Myoclonus Epilepsy and Ragged-Red Fibres (Merrf)

Abstract

Thirteen patients, including 6 from one family, with the syndrome of myoclonus epilepsy and ragged-red fibres (MERRF) were studied. There was considerable heterogeneity in the age of onset, severity and associated clinical features. Postmortem studies in 3 patients from the one family showed a particular system degeneration. In addition, the youngest and most severely affected family member showed the pathological changes of Leigh's syndrome. Cortical dysfunction is a prominent clinical feature in MERRF, but postmortem examination failed to reveal cortical abnormalities. Positron emission tomographic studies, however, showed decreased cortical metabolic rates for glucose and oxygen utilization, with normal cortical blood flow and cerebral pH. Analyses of kinetic rate constants for uptake and phosphorylation of the glucose analogue, fluorodeoxyglucose showed decreased hexokinase-mediated phosphorylation: normal K1 and k2 values but reduced k3. Phosphorus magnetic resonance spectroscopy studies suggested a normal cerebral intracellular pH. Biochemical studies on muscle homogenates in 6 patients showed partial deficiencies of the activities of certain mitochondrial enzymes in 4 cases, whereas in 2 patients no abnormality was found. Our data, combined with previous reports, show that MERRF is biochemically and genetically heterogeneous. Our experience, and analysis of the literature, suggests that many cases previously described as the Ramsay Hunt syndrome, as well as other hitherto unclassified system degenerations associated with myoclonus epilepsy, are examples of MERRF. These data permit the formulation of a hypothesis to explain the clinical, biochemical and genetic heterogeneity of MERRF, and its overlap with Leigh's syndrome. We suggest that different biochemical defects of the mitochondrial respiratory chain may cause similar cerebral metabolic effects, as measured by positron emission tomography, resulting in similar phenotypes. Reduced activity of one enzyme, however, may result in different phenotypes, depending on the severity of the defect and its tissue distribution. Moreover, the phenotypic expression of certain biochemical defects may be influenced by randomly occurring factors such as fever, which may increase metabolic demand and result in more deleterious cellular metabolic effects.

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

“…Partial seizures are most commonly found in mitochondrial encephalopathies, such as MELAS associated with mutations in the tRNA Leu gene 8,9,33,34 . In MERRF, myoclonus are clinically indistinguishable from those presented by patients with other myoclonic diseases (irregular rhythm, which may increase with movement or stimuli), but their pathogenesis has not been fully elucidated, most likely because, like most of the diseases that cause myoclonus, there are multiple affected structures in the CNS.…”

“…In MERRF, myoclonus are clinically indistinguishable from those presented by patients with other myoclonic diseases (irregular rhythm, which may increase with movement or stimuli), but their pathogenesis has not been fully elucidated, most likely because, like most of the diseases that cause myoclonus, there are multiple affected structures in the CNS. Regarding the type of myoclonus and its origin in the central nervous system, there is substantial evidence indicating the occurrence of more cortical myoclonus than subcortical type, although both may occur in patients with MERRF 34 . Cerebellar ataxia is one of the most common clinical manifestations of MERRF and is supportive of the diagnostic criteria of MERRF, occurring in up to 83% of cases 6,35 .…”

“…Cerebellar ataxia is one of the most common clinical manifestations of MERRF and is supportive of the diagnostic criteria of MERRF, occurring in up to 83% of cases 6,35 . The presence of manifestation cerebellar ataxia is an important indicator in patients with MERRF, although it may not be present in the early phase of the disease 27,34 . However, clinical and radiological findings in patients with MERRF vary and may suggest spinocerebellar degeneration, especially in early phase of the disease 36 .…”

“…MERRF preferentially involves the inferior olivary nucleus, cerebellar dentate nucleus, red nucleus and pons of the brainstem, as well as the gray matter 22,34,37 . Conventional imaging studies of the brain, such as computed tomography or magnetic resonance imaging, have confirmed that the gray matter is altered early on in patients with MERRF, while changes in the white matter can be seen more often in the later stages of the disease and are never an isolated finding 37,38 .…”

Epilepsy in adults with mitochondrial disease: A cohort study

“…Focal and generalized status epilepticus can occur in association with these stroke‐like episodes. In other syndromes, for example, M yoclonic E pilepsy with R agged R ed F ibers, usually as a result of the m.8344A>G point mutation, epilepsy is one of the defining clinical features and typically manifests as generalized myoclonus with photosensitivity 11, 12, 13, 14. As with other clinical features, the type of epilepsy found only partially reflects the underlying genotype, with a large degree of overlap found between syndromes 15, 16…”