TSC1 as a Novel Gene for Sleep-Related Hypermotor Epilepsy: A Child with a Mild Phenotype of Tuberous Sclerosis

Abstract

Sleep-related hypermotor epilepsy (SHE) is a rare syndrome that presents with hyperkinetic asymmetric tonic/dystonic seizures with vegetative signs, vocalization, and emotional facial expression, mainly during light non-rapid eye movement sleep stages. The role of various genes (CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, NPRL2, NPRL3, and PRIMA1) has previously been reported, though genetic etiology is assessed in less than 10% of cases. We report the case of a 5-year-old female carrying the TSC1 variant c.843del p.(Ser282Glnfs*36) who presented with a mild phenotype of tuberous sclerosis, including carbamazepine-responsive SHE, normal neurocognitive functioning, hypomelanotic macules, no abnormalities outside the central nervous system, and tubers at neuroimaging. The presented case extends the list of SHE-related genes to include TSC1, thus suggesting a central pathogenic role of mammalian target of rapamycin (mTOR) cascade dysfunction in SHE and introducing a possible use of mTOR inhibitors in this epileptic syndrome.

Sleep-Related Hypermotor Epilepsy: Etiology, Electro-Clinical Features, and Therapeutic Strategies

“…42 A case report suggests that SHE may also be associated with mutations in the TSC1 gene, which plays a pathogenic role in SHE through the (mTOR) pathway. 43 Recent studies in epileptic brain tissues have suggested that defective expression of circadian locomotor output cycles kaput (CLOCK), a transcription factor that regulates the circadian rhythm and mTOR pathway, may be responsible for the predisposition of epileptic seizures during sleep. 44 The genetic and structural etiologies of SHE are not mutually exclusive.…”

Nonsense mutation in DEPDC5 gene in a patient with carbamazepine-responsive focal epilepsy

“…Referencing other mTOR-pathway-related epilepsies, TS-related seizures are also noted to be carbamazepine-responsive with one large study demonstrating 55 % of TS patients were seizure-free on carbamazepine [13] . Another case-report describes carbamazepine-responsiveness in TSC1-associated SHE [14] .…”

Pathogenic genes implicated in sleep-related hypermotor epilepsy: a research progress update

“…Researchers detected the TSC1 gene mutation Ser282GInfs*36; however, despite negative paternal gene mutation test results, they were unable to determine whether the mutation was hereditary since the patient's mother was deceased. Notably, the patient's maternal aunt had a history of generalized epilepsy (26). The Ser282GInfs*36 mutation detected in TSC1 and the Arg905GIn mutation detected in TSC2 are both pathogenic variants (19,26).…”

“…Notably, the patient's maternal aunt had a history of generalized epilepsy (26). The Ser282GInfs*36 mutation detected in TSC1 and the Arg905GIn mutation detected in TSC2 are both pathogenic variants (19,26). Patients with the Ser282GInfs*36 mutation exhibited structural damage in the cerebral cortex but had a good response to medication, whereas patients with the Arg905GIn mutation did not show structural damage in the cerebral cortex but presented with refractory epilepsy.…”