In-Depth Clinical, Genetic and Neuropsychological Study of Familial and Sporadic Cases with Sleep-Related Hypermotor Epilepsy (SHE): Identification of New Genes by Whole Exome Sequencing (WES)

Licchetta, Laura (2017) In-Depth Clinical, Genetic and Neuropsychological Study of Familial and Sporadic Cases with Sleep-Related Hypermotor Epilepsy (SHE): Identification of New Genes by Whole Exome Sequencing (WES), [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze mediche specialistiche, 29 Ciclo. DOI 10.6092/unibo/amsdottorato/8079.
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Sleep-related Hypermotor Epilepsy (SHE) is a genetically heterogeneous epilepsy syndrome. Differences in epilepsy phenotype/endophenotype were associated with mutations in specific genes. However, the genes identified so far cumulatively account for 25% of cases. Moreover, systematic neuropsychological investigations on comprehensive SHE cohorts are lacking. This study provides an accurate clinical, genetic and neuropsychological characterization of a large cohort of patients diagnosed with SHE according to reliable diagnostic criteria. A subgroup underwent a preliminary screening, partly performed by dHPLC to exclude mutations in CHRNA4, CHRNB2, CHRNA2. Using a number of genetic strategies, we identified causative mutations in 10.4% of our cases. The mutation frequencies were 2.3% for KCNT1 (CI: 0.3-8.1%), 5.9% for GATOR1-complex genes (CI: 2.0-13.3%), 3.1% for CHRNA4 (CI: 0.6-8.8%) and 1.7% for SCN1A (CI 0-8.9%). WES analysis allowed the identification of a novel epilepsy gene, NPRL2, coding a component of GATOR1, a negative regulator of mTOR pathway. Altogether, mutations in the GATOR1 complex genes DEPDC5 and NPRL2 account for the majority of our cases (6%). Genotype-phenotype correlations confirmed their association with focal cortical dysplasia, higher rates of drug-resistance, aura and seizures in wakefulness, with relevant implications in diagnostic and treatment strategies. Moreover, we confirm that mutations in KCNT1 are implicated in severe forms with intellectual disability and psychiatric disorders. The unexpected detection of CHRNA4 mutations highlighted the low sensitivity of dHPLC assay. The systematic neuropsychological study showed that neurocognitive deficits are not uncommon in SHE. Mutated patients scored significantly lower at WAIS, supporting a crucial role of genetics in cognitive deficit by different biological mechanisms and molecular pathways. About 47% of patients of normal intelligence showed some degree of cognitive dysfunction. The profile of neuropsychological impairment was characterized by significant worse scores in verbal IQ, deficits in memory and in selected executive functions, with preserved shifting abilities and cognitive flexibility.

Tipologia del documento
Tesi di dottorato
Licchetta, Laura
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Sleep-related Hypermotor Epilepsy (SHE); Nocturnal Frontal Lobe Epilepsy (NFLE); genetics; neuropsychology
Data di discussione
5 Maggio 2017

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