Elsevier

Molecular Genetics and Metabolism

Volume 116, Issues 1–2, September–October 2015, Pages 4-12
Molecular Genetics and Metabolism

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MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options

https://doi.org/10.1016/j.ymgme.2015.06.004Get rights and content

Highlights

  • MELAS syndrome is a frequent maternally inherited mitochondrial disorder.

  • The cardinal features are stroke-like episodes, encephalopathy, and myopathy.

  • Pathogenesis involves energy deficiency, angiopathy, and nitric oxide deficiency.

  • Management is largely symptomatic and should involve a multidisciplinary team.

  • l-Arginine, carnitine, and coenzyme Q10 are commonly used in treating MELAS.

Abstract

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. MELAS syndrome is a multi-organ disease with broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with MELAS syndrome is the m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR). The m.3243A>G mutation results in impaired mitochondrial translation and protein synthesis including the mitochondrial electron transport chain complex subunits leading to impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the needs of various organs results in the multi-organ dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation in the smooth muscle and endothelial cells of small blood vessels leading to angiopathy and impaired blood perfusion in the microvasculature of several organs. These events will contribute to the complications observed in MELAS syndrome particularly the stroke-like episodes. In addition, nitric oxide deficiency occurs in MELAS syndrome and can contribute to its complications. There is no specific consensus approach for treating MELAS syndrome. Management is largely symptomatic and should involve a multidisciplinary team. Unblinded studies showed that l-arginine therapy improves stroke-like episode symptoms and decreases the frequency and severity of these episodes. Additionally, carnitine and coenzyme Q10 are commonly used in MELAS syndrome without proven efficacy.

Introduction

Mitochondria are double membrane organelles found in all nucleated human cells and perform a variety of essential functions, including the generation of most cellular energy in the form of adenosine triphosphate (ATP). The inner mitochondrial membrane harbors the electron transport chain (ETC) complexes that transfer electrons, translocate protons, and produce ATP. Mitochondria contain extra-chromosomal DNA (mitochondrial DNA, mtDNA). However, only a very small proportion of mitochondrial proteins are encoded by that DNA; whereas the majority of mitochondrial proteins are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction leading to mitochondrial diseases. Dysfunctional mitochondria are unable to generate sufficient ATP to meet the energy needs of various organs, particularly those with high energy demand, including the nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine systems. Some patients with mitochondrial diseases display a cluster of clinical features that fall into a discrete clinical syndrome. However, there is often considerable clinical variability, and many affected individuals do not fit into one particular syndrome [1].

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders which was first delineated in 1984 [2]. The molecular basis of MELAS syndrome was initially discovered in 1990 when adenine to guanine transition at position 3243 of mtDNA (m.3243A>G) in the MT-TL1 gene encoding tRNALeu(UUR) was found to be associated with this syndrome [3], [4]. In 1992, clinical diagnostic criteria for MELAS syndrome were published indicating that the clinical diagnosis of this syndrome is based on the following three invariant criteria: 1) stroke-like episodes before age 40 years, 2) encephalopathy characterized by seizures and/or dementia, and 3) mitochondrial myopathy evident by lactic acidosis and/or ragged-red fibers (RRFs). The diagnosis is considered confirmed if there are also at least two of the following criteria: 1) normal early psychomotor development, 2) recurrent headaches, and 3) recurrent vomiting episodes [5]. More recently, the MELAS study group committee in Japan published other diagnostic criteria by which the diagnosis is considered definitive with at least two category A criteria (headaches with vomiting, seizures, hemiplegia, cortical blindness, and acute focal lesions in neuroimaging) and two category B criteria (high plasma or cerebrospinal fluid (CSF) lactate, mitochondrial abnormalities in muscle biopsy, and a MELAS-related gene mutation) [6]. The prevalence of MELAS syndrome has been estimated to be 0.2:100,000 in Japan [6]. Other mtDNA mutations were subsequently found to cause MELAS syndrome; however, the m.3243A>G remained the commonest universally. The m.3243A>G, which was subsequently found to be associated with other phenotypes that collectively constitute a wide spectrum ranging from MELAS syndrome at the severe end to asymptomatic carrier status, was found to be relatively common with a prevalence of 16–18:100,000 in Finland [7], [8]. In this review, we summarize the clinical manifestations of MELAS syndrome along with its pathogenic mechanisms and management options.

Section snippets

Clinical manifestations

MELAS syndrome is a multi-organ disease with broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. Childhood is the typical age of onset with 65–76% of affected individuals presenting at or before the age of 20 years. Only 5–8% of individuals present before the age of 2 years and 1–6% after the age of 40 years [6], [9], [10], [11].

Individuals with MELAS syndrome frequently present

Pathogenesis

The pathogenesis of MELAS syndrome is not fully understood. The observed phenotype of MELAS syndrome can be explained by several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency (Fig. 3).

Management

There is no specific consensus approach for treating individuals with MELAS syndrome. Management is largely symptomatic and should involve a multidisciplinary team that may include a neurologist, cardiologist, endocrinologist, audiologist, ophthalmologist, physical and occupational therapists, psychologist, and social worker.

Conclusions

MELAS syndrome, which is a frequent maternally inherited mitochondrial disorder, is a multi-organ disease with broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, and myopathy. The m.3243A>G mutation in the MT-TL1 gene occurs in 80% of individuals with MELAS syndrome. Several mechanisms can interact to result in the multi-organ phenotype of MELAS syndrome including impaired mitochondrial energy production, microvasculature angiopathy, and NO deficiency.

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