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MELAS is an acronym for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke. It is a progressive neurodegenerative disorder. Other clinical features include diabetes mellitus, deafness, episodic vomiting, seizures, and cortical blindness.

In the US adult population, the frequency is approximately 16.3:100,000. Internationally, the prevalence is approximately 10.2:100,000 in the Finnish population. Affects males and females between the ages of 4 and 15 years.

Mitochondrial; the incidence of affected children is dependent upon maternal mutant load. It is a large heterogeneic syndrome with possible mutation of many genes such as MTTL1, MTND6, and MTTQs.

Multiple organ systems involved are the central nervous system, skeletal muscle, eye, cardiac muscle, and, more rarely, the gastrointestinal system. Approximately 80% of patients with the clinical characteristics of MELAS have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the tRNALeu (UUR) gene at base pair 3243 (i.e., A3243G mutation). Mitochondrial angiopathy of a small vessel is responsible for contrast enhancement of affected regions and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction may be a result of both parenchymal and vascular oxidative phosphorylation defects. The effect of potent vasodilators (e.g., nitric oxide) may be offset by increased production of free radicals in association with an oxidative phosphorylation defect leading to vasoconstriction. Defect of the respiratory chain enzymes, mainly the reduced form of nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase (complex I).

Usually based on clinical criteria; lactate levels are elevated at rest and increase further with minimal exercise. Demonstration of ragged-red fibers on muscle biopsy. Electronic microscopy may show abnormal mitochondria and mitochondrial DNA (mtDNA) testing (80% have a mutation at base 3243 and 10% at base 3271). The stroke-like episodes usually are associated with infarcts exhibited on head CT scan or MRI. These infarcts have been hypothesized to be nonvascular and caused by transient oxidative phosphorylation dysfunction within the brain parenchyma.

These children have normal early development. Onset is most often during the second decade but can be seen as early as age 4 years. The severity and form of presentation vary considerably and depend on maternal mutant mitochondrial load. The main features include subsequently poor growth and fatigability with muscle weakness. There is progressive episodic vomiting, seizures, and recurrent cerebral insults mimicking strokes and causing hemiparesis, hemianopsia, or cortical blindness. The most frequent symptom is episodic sudden headaches with vomiting and convulsions. Myopathy is associated with lactic acidosis in blood and cerebrospinal fluid. Most of the allelic variants are described with atrioventricular block, Wolff-Parkinson-White syndrome, or cardiomyopathy. Multihormonal hypopituitarism may be present. Alterations of the skin (purpura and hirsutism) occur in 45% of cases. The clinical diagnosis is based on five cardinal manifestations: clinical stroke, seizures, lactic acidosis, ragged-red fibers, and exercise intolerance.

The diagnosis of mitochondrial disease should be considered in any child with a multisystem neurologic ...

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