Early-Onset Progressive Myoclonic Epilepsy With Dystonia Mapping to 16pter-p13.3

Abstract

The authors present three patients from a consanguineous family afflicted with novel recessive myoclonic epilepsy characterized by very early onset and a steadily progressive course. The onset is in early infancy, and death occurs in the first decade. In addition to various types of myoclonic seizures, episodic phenomena such as dystonias, postictal enduring hemipareses, autonomic involvements, and periods of obtundation and lethargy were also observed. Developmental and neurological retardation, coupled with systemic infections, leads to a full deterioration. The authors designated the disease progressive myoclonic epilepsy with dystonia (PMED). A genome scan for the family and subsequent fine mapping localized the gene responsible for the disease to the most telomeric 6.73 mega base pairs at the p-terminus of chromosome 16, with a maximum multipoint logarithm-of-odds score of 7.83 and a maximum two-point score of 4.25. A candidate gene was analyzed for mutations in patients, but no mutation was found.

Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability

“…Several patients had a more severe neurological presentation (Corbett et al, 2010;Milh et al, 2013;Duru et al, 2010;Stražišar et al, 2014). Corbett et al reported a large consanguineous family with seven affected individuals, who were described as having focal seizures with prominent eye blinking, as well as facial and limb jerking, which started at two months of age and persisted throughout life (Corbett et al, 2010;Afawi et al, 2013).…”

“…EEG data were not reported. Other mutations in TBC1D24 have been found in three families with devastating infantile epileptic encephalopathy (Milh et al, 2013;Duru et al, 2010;Stražišar et al, 2014). In the first one, the patients had long-lasting myoclonic seizures that were exacerbated by common infections and that did not respond to medication, with neurological deterioration (Duru et al, 2010).…”

TBC1D24truncating mutation resulting in severe neurodegeneration

“…A patient that was given an ocular examination during late-stage disease had bilateral optic atrophy, macular degeneration, dilated pupils, and no light response. MRI findings in another patient were diffuse moderate cerebral atrophy and ventricular enlargement at 14 months of age, and severe diffuse cerebral atrophy with secondary ventricular enlargement at 37 months, indicating significant progression of the encephalopathy 7. In contrast, MRI findings in the Italian patients were normal 5.…”

“…We previously mapped to 16pter-p13.3 a severe disease characterised by early onset progressive encephalopathy associated with myoclonic epilepsy with dystonia, and developmental and neurological retardation that led to full deterioration and death during the first decade of life 7. The patients did not respond to medication.…”

Epilepsy genetics: The ongoing revolution

“…Ten years after the disease locus mapping on chromosome 16p13.3, compound heterozygous mutations have been found in TBC1D24 by targeted NGS in the affected individuals from the FIME family [174]. Additional mutations in this gene have been reported recently, thanks to WES, in patients with different clinical presentations: most of them had a more severe neurological presentation than that observed in FIME, including MPSI [128,[175][176][177]. Mutations of TBC1D24 were also recently demonstrated to be the major cause of deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome [178].…”