The phenotypic spectrum of fifty Czech m.3243A> G carriers
Introduction
First described in 1984, MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes) is one of the most common mitochondrial disorders [1]. The clinical variability of this maternally inherited disease is very broad, ranging from severe forms with manifestations early during the neonatal and infant age periods [2], [3], [4] to milder and incomplete forms presenting as late as the sixth decade of life [5]. The severity of the disease was reported to be depending on the level of mutated DNA (heteroplasmy) in affected organs [6]. Twenty-nine point mutations and one deletion in the mitochondrial DNA (mtDNA) are associated with the disease. Mutation m.3243A> G in the mitochondrial gene MTTL1, which encodes the tRNALeu(UUR) described by Goto et al. [7], has a prevalence of 80%, followed by the mutations m.13513G > A, m.3271T > C and m.3243A> G (http://www.ncbi.nlm.nih.gov/books/NBK1233/#MELAS.Molecular_Genetics). The carrier frequency for m.3243A> G is surprisingly high (236 per 100,000 in the Australian population) [8], which is in sharp contrast to the estimated incidence of affected patients (9–18 per 100,000) [9], [10], [11].
Originally reported cases presented primarily with exercise intolerance, seizures with stroke-like episodes (SLE) and sensorineural hearing loss [1], [12], [13]. Many other clinical features were later added to the list of clinical manifestations, including cardiomyopathy, chronic progressive external ophthalmoplegia (CPEO), ptosis, migraines, gastrointestinal impairment and diabetes mellitus (DM). Milder forms of MELAS syndrome are more frequently diagnosed currently, e.g. only 13 of 129 patients corresponded to the original description of MELAS given by Pavlakis in a recent UK MRC Mitochondrial Disease Patient Study [14].
Several cohorts characterizing the clinical symptoms of patients with MELAS syndrome were recently published [15], [16], [17]. However, no study focused on the timeline of the onset of various symptoms. Therefore, the main objective of our study was to describe the sequence of the emerging symptoms of MELAS syndrome in a cohort of 50 individuals with the m.3243A> G mutation. In addition, we characterized the biochemical findings and the heteroplasmy across various tissue types. This characterization may help us to better understand the natural course of the disease and improve patient care.
Section snippets
Group characterization
Fifty Czech individuals carrying the m.3243A> G mutation were included in the study. All these individuals were diagnosed between 1996 and 2015 by one centre – Department of Paediatrics and Adolescent Medicine in Prague and were routinely followed-up. Regular visits (at least once a year) included clinical and biochemistry assessments. Additional specific procedures (imaging of CNS and electrophysiological studies) were performed when needed. The clinical and laboratory data for these 50 Czech
Disease onset
The mean age of onset in all symptomatic patients was 17.4 ± 12.9 years (range 1 month–47 years). The FEP patients manifested symptoms earlier (mean 10.9 ± 8.1 years, range 6 months–29 years) than the OP patients (mean 22.5 ± 13.9 years, range 1 month–47 years). The most frequent presenting symptoms were myopathy (muscle fatigue, myalgia, intolerance of exercise) in 18%, isolated ptosis in 16%, growth retardation and hearing loss in 13% and isolated CPEO in 11% of patients, followed by DM, failure to thrive,
Discussion
The current report represents a retrospective cohort characterization of 50 individuals carrying the m.3243A> G mutation. Our aim was to provide comprehensive data on MELAS-related phenotype, with a particular emphasis on the natural chronological course of the disease, as well as its biochemical characteristics and heteroplasmic status across various tissue types. We noted considerable clinical diversity among individuals with the m.3243A> G mutation, whose presentations ranged from asymptomatic
Conflict of interest
All authors confirm that they have no competing interests to declare.
Details of ethics approval
The study was performed in accordance with the Declaration of Helsinki of the World Medical Association. Due to the nature of the study, no ethical approval was requested from the local ethics committee.
Acknowledgements
This work was supported by the Ministry of Health of the Czech Republic (MZ CR AZV 16-32341A, RVO-VFN 64165), the Grant Agency of the Czech Republic (14-36804G), and by Charles University in Prague (GAUK 38515/2015, PRVOUK P24/LF1/3, UNCE 204011/2012, SVV 260256/2016). The authors are thankful to Vaclav Capek for the statistical treatment of the data.
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Cited by (30)
Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases
2023, Molecular Genetics and MetabolismIndependent origin for m.3243A>G mitochondrial mutation in three Venezuelan cases of MELAS syndrome
2022, Clinical BiochemistryCitation Excerpt :Depending on the sample source, we observed significant variations in mtDNA heteroplasmy (%He), with urine samples from the three patients showing the highest mutational load (58 to 94 %) [14–17] followed by mucosa oral %He (14 to 53). An increased level of urinary %He had been associated with severe symptoms of the disease [18–20] such was the case for P2 who had 94 %He. Blood samples were examined in patients P1 and P2 and they show 7 and 41 %He, respectively.
Pathogenic mtDNA variants, in particular single large-scale mtDNA deletions, are strongly associated with post-lingual onset sensorineural hearing loss in primary mitochondrial disease
2022, Molecular Genetics and MetabolismCitation Excerpt :This overall prevalence of SNHL in m.3243A > G subjects is largely consistent with other reported studies. The prevalence of SNHL was 58% (n = 73/126) in an Italian m.3243A > G cohort [23], 76% (n = 25/33) in a Czech cohort [24], and 67% (n = 92/138) in a North American cohort [22]. Furthermore, 31% of MERRF subjects with m.8344A > G (12/39) had impaired hearing in this Italian cohort, similar to 27% of m.8344A > G subjects in our study [23].
Mitochondrial DNA A3243G variant-associated retinopathy: Current perspectives and clinical implications
2021, Survey of OphthalmologyCitation Excerpt :Interestingly, up to 2.8% and 7.4% of patients with diabetes and inherited sensorineural deafness, respectively, carry the m.3243A>G variant.73,116 This mutation has been reported to cause a variety of mitochondrial diseases including most commonly maternally inherited diabetes and deafness (MIDD, OMIM#: 520000, ∼30%),17,135 mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS, OMIM#: 540000, ∼10% of cases),45,68,135 chronic progressive external ophthalmoplegia (CPEO, isolated or in combination with MIDD or MELAS, ∼7% of cases),50,61,135,180 CPEO plus (∼6% of cases),44,135 as well as myoclonic epilepsy and ragged-red fibers (MERRF, OMIM#: 545000, ∼<1%).135,186,189 Other less frequent diseases may include Leigh syndrome,16,68,93,96 and Kearns-Sayre syndrome (KSS, OMIM#: 530000).81,212
Phenotypic heterogeneity of MELAS
2017, Molecular Genetics and Metabolism Reports
- 1
Preparation and drafting of the manuscript, patients clinical and laboratory data evaluation, revision of the literature, participation in the conception and design of the article.
- 2
Participation in the conception and design of the article, revision of the literature, drafting the manuscript.
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Clinical investigation, critical revision of the article.
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Molecular biology and biochemistry, assistance in drafting the figures.
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Conceiving the article outline, conception and design of the manuscript, clinical investigation, draft of the manuscript and critical revision for important intellectual content. He is the guarantor of the article, accepts full responsibility for the work submitted and controls the decision to publish.