When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

Abstract

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

Pathology of mitochondria in MELAS syndrome: an ultrastructural study

“…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.…”

“…The wide range of MELAS symptoms and differences in their intensity lead to difficulties in establishing diagnostic criteria. According to the traditional diagnostic criteria established by Hirano, encephalopa- thy with dementia and/or seizures and the presence of the young age of episodes similar to a stroke are often the major determinants of MELAS [11,21]. On the other hand, the diagnostic criteria developed by Japanese scientists placed emphasis on the importance of genetic testing to detect mutations responsible for MELAS and indicate the role of mitochondrial dysfunction studies at the ultrastructural level [11,22].…”

“…Another difficulty in identifying the genetic basis of MELAS is the fact that the disease can be caused by other less common genetic mutations in the mitochondrial DNA (mtDNA). The A3252G and C3256T mutations in tRNALeu(UUR) may serve as an example [11]. Moreover, there are also MELAS cases caused by mutations in the nuclear DNA (nDNA) in the POLG1 gene that encodes the gamma polymerase involved in the replication of mitochondrial DNA [28,29].…”

“…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].…”

“…The most commonly involved pathogenic point mutations are A3243G and T3271C in the gene encoding tRNALeu [15]. However, the A3243G mutation is responsible for the induction of MELAS in about 80% of remaining patients with MELAS and T3271C for approximately 7.5%, but in up to 10% of patients with MELAS the mutations of mtDNA remain unknown [11]. Molecular consequences of the A3243G mutation in tRNALeu(UUR) has not as yet been completely understood.…”