Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS)
Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a rare genetic disorder typically diagnosed in early childhood. It is characterized by recurrent strokelike episodes, which may include sudden headaches, vomiting, and seizures, often occurring after a period of normal development. Although many affected individuals display short stature, symptoms can vary widely, and some may also experience exercise intolerance and limb weakness. The condition arises from mutations in mitochondrial DNA, particularly the A3243G and T3271C mutations, which impair mitochondrial function and energy production.
MELAS affects various systems in the body, predominantly the central nervous system and skeletal muscles, leading to complications such as diabetes, deafness, and progressive external ophthalmoplegia. Diagnosis can involve a family history review, blood tests for lactic acid levels, and muscle biopsies to detect enzyme deficiencies. While there is no cure for MELAS, symptoms can be managed with various treatments, including anticonvulsants for seizures and dietary modifications for diabetes. Genetic counseling is advised for families, as the disorder is maternally inherited and can present with diverse symptoms across generations. Although MELAS can lead to significant disability and reduced lifespan, some individuals may live into adulthood with appropriate care.
Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS)
ALSO KNOWN AS: Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes
DEFINITION Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a multisystemic disorder, usually presenting in early childhood with recurrent strokelike episodes, which consist of sudden headaches, vomiting, and seizures. Although initial development is normal, short stature is common. In some cases exercise intolerance or limb weakness occurs before seizures. The strokelike episodes may gradually lead to impaired motor abilities and mental activity and to vision and hearing loss.
Risk Factors
MELAS is caused by mutations in mitochondrial DNA (mtDNA) and is a maternally transmitted heteroplasmic disorder, in which both normal and mutant mitochondrial genomes coexist within the mitochondria. The risk of developing MELAS increases when the heteroplasmy level (mutation load) crosses a threshold in muscle and the central nervous system (CNS).
Female carriers with a mutation load of 20 percent or more have a greater chance of transmitting MELAS, but in a retrospective study, even mothers with low heteroplasmy (1 to 19 percent) for the A3243G mutation had a 25 percent chance of having affected offspring.
Etiology and Genetics
Mitochondria, the cell’s energy producing organelles, contain multiple copies of mtDNA, a double-stranded circular genome with its own genetic code. Most subunits of the oxidative phosphorylation (OXPHOS) complexes are encoded by nuclear genes, but encodes thirteen subunits and part of the machinery necessary for their translation: two ribosomal RNA genes and twenty-two transfer RNA genes.
MELAS is caused by mutations within the mtDNA. The two most common mutations, A3243G (found in about 80 percent of MELAS patients, according to 2024 data from the online journal StatPearls) and T3271C (found in about 7.5 percent), occur in MT-TL1, which encodes Leu(UUR). Both A3243G and T3271C decrease posttranscriptional modification of the tRNA Leu anticodon, causing reduced translational efficiency of mitochondrial transcripts and/or misincorporation errors during translation.
There is considerable variability in phenotypic expression within families, due to heteroplasmy and putative tissue specific factors. Initially, random occurs during oogenesis; some oocytes receive a high proportion of mutant mtDNA, while others receive low or undetectable levels. After fertilization, cells with varied levels of heteroplasmy segregate into tissues; those tissues with a higher local proportion of mutant mtDNA, above a tissue-specific threshold, are more severely impacted. Heteroplasmy can also change with time; mutations can accumulate in slowly dividing tissues, such as CNS and muscle.
Symptoms
MELAS is multisystemic, affecting tissues with high energy requirements, such as CNS and skeletal muscle. Strokelike episodes and mitochondrial myopathy characterize MELAS, but other common symptoms include diabetes, deafness, progressive external ophthalmoplegia (paralysis of extraocular eye muscle), recurrent headaches, and vomiting. Maternal family members can have isolated symptoms, especially diabetes, which is generally type II (non-insulin dependent).
Onset is usually between the ages of two and ten years, after a period of normal psychomotor development (except for short stature). MELAS usually presents with headaches/migraines, vomiting, and seizures. After these strokelike episodes, patients may experience partial blindness or paralysis. Over time, MELAS usually progresses to visual, mental, and motor system dysfunction. Patients often die between ten and thirty-five years of age, but some individuals have a nearly normal life span.
Screening and Diagnosis
MELAS occurs in people of all races and sexes. A family history showing features of mitochondrial disease helps in the diagnosis of MELAS.
Lactic acidosis is typically present, reflecting respiratory chain defects. In some MELAS patients the elevated lactic acid levels may not be detectable in blood, so cerebrospinal fluid is also tested. OXPHOS enzyme deficiencies, particularly of Complex I, are detected in skeletal muscle biopsies.
While blood can be screened for MELAS mutations, of mtDNA mutations during in these rapidly dividing cells can cause false negative results. Skeletal muscle is the most reliable source for molecular diagnosis, though accessible tissues with a higher mutation load than blood can also be used for more accurate diagnosis: urinary sediment, skin fibroblasts, and buccal mucosa.
Brain imaging studies (CT scan or MRI) after a strokelike episode show evidence of infarction. Positron emission tomography may show reduced cerebral oxygen metabolism. Cardiomyopathy is a rare feature and can be evaluated by echocardiogram.
Treatment and Therapy
While there is no specific therapy, individual symptoms have corresponding treatments. Seizures may be treated with anticonvulsants, mellitus with dietary modification and insulin, and sensorineural hearing loss with cochlear implants. Metabolic therapies aim to increase ATP production or slow deterioration (coenzyme Q10, L-carnitine). Good nutritional status is important.
Prevention and Outcomes
Genetic counseling is recommended. However, a prenatal diagnosis cannot predict the condition's severity. Symptoms are not preventable, but careful monitoring is indicated to allow timely treatment.
Bibliography
Chinnery, P. F., et al. “MELAS and MERRF: The Relationship between Maternal Mutation Load and the Frequency of Clinically Affected Offspring.” Brain 121 (1998): 1889–94. Print.
Ciafaloni, Emma, Patrick F. Chinnery, Robert C. Griggs, eds. Evaluation and Treatment of Myopathies. 2nd ed. New York: Oxford UP, 2014. Print.
Gorelick, Philip B. et al., eds. Hankey's Clinical Neurology. 2nd ed. Boca Raton: CRC, 2014. Print.
Goto, Y., et al. “A Mutation in the tRNA(Leu)(UUR) Gene Associated with the MELAS Subgroup of Mitochondrial Encephalomyopathies.” Nature 348 (1990): 651–53. Print.
"Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)." National Library of Medicine, 1 Dec. 2013, medlineplus.gov/genetics/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes/. Accessed 4 Sept. 2024.
Pia, Shermila, and Forshing Lui. "Melas Syndrome." StatPearls, 25 Jan. 2024, www.ncbi.nlm.nih.gov/books/NBK532959/. Accessed 4 Sept. 2024.
Shanske, S., et al. “Varying Loads of the Mitochondrial DNA A3243G Mutation in Different Tissues: Implications for Diagnosis.” American Journal of Medical Genetics 130 (2004): 134–37. Print.
Yasukawa, T., et al. “Modification Defect at Anticodon Wobble Nucleotide of Mitochondrial tRNAs(Leu)(UUR) with Pathogenic Mutations of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes.” Journal of Biological Chemistry 275 (2000): 4251–57. Print.