Mitochondrial Encepalopathy, Lactic Acidosis And Stroke Like Episodes

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Mitochondrial encephalopathy, lactic acidosis and stroke like episodes - abbreviated to MEALS - is one of the family of mitochondrial encephalopathies, which also include MERRF, and Leber's Optic Hereditary Atrophy. A feature of this disease is that they are caused by defects in mitochondrial genome which is inherited purely from the female parent. The disease can manifest in both sexes.

PRESENTATION

MELAS is condition that affects many parts of the body, mainly the brain and nervous system (encephalo) and muscle (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).

Most people with MELAS have a buildup of lactic acid in their body, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly peoples with MELAS experience involuntary muscle spasms (myoclonus), impaired muscle co-ordination (ataxia), hearing loss, heart and kidney problems, diabetes, epilepsy and hormonal imbalance.

The presentations of some cases are similar to Kearns-Sayre syndrome.

(a) A computed tomography brain scan showing bilateral basal ganglia calcification; the cerebellum shows prominent folia indicating mild cerebellar atrophy. (b) Axial T2 brain magnetic resonance image scan showing left temporo-parieto occipital ischemic lesion. (c) Axial T2 brain magnetic resonance image scan showing the extension of the parietal temporal region to the occipital lobe, and also showing a right occipital lesion. (d) Magnetic resonance spectroscopy showing inversion of J-coupling phenomenon at 1.3 ppm, indicating lactate peak

PATHOPHYSIOLOGY

Approximately 80% of patients with clinical characteristics of MELAS syndrome have a heteroplasmic A- to- G point mutation in dihydrouridine loop of tRNA at base pair (bp) 3243. However other mitochondrial DNA mutations are observed, including the m.3244 G → A, m.3258 T → C, m.3271 T → C, and m.3291 T → C in the mitochondrial tRNALeu (UUR) gene.

The pathogenesis of stroke like episodes in the syndrome has not been completely elucidated. This metabolic stroke like episodes may be non vascular and due to transient oxidative phosphorylation (OXPHOS) dysfunction with in the brain parenchyma. A mitochondrial angiopathy of small vessels is responsible for contrast enhancement of affected region and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction of patient with MELAS syndrome is because of both parenchyma and vascular OXPHOS defects. Increased production of free radicals is due to the OXPHOS defect leading to vasoconstriction may offset the effect of potential vasodilator (nitric oxide).

The stroke like episodes and high morbidity seen in MELAS syndrome is associated with the alteration in nitric oxide homeostasis causes micro vascular damage. Nitric oxide can bind with cytochrome c oxidase- positive sites in blood vessels present in the CNS and this will displace the oxygen bound heme and causes defect in oxygen in the surrounding tissues and decreases free nitric oxide. Coupling of the vascular mitochondrial dysfunction with cortical spreading depression might underlie the selective distribution of ischemic lesions in the posterior cortex in these subjects.

Modified Gomori trichrome stain showing several ragged red fibers (arrowhead). (b) Cytochrome c oxidase stain showing Type-1 lightly stained and Type II fibers, darker fibers, and a few fibers with abnormal collections of mitochondria (arrowhead). Note cytochrome c oxidase negative fibers as usually seen in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). (c) Succinate dehydrogenase staining showing a few ragged blue fibers and intense staining in the mitochondria of the blood vessels (arrow). (d) Electron microscopy showing abnormal collection of mitochondria with paracrystalline inclusions (arrowhead), osmiophilic inclusions (large arrowhead) and mitochondrial vacuoles (small arrowhead).

GENECTICS

MELAS is caused by mutation in the genes in mitochondrial DNA.

NADH Dehydrogenase

Some of the genes (MT-ND1, MT-ND5) related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are the part of large enzyme complex (NADH dehydrogenase, also called complex I) in the mitochondria that converts free oxygen and sugar to energy.

TRANSFOR RNAs

Other genes (MT-TH, MT-TL1, and MT-TV) associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

INHERITANCE

This condition is inherited in mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance is applied to genes contained in mitochondrial DNA. Because egg cells not the sperm cells contribute mitochondria to the developing embryo, only female pass mitochondrial condition to their children. Mitochondrial disorders can appear in every generation of the family and can affect both male and female, but fathers do not pass their mitochondrial traits to their children. In most cases people with MELAS syndrome inherit an altered mitochondrial gene from their mother. Less orderly the disease generate from new mutation in the mitochondrial gene and occurs in patients with no family history of MELAS.

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