. (C) Single muscle fiber mutation load segregation. The graph shows the mutation load measured in individual COX-positive (closed circles) and COX-deficient fibers (open circles) laser-microdissected from muscle biopsies of the 5 patients. In each case, the candidate MT-TP mutation segregates with the biochemical (COX) defect in single muscle fibers.