The syndrome of myoclonus epilepsy with ragged red fibers (MERRF) has emerged as one of the most common causes of PME. It may be familial or sporadic, and its clinical features and severity are extremely variable.
Myoclonus epilepsy with ragged red fibers was first described in cases with a florid clinical myopathy and myoclonus epilepsy (22, 23). It is now clear that the clinical spectrum of MERRF is extremely broad. It should be suspected in a wide variety of situations, even when clinical and pathologic evidence of myopathy are absent (24). Symptoms may begin at any age, and there may be marked intrafamily variation in the age of onset and clinical severity (24, 25). The clinical features include myoclonus, tonic-clonic seizures, dementia, and ataxia, with less common findings of myopathy, neuropathy, deafness, and optic atrophy. Some cases show striking axial lipomas. Occasional patients or families have focal neurologic events, and there is an overlap with the syndrome of mitochondrial encephalomyopathy, lactic acido-sis, and strokelike episodes (MELAS), in which strokelike episodes, frequently preceded by migrainous headaches with vomiting, are characteristic.
The EEG shows slowly progressive background slowing, paralleling the degree of clinical deterioration. There are generalized spike-and-wave discharges at 2-5 Hz or multiple spike-and-wave discharges. Sporadic occipital spikes and sharp waves may be seen. Prominent photosensitivity may occur. Non-REM sleep is disorganized, and spike-and-wave discharges are diminished (11, 26).
Virtually all familial cases of MERRF are transmitted through the maternal line and are examples of mitochon-drial inheritance (25). The peculiarities of mitochondrial inheritance provide an explanation for the wide pheno-typic variability in patients with MERRF and the extraordinary intrafamily variation.
A single base substitution at nucleotide pair 8344 of mitochondrial DNA, causing an A-to-G substitution in the tRNALys gene, occurs in many familial cases of MERRF (27). The fact that this mutation affects tRNA rather than a gene for a respiratory enzyme probably explains the heterogeneous results for respiratory enzyme assays reported in MERRF. This tRNALys mutation has been confirmed in numerous laboratories around the world and appears to underlie most but not all familial cases and some sporadic examples of MERRF. Other rare identified molecular causes of MERRF are mutations at nucleotides 8356 and 8363 in the same tRNALys (28, 29) and mutations in tRNASer (30), but in some cases no molecular defect has been found. Recently, autosomal recessive mutations in the nuclear encoded mitochondrial gene polymerase gamma (POLG) have been identified in some MERRF cases (31).
Diagnosis can usually be suspected clinically but may be difficult to confirm with laboratory markers. The clinical clues to the diagnosis include deafness, optic atrophy, myopathy, lipomas, intrafamily variation in age of onset and severity, and a pattern of inheritance compatible with maternal transmission. Serum lactate, ragged red fibers, and respiratory enzyme activities in muscle can all be normal in patients known to be affected (e.g., family members of proven cases). Magnetic resonance spectroscopy (MRS) of muscle may show elevated levels of inorganic phosphate and a decrease of the phosphocreatine:inorganic phosphate concentration ratio (32). When present, molecular defects in mitochondrial DNA can be detected in peripheral blood or muscle (33, 34).
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