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The mystery of MELAS: Why does this rare disease affect multiple body systems?
MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is a familial mitochondrial disorder that also includes MIDD (maternally inherited diabetes mellitus and hearing loss), MERRF syndrome, and Leber hereditary optic neuropathy. The disorder was first defined as MELAS in 1984, suggesting that the disorder arises from a maternally inherited defect in the mitochondrial genome. The most common MELAS mutation is m.3243A>G.
MELAS is a disease that affects multiple body systems, especially the brain and nervous system, as well as the muscular system.
Symptoms of MELAS usually develop in childhood, with early development being relatively normal, with symptoms usually beginning between the ages of 2 and 10 years. Although relatively uncommon, onset in infancy may result in poor growth, developmental delays, and progressive hearing loss. In older children, symptoms often manifest as recurring migraine-like headaches, loss of appetite, vomiting, and seizures. These children typically have short stature and elevated levels of lactic acid in their bodies, leading to symptoms of lactic acidosis, including vomiting, abdominal pain, extreme tiredness, muscle weakness, loss of bowel control, and difficulty breathing.
The increase in body acidity caused by lactic acidosis may lead to many systemic reactions and have a profound impact on the patient's daily life.
More rarely, patients may face complications including involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, epilepsy, and hormone imbalances.
Differential diagnosis
The clinical presentation of MELAS is similar to that of Kearns–Sayre syndrome and overlaps with disorders such as myoclonic epilepsy and red villous fiber epilepsy (MERRF), particularly seizures, mental deterioration, and muscle atrophy on red villous fiber muscle biopsy. . Although patients with MERRF often present with typical myoclonic epilepsy, genetic testing should be considered for an accurate diagnosis. Leigh syndrome may also present with progressive neurodegeneration, seizures, and vomiting, primarily in young children.
Genetics
MELAS is primarily caused by mutations in genes in mitochondrial DNA, but may also be caused by mutations in genes in nuclear DNA. Some of the affected genes, such as MT-ND1 and MT-ND5, encode components of the mitochondrial enzyme NADH dehydrogenase, or complex I, a protein that helps convert oxygen and simple sugars into energy. Other genes, such as MT-TH, MT-TL1, and MT-TV, encode specific transfer RNAs (tRNAs), and mutations in MT-TL1 are found in more than 80% of MELAS cases.
Although MELAS was first described in 1984, its history dates back much earlier, particularly with multiple cases found in the Wedgwood-Darwin family, all of which were inherited maternally.
The inheritance pattern of this type of disease is called mitochondrial inheritance, also known as maternal inheritance and heteroplasmy. Because only the mother provides the mitochondria of the developing embryo, men cannot pass such diseases to their children. In most cases, MELAS patients inherit the altered mitochondrial gene from their mother, but sometimes it can occur as a new mutation in an individual with no history of the disease.
Diagnosis
Diagnosis of MELAS usually relies on MRI, which often reveals multiple areas of cortical ischemia that do not conform to any known vascular territories. Lactate levels in serum and cerebrospinal fluid are usually elevated, and muscle biopsy may show red villous fibers. In addition, genetic evaluation should be performed first, as its results can avoid muscle biopsy in most cases. Diagnosis can be molecular or clinical.
Genetic testing based on symptoms and family history can effectively distinguish between different mitochondrial diseases.
There is currently no cure for MELAS. Because the disease is progressive and fatal, patient management is tailored primarily to which part of the body is affected. Typical treatments include supporting remaining healthy mitochondria, avoiding known mitochondrial toxins, and supplementing with supporting enzymes, amino acids, antioxidants, and vitamins. However, the effectiveness of supplementing with CoQ10, B vitamins, and other adjunctive approaches is still being studied.
EpidemiologyThe exact incidence of MELAS is unclear; however, it is considered to be one of the more common conditions among mitochondrial diseases, with an overall incidence of approximately one case per 4,000 people. As medical research progresses, our understanding of this rare disease is growing.
How many unsolved mysteries are hidden behind a disease that affects multiple systems?
