MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options

El‐Hattab, Ayman W.; Adesina, Adekunle M.; Jones, Jeremy; Scaglia, Fernando

doi:10.1016/j.ymgme.2015.06.004

Cited by 460 publications

(532 citation statements)

References 71 publications

(125 reference statements)

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“…12 The most common point mutation is an adenine to guanine transition at nucleotide position 3243 (m3243G), in the MT-TL1 gene (mitochondrially encoded tRNA leucine 1 (UUA/G)), responsible for several clinical phenotypes, including syndromes characterized by mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), cardiomyopathy, and maternally inherited diabetes and deafness (MIDD). 13,14 Human cells have thousands of copies of mtDNA and individuals with pathogenetic mtDNA mutations often carry a mixture of mutated and wild-type (WT) mtDNAs in their cells, a situation referred to as heteroplasmy. A specific threshold level of mutant mtDNA must be exceeded to cause a respiratory chain defect in the cells.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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Pathological mutations in the mitochondrial DNA (mtDNA) produce a diverse range of tissue-specific diseases and the proportion of mutant mitochondrial DNA can increase or decrease with time via segregation, dependent on the cell or tissue type. Previously we found that adenocarcinoma (A549.B2) cells favored wild-type (WT) mtDNA, whereas rhabdomyosarcoma (RD.Myo) cells favored mutant (m3243G) mtDNA. Mitochondrial quality control (mtQC) can purge the cells of dysfunctional mitochondria via mitochondrial dynamics and mitophagy and appears to offer the perfect solution to the human diseases caused by mutant mtDNA. In A549.B2 and RD.Myo cybrids, with various mutant mtDNA levels, mtQC was explored together with macroautophagy/autophagy and bioenergetic profile. The 2 types of tumor-derived cell lines differed in bioenergetic profile and mitophagy, but not in autophagy. A549.B2 cybrids displayed upregulation of mitophagy, increased mtDNA removal, mitochondrial fragmentation and mitochondrial depolarization on incubation with oligomycin, parameters that correlated with mutant load. Conversely, heteroplasmic RD.Myo lines had lower mitophagic markers that negatively correlated with mutant load, combined with a fully polarized and highly fused mitochondrial network. These findings indicate that pathological mutant mitochondrial DNA can modulate mitochondrial dynamics and mitophagy in a cell-type dependent manner and thereby offer an explanation for the persistence and accumulation of deleterious variants.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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“…We also described potential co-existing symptoms, such as hearing loss, visual disturbance, frequent severe migraine, headaches and short stature. Clinical manifestations of MELAS symptoms are quite common in children and young adults (like in our patient), and less common in adults [11,12]. The wide range of MELAS symptoms and differences in their intensity lead to difficulties in establishing diagnostic criteria.…”

Section: Discussionmentioning

confidence: 71%

“…One of them is mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome [7,8]. Clinical features suggesting MELAS were first described in patients with a common characteristic sign, namely the presence of mitochondrial myopathy associated with brain changes, such as mental retardation, seizures, myoclonus, ophthalmoplegia, retinitis pigmentosa, blindness, calcification in basal ganglia and sudden hemiplegia suggestive of stroke [9,10,11,12]. MELAS is a multi-system disease, involving the brain, peripher-al nervous system, eyes, endocrine glands, heart, guts, kidneys, or dermis [13].…”

Section: Introductionmentioning

confidence: 99%

Pathology of mitochondria in MELAS syndrome: an ultrastructural study

Felczak¹,

Lewandowska²,

Stępniak³

et al. 2017

pjp

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Ultrastructural changes in skeletal muscle biopsy in a 24-year-old female patient with clinically suspected mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome are presented. We observed proliferation and/or pleomorphism of mitochondria in skeletal muscle and smooth muscle cells of arterioles, as well as in pericytes of capillaries. Paracrystalline inclusions were found only in damaged mitochondria of skeletal muscle. Genetic testing revealed a point mutation in A3243G tRNALeu(UUR) typical for MELAS syndrome. We conclude that differentiated pathological changes of mitochondria in the studied types of cells may be associated with the different energy requirements of these cells.

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“…[58][59][60] Severe headaches in MELAS patients have been associated with stroke-like episodes and seizures. 58 There are no studies looking at the treatment of headache in patients with mitochondrial disease.…”

Section: Headachesmentioning

confidence: 99%

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

Parikh

Goldstein

Karaa

et al. 2017

Genetics in Medicine

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204

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Purpose The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients.Methods Working Group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.

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MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options

Cited by 460 publications

References 71 publications

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Pathology of mitochondria in MELAS syndrome: an ultrastructural study

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

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