Mitochondrial Encephalopathy Lactic Acidosis and Strokelike Episodes

About 80 percent of MELAS patients exhibit a heteroplasmic A to G point mutation in the dihydrouridine loop of the tRNA Leu(UUR) gene at mt3243.y Two other mutations in the same gene, at mt3250 and mt3271, have been identified in the remaining cases. The MELAS3243 mutation alters the dihydrouridine loop of the tRNALeu(UUR) gene and changes a nucleotide at the binding site for a nuclear DNA encoded transcription termination factor. It is hypothesized that the mutation reduces the binding affinity of the transcription termination factor. Another possibility is that this mutation impairs protein synthesis by interfering with polypeptide chain elongation. The cerebral infarcts are nonvascular, owing to transient dysfunction of oxidative phosphorylation within parenchyma. Areas of neuronal loss, demyelination, and astrocytic proliferation are found in the infarct-like brain areas. PET studies show reduced cerebral metabolic rates for oxygen but normal glucose utilization. Mitochondrial abnormalities of endothelial cells and smooth muscle cells produce a mitochondrial angiopathy. The vascular metabolic dysfunction may cause increased production of free radicals, which could damage vasodilators such as nitrous oxide, causing vasoconstriction.

The exact incidence is unknown. Most cases occur before age 20, and about a fourth of patients have a positive family history consistent with maternal inheritance.

Patients may present sporadically or in maternal pedigrees, in infancy, childhood, or adulthood. The overall course is of a progressive degenerative disease with strokelike episodes and a mitochondrial myopathy. Various symptoms appear singly or in combination and include hemiplegia, sudden cortical blindness, hemianopia, episodes of confusion and hallucination with fever, aphasia, migraine headaches in a maternal lineage preceding strokelike episodes, and maternally inherited diabetes mellitus type II and deafness. Multisystem complaints and signs include myalgia, fatigability, weakness, ophthalmoplegia, pigmentary retinal degeneration, cardiomyopathy, cardiac conduction defects and block, dementia, deafness, ataxia, myoclonus, seizures, lactic acidosis, and proximal renal tubule dysfunction.

Conditions to exclude include any other causes of stroke in childhood, infancy, or adulthood; other mitochondrial multisystem disorders, such as MERRF or KSS/chronic progressive external ophthalmoplegia (CPEO), or other uncharacterized disorders; and any neurological disease in adulthood with an overall progressive course but relapses that leave residuals, such as multiple sclerosis or other demyelinating diseases.

In the general diagnostic approach (see Fig. 31-4 (Figure Not Available) ), the best diagnostic clues are found on CT and MRI, which show cortical infarcts that are not wedge shaped but cut across several vascular territories, usually located in the posterior quadrants initially. Basal ganglia calcifications, in particular, occur and are seen better by CT than MRI. Ventricular dilation and cortical atrophy are also seen. With a history of strokelike episodes, these neuroimaging findings, associated with lactic acidosis and a myopathy, should strongly suggest the diagnosis. Functional neuroimaging studies, such as SPECT using N-isopropyl- p-[123 I]-iodoamphetamine (IMP) tracer can detect regional hypoperfusion when structural studies (CT, MRI) are unrevealing. SPECT is useful not only in delineating the lesion but also in following the course. Analysis of mtDNA for the known point mutations on blood and muscle confirms the diagnosis.

Coenzyme Q10 in doses up to 300 mg/day may be needed for optimal benefit, starting at 4.3 mg/kg/day. Corticosteroids and a novel quinone not available in the United States, idebenone, have shown some benefit. MELAS is a progressive neurodegenerative disease with a guarded prognosis.

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