Chapter

MELAS

In book: GeneReviews™, Publisher: University of Washington, Seattle, Editors: Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam
Source: PubMed

ABSTRACT MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with onset typically in childhood. Early psychomotor development is usually normal, but short stature is common. Onset of symptoms is frequently between the ages of two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness. These stroke-like episodes may be associated with altered consciousness and may be recurrent. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common.
The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing. Mutations in the mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNALeu(UUA/UUG) are causative. The most common mutation, present in about 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 (m.3243A>G). Mutations in MT-TL1 or other mtDNA genes, particularly MT-ND5, can also cause this disorder. Mutations can usually be detected in mtDNA from leukocytes in individuals with typical MELAS; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may be detected only in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or, most reliably, skeletal muscle.
Treatment of manifestations: No specific treatment for MELAS exists. Sensorineural hearing loss has been treated with cochlear implantation; seizures respond to traditional anticonvulsant therapy. Diabetes mellitus is managed by dietary modification, oral hypoglycemic agents, or insulin therapy. L-arginine showed promise in treating stroke-like episodes. Migraine headaches and cardiac manifestations are treated in the usual manner. Prevention of primary manifestations: Coenzyme Q10 and its analog, idebenone, have been beneficial in some individuals. Surveillance: Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, cardiologic, and endocrinologic evaluations are recommended. Agents/circumstances to avoid: Dichloroacetate (DCA) because of increased risk for peripheral neuropathy; valproic acid.
MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk of having the disease-causing mtDNA mutation. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. A man with an mtDNA mutation cannot transmit the mutation to any of his offspring. A woman (affected or unaffected) transmits the mutation to all of her offspring. Prenatal diagnosis for MELAS is possible if a mtDNA mutation has been detected in the mother. However, because the mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues, and because the mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.

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