Francesca Bisulli

Mutations in DEPDC5 cause familial focal epilepsy with variable foci

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.

Determinants of health-related quality of life in pharmacoresistant epilepsy: Results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments

Purpose:  To evaluate the relative contribution of demographic and epilepsy‐related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health‐related quality of life (HRQOL) in adults with pharmacoresistant epilepsy.

Autosomal Dominant Lateral Temporal Epilepsy: Clinical Spectrum, New Epitempin Mutations, and Genetic Heterogeneity in Seven European Families

Summary:  Purpose: To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE).

Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787

Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies.

Limbic encephalitis (LE) is a neurological syndrome that may present in association with cancer, infection, or as an isolate clinical condition often accompanying autoimmune disorders. Here we have characterized the clinical and laboratory features of two patients presenting with subacute onset, and chronic evolution, of anterograde amnesia and drug-resistant epilepsy associated with thyroid autoimmunity and in absence of tumoral pathology despite long follow-up. Antibodies against onconeural antigens, voltage gated potassium channel and glutamate receptors, which may accompany paraneoplastic as well as non-paraneoplastic LE, were negative. However, biochemical studies showed high titers, and sustained intrathecal synthesis, of antibodies directed against neuronal glutamic acid decarboxylase (GAD). In one patient, plasma exchange determined a dramatic improvement of the neurological deficits along with the decrease of autoantibodies.

Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: A common mechanism?

Purpose:  Retrospective observations disclosed an overlap between parasomnias and nocturnal frontal lobe epilepsy (NFLE) not only in patients but also in their relatives, suggesting a possible common pathogenetic mechanism. This study aimed to verify whether relatives of patients with NFLE have a higher frequency of parasomnias, namely arousal disorders, and thereby shed light on the still unknown pathophysiologic mechanisms underlying NFLE.

Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.

Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.

Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.

A DE NOVO LGI1 MUTATION CAUSING IDIOPATHIC PARTIAL EPILEPSY WITH TELEPHONE-INDUCED SEIZURES

Telephone-induced seizures have recently been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone.1 Typical auras consist of auditory or vertiginous symptoms and the inability to speak or understand spoken voices. These features, along with specific EEG ictal findings in one patient, suggest that this condition involves the lateral temporal area.1 Autosomal dominant partial epilepsy with auditory features (ADPEAF; OMIM 600512), or autosomal dominant lateral temporal epilepsy (ADLTE), is a rare familial partial epilepsy syndrome with onset in childhood/adolescence and benign evolution.2,3 The hallmark of the syndrome consists of the presence of typical auditory auras or ictal aphasia in most affected family members, sometimes triggered by environmental sounds and noises. ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 ( LGI1)/Epitempin gene,3,4 the function of which is still unclear. Earlier we described a series of sporadic patients with idiopathic partial epilepsy with auditory features (IPEAF) who were clinically indistinguishable from ADPEAF cases5 …

Mutations in the mTOR pathway regulators NPRL2 and NPRL3 cause focal epilepsy

Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.