Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report

Abstract

BackgroundPure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient’s exercise intolerance through detailed exercise testing.Case presentationA 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient’s mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min−1 × kg−1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios.ConclusionThe findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype.

Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-Eclampsia

“…Moreover, the heteroplasmic G12294A variant disrupted a Watson-Crick base-pairing that was highly conserved in the anticodon stem of the tRNA Leu(CUN) [53], and biochemical analysis revealed that the G12294A significantly reduced activities of complexes I, III, and IV. Exercise physiological studies in the patient with this variant demonstrated a significantly reduced maximal oxygen uptake as well as threefold elevated lactate/pyruvate ratios strongly indicated that G12294A was pathogenic [54]. Furthermore, the G-to-A substitution at position 15995 occurred at anticodon stem of tRNA Pro , which was predicted to abolish the highly conserved Watson-Crick base-pairing.…”

Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?

“…Indeed, it is an elusive symptom, which sometimes could be missed. However, exercise intolerance can be quantified through measurement of the maximal oxygen uptake, by evaluating resting and peak exerciseinduced serum lactate levels, as well as by examining lactate/pyruvate ratios [11]. Owing to exercise performance limitations, patients with exercise intolerance can be mistaken for having cardiopulmonary diseases.…”

Molecular Genetics Overview of Primary Mitochondrial Myopathies

“…Mt-tRNA defects manifested also with a CPEO phenotype, and several point mutations have been reported. A sporadic case of a heteroplasmic substitution in position 12316G>A in MT-TL2 causing cPEO with COX-negative fibers and RRF was described [99]; Karadimas CL et al described an m.12315G>A mutation in the MT-TL2 gene in a woman with cPEO [100]; Soldath P et al reported an m.12294 G>A in the MT-TL2 gene in an individual with cPEO and exercise intolerance [101].…”