The phenotypic spectrum of fifty Czech m.3243A> G carriers

https://doi.org/10.1016/j.ymgme.2016.06.003Get rights and content

Highlights

  • Myopathy is the most common presenting symptom and rhabdomyolysis may develop.

  • Stroke-like episodes always ensue other symptoms and in 58% are preceded by migraines.

  • Any symptom of MELAS may come first and intersymptom interval may reach up to 28 years.

  • Juvenile form has a higher mortality rate than adult form of the disease.

  • Even mono and oligosymptomatic patients should be taken into consideration for MELAS.

Abstract

Background

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes syndrome (MELAS) is a common mitochondrial disorder with varying multisystemic clinical manifestation. We present a comprehensive clinical picture of 50 Czech m.3243A> G carriers with emphasis on the sequence of symptoms in symptomatic patients.

Results

Symptoms developed in 33 patients (66%) and 17 carriers remained unaffected (34%). The age of onset varied from 1 month to 47 years of age, with juvenile presentation occurring in 53% of patients. Myopathy was the most common presenting symptom (18%), followed by CPEO/ptosis and hearing loss, with the latter also being the most common second symptom. Stroke-like episodes (SLE) occurred in fourteen patients, although never as a first symptom, and were frequently preceded by migraines (58%). Rhabdomyolysis developed in two patients. The second symptom appeared 5.0 ± 8.3 years (range 0–28 years) after the first, and the interval between the second and third symptom was 2.0 ± 6.0 years (range 0–21 years). Four of our patients remained monosymptomatic up to 12 years of follow-up. The sequence of symptoms according to their time of manifestation was migraines, myopathy, seizures, CPEO/ptosis, SLE, hearing loss, and diabetes mellitus. The average age at death was 32.4 ± 17.7 years (range 9–60 years) in the juvenile form and 44.0 ± 12.7 years (range 35–53 years) in the adult form. Some patients with SLE harboured very low heteroplasmy levels in various tissues. No threshold for any organ dysfunction could be determined based on these levels.

Conclusions

Sufficient knowledge of the timeline of the natural course of MELAS syndrome may improve the prediction and management of symptoms in patients with this mitochondrial disease.

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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