Excerpt from MELAS Syndrome

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Background

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) is a progressive neurodegenerative disorder. Patients may present sporadically or as members of maternal pedigrees with a wide variety of clinical presentations. The typical presentation of patients with MELAS syndrome includes features that comprise the name of the disorder, such as mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Other features, such as seizures, diabetes mellitus, hearing loss, short stature, and exercise intolerance are clearly part of the disorder.

Pathophysiology

Strokelike episodes and mitochondrial myopathy characterize MELAS. Multisystemic organ involvement is seen, including the central nervous system (CNS), skeletal muscle, eye, cardiac muscle, and, more rarely, the GI and renal systems.

Approximately 80% of patients with the clinical characteristics of MELAS have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the transfer RNA (tRNA)^{Leu (UUR)} gene at base pair (bp) 3243 (ie, 3243 A®G mutation). However, other mitochondrial DNA (mtDNA) mutations are observed, including the 3244 G®A, 3258 T®C, 3271 T®C, and 3291 T®C in the mitochondrial tRNA^Leu(UUR) gene.

The pathogenesis of the strokelike episodes in MELAS has not been completely elucidated. These metabolic strokelike episodes may be nonvascular and due to transient oxidative phosphorylation (OXPHOS) dysfunction within the brain parenchyma. A mitochondrial angiopathy of 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 in patients with MELAS may be due to both parenchymal and vascular OXPHOS defects. Increased production of free radicals in association with an OXPHOS defect leading to vasoconstriction may offset the effect of potent vasodilators (eg, nitric oxide).

The unusual strokelike episodes and higher morbidity observed in MELAS syndrome may be secondary to alterations in nitric oxide homeostasis that cause microvascular damage. Nitric oxide can bind the cytochrome c oxidase–positive sites in the blood vessels present in the CNS, displacing heme-bound oxygen and resulting in decreased oxygen availability in the surrounding tissue and decreased free nitric oxide.

Mutations in this disorders affect mitochondrial tRNA function, leading to the disruption of the global process of intramitochondrial protein synthesis. Measurements of respiratory enzyme activities in intact mitochondria have revealed that more than one half of the patients with MELAS may have complex I or complex I + IV deficiency. A close relationship appears to exist between MELAS and complex I deficiency. The decreased protein synthesis may ultimately lead to the observed decrease in respiratory chain activity by reduced translation of UUG-rich genes such as ND6 (component of complex I).

Frequency

United States

No estimates concerning the prevalence of the common MELAS mutation are available for the North American population; however, the syndrome has been observed to be less frequent in African Americans.

International

The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the 3243A®G mutation in the adult Finnish population. If the assumption is made that all first-degree maternal relatives of a verified mutation carrier also harbor the mutation, prevalence increases to more than 16.3 per 100,000. This high prevalence suggests that mitochondrial disorders may constitute one of the largest diagnostic categories of neurogenetic diseases among adults. In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.

Mortality/Morbidity

The progressive disorder has a high morbidity and mortality. The encephalomyopathy, associated with strokelike episodes followed by hemiplegia and hemianopia, is severe. Focal and general convulsions may occur in association with these episodes.

Other abnormalities that may be observed are ventricular dilatation, cortical atrophy, and basal ganglia calcification. Mental deterioration usually progresses after repeated episodic attacks. Psychiatric abnormalities and cognitive decline (eg, altered mental status, schizophrenia) may accompany the strokelike episodes. Myopathy may be debilitating. The encephalopathy may progress to dementia; eventually, the clinical course rapidly declines, leading to severe disability and premature death.

Another cause of high mortality is the less common feature of cardiac involvement, which can include hypertrophic cardiomyopathy and conduction abnormalities, such as atrioventricular blocks or Wolff-Parkinson-White syndrome. Some patients may develop Leigh syndrome (ie, subacute necrotizing encephalopathy). Patients may develop renal failure due to focal segmental glomerulosclerosis.

More rarely, these patients may exhibit severe GI dysmotility and hypothalamic pituitary dysfunction.

Race

No predilection for a particular ethnic group exists.

Sex

No sexual predilection exists.

Age

In many patients with MELAS, presentation occurs with the first strokelike episode, usually when an individual is aged 4-15 years. Less often, onset of disease may occur in infancy with delayed developmental milestones and learning disability. One presentation of the disorder was reported in a 4-month-old infant.

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