Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1

Abstract

This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy

“…To test if the m. The m.3250T>C variant has been previously been reported in patients with mitochondrial myopathy and exercise intolerance (Arpa et al, 2003;Darin et al, 2017;Goto et al, 1992;Internullo et al, 2016;Ogle et al, 1997). Our data were congruent with previous reports, as affected individuals often presented with similar symptoms.…”

“…Complex I and IV deficiencies have been found in several affected individuals. While mitochondriopathy was reported in some individuals, benign or mild phenotypes were also present, complicating the classification of the m.3250T>C variant (Darin et al, 2017). Asymptomatic clinical presentations and likely benign in silico predictions provide evidence to classify the m.3250T>C variant as a variant of unknown significance rather than pathogenic (Lott et al, 2013; Wong et al, 2020).…”

“…variant (Darin et al, 2017). Asymptomatic clinical presentations and likely benign in silico predictions provide evidence to classify the m.3250T>C variant as a variant of unknown significance rather than pathogenic (Lott et al, 2013;Wong et al, 2020).…”

“…While some MT-TL1 variants have been adequately described in the current literature, other MT-TL1 variants have yet to be fully characterized. To our knowledge, the MT-TL1 m.3250T>C variant has been described in several families (Arpa et al, 2003;Darin et al, 2017;Goto et al, 1992;Internullo et al, 2016;Ogle et al, 1997). The majority of these patients present with lactic acidosis, chronic fatigue, exercise intolerance, and muscle weakness.…”

Progress in neurology 2017–2018

“…Neuromuscular disorders encompassing primary myopathies, neuropathies and diseases of the neuromuscular junction are together a group of diseases that are often challenging to disentangle diagnostically . Many of these have a genetic basis and novel causative mutations continue to be identified and the clinical phenotype of existing mutations more clearly defined . Treatment modalities are limited, with the exception of the immune‐mediated diseases and those with a defined biochemical cause that lends itself to specific therapy such as Pompe disease .…”