Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of benign adult familial myoclonic epilepsy, BAFME, autosomal dominant cortical myoclonus and epilepsy, benign adult familial myoclonic epilepsy, familial adult myoclonic epilepsy, and familial cortical myoclonic tremor and epilepsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Benign adult familial myoclonic epilepsy is an inherited epileptic syndrome characterized by cortical hand tremors, myoclonic jerks, and rare convulsive seizures. In most affected individuals, the disease takes a benign course; however, at an advanced age, worsening of the tremor and myoclonus is common, and slight intellectual disability is present in a subset of patients. Prevalence is unknown but is estimated to be less than 1 out of 35,000. It is transmitted autosomal dominantly, and penetrance is high. This is a well-delineated disease with remarkable features that clearly distinguish it from other forms of myoclonic epilepsies. Genetic studies of the families show heterogeneity, and different susceptible chromosomal loci have been identified. Diagnosis is based on clinical and electrophysiological findings. It must be differentiated from epilepsy syndromes with prominent myoclonus features. Valproate, levetiracetam, and benzodiazepines are the most beneficial treatments.
• Benign adult familial myoclonic epilepsy usually presents in the second decade of life with a mild hand tremor that is myoclonus-exacerbated by fatigue or emotional stress. Myoclonus usually appears around the same age and consists of erratic, arrhythmic, segmental jerks of the upper limbs heightened by posture and action. Rare or sporadic bilateral tonic-clonic seizures are also a manifestation and are often precipitated by photic stimulation, emotional stress, and sleep deprivation.
• Diagnosis is based on clinical and electrophysiological findings. EEG findings include a photomyoclonic response along with abnormality of polyspikes and waves. Patients also display extremely enlarged cortical components of somatosensory-evoked potentials and an enhanced C-reflex. Jerk-locked average analysis reveals positive-negative, biphasic spikes preceding myoclonus.
• Benign adult familial myoclonic epilepsy is transmitted autosomal dominantly, and it must be differentiated from idiopathic epilepsy syndromes with prominent myoclonus features (eg, juvenile myoclonic epilepsy syndrome) and from progressive myoclonus epilepsies.
• Valproate, levetiracetam, and benzodiazepines are the most beneficial treatments. Convulsive seizures are rare and usually responsive to therapy.
The term “cortical tremor” was introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands mimicking essential tremor but showing the electrophysiological findings of cortical reflex myoclonus, that is: (1) brief EMG burst of about 50 msec duration; (2) no definite synchronization or reciprocity in antagonist muscles; (3) positive spikes preceding EMG bursts at the jerk-locked averaging; (4) enlarged cortical components of somatosensory-evoked potentials; (5) enhanced long-loop reflex I (or C-reflex) (15).
Uyama and colleagues first reported a patient with adult-onset fine finger tremulous movement, myoclonic jerks, and 2 generalized seizures coming from a family that was affected with the same condition through 3 generations with high penetrance (40). None of the patients showed other neurologic signs nor abnormal neuroradiological findings; electrophysiological study indicated cortical reflex myoclonus. Subsequently, the same group reported 4 unrelated families, including 27 affected members through 3 generations with high penetrance (39). In 1991, Yasuda used the term "benign adult familial myoclonic epilepsy" (BAFME) to describe 2 pedigrees in which affected members showed autosomal dominant hand tremor, myoclonus, and epileptic seizures with a nonprogressive course (45). Also, in these patients, electrophysiological studies showed evidence of cortical reflex myoclonus. In 1999, Plaster and colleagues and Mikami and colleagues mapped the disease on chromosome 8q24 (27; 29).
Although this condition was exclusively reported from Japan until the 1990s, several reports on pedigrees with similar clinical features but with different genetic identifiers appeared from different European countries and worldwide over the past decade with different names, such as autosomal dominant cortical myoclonus and epilepsy, familial adult myoclonic epilepsy, familial cortical myoclonic tremor, familial essential myoclonus and epilepsy, familial benign myoclonus epilepsy of adult-onset, and familial tremor and epilepsy. Despite phenotypic and genetic differences, the clinical and electrophysiological data point toward 1 syndrome (35; 36).
Genetic studies of families have revealed a large genetic heterogeneity with different identified loci, including 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4), but a unique underlying causative mechanism, ie, pentameric intronic expansions (see section 4).
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