Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G&gt;A mutation in the tRNA<sup>Ser(UCN)</sup> gene

Grafakou, Olga; Hol, F.A.; Schwab, Karl Otfried; Siers, Marloes H.; Laak, Henk ter; Trijbels, Frans J.M.; Ensenauer, Regina; Boelen, C; Smeitink, Jan A.M.

doi:10.1023/a:1025960300710

Cited by 20 publications

(7 citation statements)

References 23 publications

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“…Two additional pathogenic heteroplasmies reported in MITOMAP (Lott et al, 2013) were observed in the data set. Variant m.7497G>A was reported to be associated with exercise intolerance, muscle pain, and lactic acidaemia (Grafakou et al, 2003). This variant was observed in the GM in family 18 with a frequency of 7.7% and disappeared in MO.…”

Section: Resultsmentioning

confidence: 99%

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The transmission of human mitochondrial DNA in four‐generation pedigrees

et al. 2022

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Most of the pathogenic variants in mitochondrial DNA (mtDNA) exist in a heteroplasmic state (coexistence of mutant and wild‐type mtDNA). Understanding how mtDNA is transmitted is crucial for predicting mitochondrial disease risk. Previous studies were based mainly on two‐generation pedigree data, which are limited by the randomness in a single transmission. In this study, we analyzed the transmission of heteroplasmies in 16 four‐generation families. First, we found that 57.8% of the variants in the great grandmother were transmitted to the fourth generation. The direction and magnitude of the frequency change during transmission appeared to be random. Moreover, no consistent correlation was identified between the frequency changes among the continuous transmissions, suggesting that most variants were functionally neutral or mildly deleterious and thus not subject to strong natural selection. Additionally, we found that the frequency of one nonsynonymous variant (m.15773G>A) showed a consistent increase in one family, suggesting that this variant may confer a fitness advantage to the mitochondrion/cell. We also estimated the effective bottleneck size during transmission to be 21−71. In summary, our study demonstrates the advantages of multigeneration data for studying the transmission of mtDNA for shedding new light on the dynamics of the mutation frequency in successive generations.

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Section: Resultsmentioning

confidence: 99%

“…Variant m.7497G>A was reported to be associated with exercise intolerance, muscle pain, and lactic acidaemia (Grafakou et al, 2003). This variant was observed in the GM in family 18 with a frequency of 7.7% and disappeared in MO.…”

Section: T a B L Ementioning

confidence: 97%

The transmission of human mitochondrial DNA in four‐generation pedigrees

et al. 2022

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“…Using the sequnce data, we detected three clinically-validated mtDNA mutations in the CFS patients substantially below the levels required to cause mtDNA disease these were m.7497G > A [15, 16], m.9185 T > C [17] and m.10197G > A [18], see Additional file 1: Table S1. The low frequency clinically-proven variants detected in the first phase of the analysis appeared to be genuine low-level heteroplasmies.…”

Section: Resultsmentioning

confidence: 99%

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

et al. 2017

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BackgroundChronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations.MethodsMtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.ResultsWe report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.ConclusionThe work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0387-6) contains supplementary material, which is available to authorized users.

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“…At rest or exercise-related muscle pain was also described, usually as isolated case reports, in some patients harboring mitochondrial tRNA gene mutations, including MT-TL1, MT-TS1 and MT-TK [7][8][9][10][11][12].…”

Section: Discussionmentioning

confidence: 99%

“…Muscle pain can be part of many neuromuscular disorders including myopathies, peripheral neuropathies and lower motor neuron diseases [5]. Although it has been reported also in mitochondrial patients, no extensive studies to quantify and clinically characterize muscle pain in MD have been performed so far [6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Muscle pain in mitochondrial diseases: a picture from the Italian network

et al. 2019

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Muscle pain may be part of many neuromuscular disorders including myopathies, peripheral neuropathies and lower motor neuron diseases. Although it has been reported also in mitochondrial diseases (MD), no extensive studies in this group of diseases have been performed so far. We reviewed clinical data from 1398 patients affected with mitochondrial diseases listed in the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", to assess muscle pain and its features. Muscle pain was present in 164 patients (11.7%). It was commonly observed in subjects with chronic progressive external ophthalmoplegia (cPEO) and with primary myopathy without cPEO, but also-although less frequently-in multisystem phenotypes such as MELAS, MERFF, Kearns Sayre syndrome, NARP, MNGIE and Leigh syndrome. Patients mainly complain of diffuse exercise-related muscle pain, but focal/multifocal and at rest myalgia were often also reported. Muscle pain was more commonly detected in patients with mitochondrial DNA mutations (67.8%) than with nuclear DNA changes (32.2%). Only 34% of the patients showed a good response to drug therapy. Interestingly, patients with nuclear DNA mutations tend to have a better therapeutic response than patients with mtDNA mutations. Muscle pain is present in a significant number of patients with MD, being one of the most common symptoms. Although patients with a myopathic phenotype are more prone to develop muscle pain, this is also observed in patients with a multi system involvement, representing an important and disabling symptom having poor response to current therapy.

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Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G>A mutation in the tRNA^Ser(UCN) gene

Cited by 20 publications

References 23 publications

The transmission of human mitochondrial DNA in four‐generation pedigrees

The transmission of human mitochondrial DNA in four‐generation pedigrees

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

Muscle pain in mitochondrial diseases: a picture from the Italian network

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Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G>A mutation in the tRNASer(UCN) gene

Cited by 20 publications

References 23 publications

The transmission of human mitochondrial DNA in four‐generation pedigrees

The transmission of human mitochondrial DNA in four‐generation pedigrees

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

Muscle pain in mitochondrial diseases: a picture from the Italian network

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Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G>A mutation in the tRNA^Ser(UCN) gene