Myoclonic Epilepsy and Ragged Red Fibers Syndrome

The majority of cases of MERRF syndrome have a heteroplasmic G to A point mutation at bp8344 in the tRNALys gene.y This results in protein synthesis defects involving primarily complexes I and IV, which have the greatest number of mtDNA coded subunits. Any quantitative measure of energy metabolism-- y P-NMR, anerobic threshold determination, or biochemical analysis of skeletal muscle--shows decreased ATP-generating capacity. When mutant mtDNAs exceed 85 percent in a tissue, the patient becomes symptomatic. Neuropathology shows degeneration of cerebellar cortex, substantia nigra, dentatorubral and pallidoluysian systems, locus ceruleus, inferior olivary nucleus, and pontine tegmentum.

The exact incidence is not known. Familial occurrence with maternal inheritance, usually before age 20, is the rule. Commonly, symptoms and signs overlap among MERRF, mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS), and Kearns-Sayre syndrome (KSS).

The classic presentation is usually in late childhood, although it may begin in early adulthood, with progressive myoclonic epilepsy, ataxia, and action-induced polymyoclonus. Weakness and hypotonia due to a mitochondrial myopathy and a progressive dementia follow. Hearing loss may be associated. This presentation resembles the historical Ramsay Hunt syndrome of dysergia cerebellaris myoclonica.

MERRF is differentiated clinically from MELAS (see next section) by the lack of strokelike episodes in MERRF. Benign essential familial myoclonus is nonprogressive. The principal differential is with other causes of progressive myoclonic epilepsy in late childhood/early adolescence. These are storage diseases--neuronal ceroid lipofuscinosis (Kufs' type) and neuraminidase deficiency (sialidosis type 1); diseases of unknown etiology--Lafora's disease, Baltic myoclonus; and slow virus and prion diseases--subacute sclerosing panencephalitis and early-onset spongiform encephalopathy.

Tests to be ordered include serum and CSF lactate, pyruvate, and alanine levels; EEG and visual evoked potentials; MRI of the brain, which often shows areas of increased intensity in T2-weighted sequences; y P-NMR of muscle; muscle biopsy for biochemical tests of oxidative phosphorylation and for visualizing ragged red fibers, by light microscopy using the Gomori's trichrome stain, and by electron microscopy; and mtDNA analysis, looking for the MERRF and MELAS point mutations.

Seizures can be symptomatically treated with valproate (watching for carnitine deficiency) and clonazepam. There is a dearth of data as to whether measures for refractory myoclonic epilepsy--ketogenic diet, adrenocorticotropic hormone or corticosteroids, or L-5-hydroxytryptophan plus carbidopa--have been effective. Corticosteroids have been used for the myopathy and improvement has been noted,

but this is not generally recommended at present. Because coenzyme Q10 improves electron transfer from complex I and riboflavin serves as a cofactor for electron transport in complex I (and II), these agents are reasonable to try (see Fig. 31-4 (Figure Not Available) ). Use of vitamin K (menadione and phytonadione) has less rationale.

The course is chronic and slowly progressive. Different family members may become symptomatic, with different phenotypes, at different ages, depending on the percentage of the mutant DNA in muscle and brain. It would be important for all maternal relatives to have blood analyses for the mutant DNA and, if negative on muscle, to determine the risk of becoming symptomatic with age. Prenatal diagnosis by amniocentesis or chorionic villus sampling for mtDNA point mutations is unreliable presently because the genotype of that tissue may not reflect that of the embryo's muscle and brain.

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