Rolandic epilepsy and other genetic focal childhood epilepsies, some occurring with focal cortical dysplasia, are part of the phenotypic spectrum of inherited focal epilepsy syndromes caused by mutations in the recently described DEPDC5 gene, according to studies on families and unrelated individuals with the disorders by two separate groups of investigators.
The researchers described truncating and nonsense mutations in DEPDC5 (Dishevelled, Egl-10, and Pleckstrin-domain-containing protein 5) that would likely prevent its encoded protein from being translated or cause it to lose its functional abilities, as well as missense mutations, which were of uncertain significance. However, these mutations appeared to have low penetrance in some instances in the families of affected index patients.
DEPDC5 is a member of a complex of proteins involved in controlling mTOR (mammalian target of rapamycin) signaling, which regulates processes involved in cell growth and homeostasis and is involved in other forms of epilepsy, such as tuberous sclerosis. Individuals with mutations in DEPDC5, which normally acts as a repressor of mTOR activity, could be responsive to treatment with drugs in the rapamycin family of drugs, such as sirolimus, according to study investigators.
Dr. Bernd A. Neubauer
In one study, senior investigator Dr. Bernd A. Neubauer and first author Dennis Lal, Ph.D., of the department of neuropediatrics at University Medical Center Giessen and Marburg, Germany, and their colleagues reported finding five DEPDC5 mutations in 207 patients with rolandic epilepsy (also known as benign epilepsy with centrotemporal spikes). In all, 87 of these patients were index patients in families with at least two affected siblings, and 120 were unrelated. The 87 index patients from multiplex families had either rolandic epilepsy (72), an atypical form of rolandic epilepsy (12), or electrical status epilepticus of sleep (3). The investigators also found two mutations in 82 unrelated patients with genetic focal or cryptogenic epilepsy who had variable degrees of intellectual disability and had been referred to centers in the study for diagnosis (Ann. Neurol. 2014 March 1 [doi: 10.1002/ana.24127]).
The researchers tracked the segregation of the mutations in families of six of the seven patients in whom DEPDC5 mutations were discovered. In one family, 4 of 18 carriers of a mutation were affected by rolandic epilepsy (one with centrotemporal spikes without seizures, and two with focal genetic epilepsy with centrotemporal spikes that persisted into adulthood). Another family had four members with unclassified focal childhood epilepsies, one of whom had a "relatively benign course." The father of the index individual in another family was homozygous for DEPDC5 mutations but was unaffected. But throughout all the families, those who had seizures carried a mutation in DEPDC5.
The other study described a family with six affected males with focal epilepsy and a truncation mutation in DEPDC5. Frontal focal cortical dysplasia was present in two of the affected individuals in the family, as well as in two other patients from the original two families in whom mutations in DEPDC5 were first described (Nat. Genet. 2013;45:546-51).
Magnetic resonance imaging showed in three of the individuals a bottom-of-the-sulcus dysplasia in a distinct region of the frontal lobe. In the fourth individual, there was unilateral, subtle band heterotopia in the white matter adjacent to dysplastic cortex in the left frontal lobe, Dr. Ingrid E. Scheffer of the Epilepsy Research Centre at the University of Melbourne and her associates reported (Ann. Neurol. 2014 March 1 [doi: 10.1002/ana.24126]).
Dr. Ingrid E. Scheffer
"The concept that a single gene mutation may produce nonlesional focal epilepsy in one family member and focal cortical dysplasia in another challenges previous notions of the separation of genetic malformation syndromes from nonlesional epilepsy syndromes," the authors wrote, making one wonder whether more powerful imaging techniques could detect subtle dysgenesis in the patients without dysplasia detected by MRI. They noted that while "rare individuals with genetic malformation syndromes have no visible lesion on imaging (e.g., mildly affected subjects with DCX mutations), the inverse, where a proportion of subjects with a genetic epilepsy syndrome have a subtle malformation, has not previously been described."
Dr. Lal’s and Dr. Neubauer’s study was funded by grants from the EuroEPINOMICS Programme within the European Science Foundation. The study by Dr. Scheffer and her colleagues was supported by the National Health and Medical Research Council of Australia. No financial disclosures were made.