Mitochondrial myopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS) 

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BACKGROUND AND CLINICAL INFORMATION: Head  

MELAS is a clinically and pathologically defined multisystem disease associated with abnormal mitochondrial functions. Characteristic pathologic features include multifocal necrosis not corresponding to any vascular territory and enlarged choroid plexus epithelial cells.

Diagnostic criteria include:

• stroke-like episode

• lactic acidosis, Ragged red fibers, or both

• at least two of the followings: seizures, dementia, recurrent headache, and vomiting.

Inheritance: Although there is maternal inheritance, familial cases are uncommon.

Clinical: MELAS is characterized by periodic stroke like episodes beginning before age 40, usually before age 15, with seizures and progressive encephalopathy leading to dementia. Patients with full expression often die before 20 years old. Hearing loss is a common onset symptom. The patients have stunt growth (short stature). Cortical blindness and hemianopia may also be seen. There is also exercise intolerance and episodic lactic acidosis. Endocrine dysfunction resulting in poor growth, infertility, and diabetes melitis may occur.

• Lactate level is always high, especially in CSF.

• Muscle biopsy: red ragged fibers are frequently seen.

Molecular biology: MELAS is often associated with specific point mutations of mitochondrial DNA (mtDNA).

Mutations:

• Most common mutation: (over 80% of cases) an A for G substitution at nucleotide 3243 in the transfer tRNALeu gene. Mutation at this site does not produce only MELAS. Leigh syndrome, MERRF, maternally inherited progressive external ophthalmoplegia (PEO), MELAS+PEO,  and mitochondrial diabetes mellitus have also been reported.

• Less common mutation: a T to C transition at nucleotide 3271 in the tRNALeu gene. Mutation at position 3291 is also common.

• Occasional mutation: A to G transition at nucleotide 11,084 in the ND4 gene. This may, however, be part of the normal polymorphism.

• Dosage effect: the likehood of developing symptomatic MELAS is related to the proportion of mtDNA that contains the mutation. The same mutation can produce very different clinical phenotypes. Differences in the mutation load and in the somatic distribution of the mutation among different cells and tissues probably produce different clinical phenotypes. The correlation between the proportion of mutation and distribution of lesion is usually poor.

• There is an inverse relationship between cytochrome c oxicase activity in red ragged fibers and the percentage of mutated mtDNA.

NEUROIMAGING: Head  

MELAS has distinctive imaging features. During the stroke-like episodes, CT and MRI reveal multifocal, predominantly cortical, infarction-like lesions. In contrast to typical ischemic strokes, these lesions are not confined to vascular territories.

• The imaging may suggest an embolic or vasculitic disease.

• Calcification may be present within the basal ganglia.

GROSS PATHOLOGY: Head  

The brain is small, atrophic, and may weigh around 800 grams. The ventricle is often enlarted. There is lamina and cystic lesions in the cerebral frontal, temporal, parietal, and occipital areas. The cerebellum is atrophic and may have multifocal necrosis. The brain stem and spinal cord appear normal. Blood vessels are grossly normal.

• The distribution of necrotic lesions does not correspond to any vascular territory.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Multifocal necrosis in the cerebral cortex and subcortical white matter. There is neuronal loss, gliosis and capillary proliferation in the necrotic areas.

Diffuse atrophy of the cerebral cortex with gliosis. The six cortical layers are preserved. The cortical atrophy tends to be more prominent in the occipital lobe but independent of the necrotic lesions.

Thalamus and basal ganglia are usually free of necrosis. They may show calcification of the vessel wall and mild gliosis.

Cerebellum: there is atrophic changes in the folia and gliosis in the white matter. The vermis is most affected. Multiple foci of necrosis are also seen. The molecular layer is thin, gliotic, and shows loss of Purkinje cells and granule cells. Segmental swelling of the dendrites of Purkinje cells, called "cactus", are also seen and is best demonstrated by immunostaining for mitochondria.

Choroid plexus: the epithelial cells appear larger than usual and contain red cytoplastic granules with Gomori's trichrome stain. These granules are stained positive with immunostaining for mitochondria. EM reveals cytoplasm packed with mitochondria.

Blood vessels: there is increase in number of mitochondria in the cytoplasm of endothelial cells and smooth muscle cells under EM [Ohama E, 1987; Sakuta R, 1989; Mizukami K, 1992; Forster C, 1992; Molnar M, 1995]. However, MELAS does not appear to be a functional disturbance of arterioles leading to an ischemic vascular event [Molnar MJ et al., 2000].

REFERENCES: Head

Kogo R et al., Acta Neuropathologica 2000 99:186

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Background    Neuroimaging    Gross Pathology    Histopathology & Immunohistochemistry  Reference