Myoclonus epilepsy with ragged-red fibers
Jun. 18, 2022
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This article includes discussion of autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE, autosomal dominant sleep-related hypermotor epilepsy, ADSHE, nocturnal frontal lobe epilepsy, and NFLE. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Since autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (also known as autosomal dominant nocturnal frontal lobe epilepsy; ADNFLE) was described in 1994, this dramatic disorder of motor seizures in sleep has been widely recognized. With the discovery of a mutation in the nicotinic acetylcholine receptor alpha4 subunit gene in 1 family, ADSHE became the first human epilepsy in which a gene was identified. Mutations have been found in genes encoding the nicotinic acetylcholine receptor alpha4, beta2, and alpha2 subunits. A sodium-gated potassium channel gene, KCNT1, has also been identified in severe ADNFLE, associated with intellectual disability and psychiatric features. Missense mutations in both the promoter and coding regions of CRH, the gene encoding corticotropin-releasing hormone, have been identified in ADSHE families. Mutations in mTOR regulator genes, DEPDC5, NPRL2, and NPRL3, have been identified as causes of familial focal epilepsy with variable foci, of which a subgroup of families has ADSHE.
• Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures.
• Seizures may be misdiagnosed as parasomnias, nightmares, and even hysteria.
• More severe cases may have intellectual disability and psychiatric features.
• ADSHE follows autosomal dominant inheritance with incomplete (70%) penetrance.
• ADSHE is associated with mutations of acetylcholine nicotinic receptor genes CHRNA4, CHRNB2, and CHRNA2, the sodium-gated potassium channel gene KCNT1, corticotropin-releasing hormone gene (CRH), and the genes DEPDC5, NPRL2, and NPRL3 involved in mTOR regulation.
• Some ADSHE families may be regarded as a subset of familial focal epilepsy with variable foci due to mutations in the GATOR1 genes, DEPDC5, NPRL2, and NPRL3.
In 1981, 5 patients with frequent sleep-related events were reported by Lugaresi and Cirignotta (33). These individuals had frequent stereotyped events, occurring almost every night, characterized by tonic and dystonic posturing and coarse, violent movements. The episodes all arose from stage 2 sleep, were not associated with epileptiform abnormalities on EEG, and were responsive to carbamazepine. Lugaresi and Cirignotta named this condition hypnogenic paroxysmal dystonia and suggested 3 possible underlying mechanisms. They suggested that the movements could be a form of sleep terror (ie, a benign parasomnia), a form of paroxysmal dystonia triggered by arousal from sleep (ie, a movement disorder), or a form of epilepsy arising from deep or mesial structures.
Over the next decade, further reports of this condition appeared in the literature. Although evidence for an epileptic basis was seen in some cases, in others the association with the subsequent development of Huntington disease (34) or concurrent reflex dystonia (30) suggested that nocturnal paroxysmal dystonia was in fact a movement disorder. It was hypothesized, therefore, that the condition was heterogeneous and included paroxysmal disorders with different underlying etiologies. In general, brief attacks (which tended to be more responsive to antiepileptic agents) were held to be epileptic in origin, whereas the rarer longer attacks (many of which did not respond to antiepileptic drugs) were thought to represent extrapyramidal disturbances (78). The condition became widely known as nocturnal paroxysmal dystonia.
At this time, reports were also emerging of patients with multiple, very brief, arousals from NREM sleep. These arousals caused significant sleep fragmentation and daytime somnolence, and in some cases appeared to have an epileptic basis (52; 43). In addition, the phenomenon of episodic nocturnal wanderings was described (51; 36), characterized by longer episodes of vocalization, complex and sometimes violent automatisms, and ambulation.
The nature of these episodes, particularly nocturnal paroxysmal dystonia, was widely debated (29; 08), but as more work was performed on the semiology of frontal lobe epilepsy, the similarities between nocturnal paroxysmal dystonia and frontal lobe seizures became apparent. Both conditions presented with prominent tonic and dystonic features or bizarre automatisms, were often associated with preservation of consciousness, and frequently had no associated ictal EEG changes (63; 72; 83; 81; 45). The tendency of frontal lobe seizures to occur in sleep was also recognized. These striking similarities, combined with the presence of definite epileptiform discharges in a number of nocturnal paroxysmal dystonia patients, resulted in the view of some that most (if not all) nocturnal paroxysmal dystonia cases were epileptic in origin (77; 37), and the term “nocturnal frontal lobe epilepsy” (NFLE) was coined. In 2016, the results of a consensus conference were published, proposing the name be changed to “sleep-related hypermotor epilepsy” (SHE), emphasizing the importance of sleep triggering seizure onset rather than time of day and the evidence that seizures do not always arise in the frontal lobe (76).
In 1994, Scheffer and colleagues reported a group of families from Australia, Canada, and the United Kingdom in whom SHE was inherited in an autosomal dominant fashion, thus, describing autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (68). The largest family in this study was mapped with linkage analysis to chromosome 20q (55), and a genetic mutation was subsequently identified in a nicotinic acetylcholine subunit gene (74), making ADSHE the first form of human epilepsy for which the fundamental genetic basis had been established.
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