The packet lists no known causative genes for MELAS syndrome, so it contains no certified gene-level causative claim, and no gene is named here. The packet's inheritance field lists mitochondrial inheritance.

GeneReviews states that MELAS is caused by pathogenic variants in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. It notes that in mtDNA-related disorders, penetrance typically depends on mutational load and tissue distribution, which show random variation within families. GeneReviews reports that no clear genotype-phenotype correlations have been identified.

The GeneReviews differential diagnosis notes that a MELAS-like phenotype has been reported with defects in certain nuclear genes.

GeneReviews notes that clinical diagnostic criteria for MELAS have been published. It describes the condition as suspected in individuals with features such as stroke-like episodes before age 40 years, acquired encephalopathy with seizures and/or dementia, recurrent headaches, muscle weakness and exercise intolerance, cortical vision loss, hemiparesis, recurrent vomiting, short stature, hearing impairment, normal early psychomotor development, peripheral neuropathy, and learning disability.

Brain MRI during stroke-like episodes is described as showing areas of increased T2 signal that do not follow the classic vascular distribution, are asymmetric, and typically involve the posterior cerebrum. Diffusion-weighted MRI shows increased apparent diffusion coefficient in these lesions, in contrast to the decreased coefficient seen in ischemic strokes; MR angiography is usually normal, and MR spectroscopy shows decreased N-acetylaspartate and accumulation of lactate. Electromyography and nerve conduction studies are described as consistent with a myopathic process, with possible coexisting neuropathy.

Laboratory findings described by GeneReviews include lactic acidosis in blood and cerebrospinal fluid. GeneReviews points out that lactic acidemia is not specific to MELAS, since it occurs in other mitochondrial diseases, metabolic diseases, and systemic illness, and that lactate can be normal in a minority of affected individuals. Muscle biopsy findings include ragged red fibers, most of which stain positively with cytochrome c oxidase in MELAS, and multiple partial respiratory chain defects, especially involving complex I and/or complex IV.

The GeneReviews differential diagnosis lists other causes of stroke in a young person, including heart disease, vasculopathies, venous thrombosis, moyamoya disease, complicated migraine, Fabry disease, and homocystinuria. The packet does not certify a newborn screening status for this condition.

GeneReviews states that treatment for MELAS is primarily supportive.

The packet lists no active verified FDA-approved treatment record for MELAS. Orphan drug records are present: one idebenone designation carries a withdrawn status, and two further designations (a stilbene-type compound and nicotinamide riboside) carry designated status. An orphan designation is not an approval and does not indicate that a product is in use or under development.

GeneReviews describes arginine therapy in the setting of stroke-like episodes, both during an acute episode and as ongoing use after a first episode to reduce the risk of recurrence. For the overall disease process, GeneReviews lists coenzyme Q10, L-carnitine, and creatine, noting that coenzyme Q10 may benefit some individuals. Manifestation-specific measures described by GeneReviews include eyelid procedures for ptosis, cochlear implantation for hearing loss (reported as successful in some), standard pharmacologic therapy for cardiomyopathy and conduction defects, aerobic exercise, conventional anticonvulsant therapy for seizures, standard analgesics for migraine, and dietary modification, oral hypoglycemic agents, or insulin for diabetes mellitus. GeneReviews also describes standard childhood, influenza, and pneumococcal vaccination because febrile illnesses may trigger acute exacerbations.

GeneReviews identifies certain agents as being of concern in MELAS: mitochondrial toxins such as aminoglycoside antibiotics and linezolid, valproic acid for seizures, metformin because of its propensity to cause lactic acidosis, and dichloroacetate, a study of which was terminated because of peripheral neuropathy.

GeneReviews lists multidisciplinary evaluations across the eyes, ears, cardiovascular, renal, musculoskeletal, neurologic, and endocrine systems, and describes annual surveillance of eyes, ears, heart (electrocardiogram and echocardiogram), kidneys (urinalysis), and fasting blood glucose, with affected individuals and at-risk relatives followed at regular intervals.

Among investigational concepts, GeneReviews describes nuclear transfer from zygotes carrying an mtDNA pathogenic variant as a theoretical way to prevent transmission, with proof of concept shown in abnormally fertilized zygotes.

The packet does not certify a structured natural history record for MELAS. The disease definition describes the condition as progressive. GeneReviews describes stroke-like episodes as presenting with partially reversible deficits and an eventual progressive accumulation of neurologic deficits, and describes dementia as arising from both underlying neurologic dysfunction and accumulating cortical injury. The packet does not certify survival or life-expectancy data.

The packet lists active clinical studies for MELAS. The studies include a Phase 3 trial of an investigational drug in primary mitochondrial diseases, an open-label extension safety study in MELAS, an early-phase compound study, a ketogenic diet study, and registry and natural history studies for mitochondrial disorders. The packet's trial summary indicates no gene therapy trials among them, and its publication overview describes the literature as dominated by case reports and case series. Active clinical trials for this condition are listed on ClinicalTrials.gov.