Background: Mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS) is a progressive neurodegenerative disorder. Patients may present as sporadic cases 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 diabetes mellitus and hearing loss, clearly are part of the disorder.
Pathophysiology: MELAS is characterized by strokelike episodes and a mitochondrial myopathy. Organ systems included in the multisystemic involvement 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 (ie, A3243G mutation). The strokelike 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 (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. The effect of potent vasodilators (eg, nitric oxide) may be offset by increased production of free radicals in association with an OXPHOS defect leading to vasoconstriction.
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 defect in complex I currently is the best candidate for the underlying biochemical abnormality induced by the mitochondrial deoxyribonucleic acid (mtDNA) mutation in MELAS.
Frequency:
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In the US: In adult populations, the frequency of the A3243G mutation approximates 16.3 per 100,000. No estimates about the incidence of the disease are available. |
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Internationally: The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the A3243G 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. No information is available regarding frequency of the mutation in other populations. |
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 that are associated with infarcts may occur in 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 (eg, altered mental status, schizophrenia) may accompany the strokelike episodes. Myopathy may be very debilitating. The encephalopathy may progress to dementia, and eventually the patient may become quite cachectic and die.
Another cause of high mortality is the less common feature of cardiac involvement. Causes can be a hypertrophic cardiomyopathy and conduction abnormalities, such as atrioventricular blocks or Wolff-Parkinson-White syndrome. Some patients may have the presentation of Leigh syndrome (ie, subacute necrotizing encephalopathy). Patients may go into renal failure due to focal segmental glomerulosclerosis.
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. (Nicholas' case)
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Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance. |
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MELAS onset may occur early in infancy with a history of developmental delay and learning disabilities. Developmental delay, learning disability, or attention deficit disorder mainly is found in patients prior to the development of the first stroke. An encephalopathic picture that is progressive and leads to dementia may be present. Patients may be apathetic. |
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Failure to thrive may be the presenting feature in some patients with MELAS. |
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Strokelike episodes are the hallmark feature of this disorder. Episodes initially may manifest with vomiting and headache that may last up to several days. These patients also may be affected with episodes of seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic. |
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Migraine or migrainelike headaches observed in these patients also may reflect the strokelike episodes. Pedigrees of patients with classic MELAS identify many members whose only manifestations are migraine headaches. |
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Patients may have visual complaints due to ophthalmoplegia, and they may experience blindness due to optic atrophy and difficulties with night vision due to pigmentary retinopathy. |
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Some patients may experience hearing loss, which may accompany diabetes. It may be observed in association with the classic disorder of MELAS. |
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Polydipsia and polyuria may be the presenting signs of diabetes, which appears to be the most common manifestation of MELAS. Usually, type II diabetes is described in individuals with MELAS, although type I or insulin-dependent diabetes also may be observed. |
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Palpitations and shortness of breath may be present in some patients with MELAS secondary to cardiac conduction abnormalities such as Wolff-Parkinson-White syndrome. Patients may experience shortness of breath secondary to cardiomyopathy, which usually is of the hypertrophic type; however, dilated cardiomyopathy also has been described. |
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Acute onset of gastrointestinal manifestations (eg, acute onset of abdominal pain) may reflect pancreatitis, ischemic colitis, and intestinal obstruction. |
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Numbness, tingling sensation, and pain in the extremities can be manifestations of peripheral neuropathy. |
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Psychiatric disorders (eg, depression) can be associated with the A3243G mutation. Dementia has been another clinical manifestation. |
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Oliguria can be associated with MELAS and can indicate the onset of nephrotic syndrome. |
Physical:
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Myopathy presents with hypotonia and weakness on physical examination. Proximal muscles tend to be more involved than distal muscles. Musculature is thin, and patients may present with a myopathic face. |
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Strokelike episodes may present with convulsions, visual abnormalities, numbness, hemiplegia, and aphasia. Episodes may be followed by transient hemiplegia or hemianopia lasting a few hours to several weeks. |
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Additional features on the neurologic examination may include ataxia, tremor, myoclonus, dystonia, visual disturbances, and cortical blindness. Some patients may present with ophthalmoplegia and ptosis. |
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On ophthalmologic examination, patients have presented with pigmentary retinopathy. |
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Sensorineural deafness has been reported as part of the disorder in approximately 25% of patients with MELAS. |
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Cardiomyopathy with signs of congestive heart failure (CHF) also may be observed in the physical examination. |
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Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS. |
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Short stature may be the first manifestation of MELAS in many patients. |
Causes: MELAS has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNALeu (UUR) gene in MELAS. The most common mutation, found in 80% of individuals with MELAS, is an A-to-G transition at nucleotide (nt)-3243 in the tRNALeu (UUR) gene. An additional 7.5% have a heteroplasmic T-to-C point mutation at base pair (bp) 3271 in the terminal nucleotide pair of the anticodon stem of the tRNALeu (UUR) gene.
These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS reflects variable segregation in the ovum. Mutations in tRNALys may be expected to have an important effect on translation and protein synthesis in mitochondria. The MELAS disorder–associated human mitochondrial tRNALeu (UUR) mutation causes aminoacylation deficiency and a concomitant defect in translation initiation.
Patients with MELAS disorder have been found to have a marked decrease in the activity of complex I. The major effects observed secondary to nt-3243 and nt-3271 mutations have been a reduction in protein synthesis and the activity of complex I. These effects have been demonstrated studying cybrids by fusing human cell lines without mtDNA with exogenous mitochondria containing 0-100% of the common 3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.
