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
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 ...