(The American Journal of Human Genetics 95, 360–370; October 2, 2014) In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom’s name was misspelled as Amron. The authors regret the error. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic EncephalopathiesAppenzeller et al.The American Journal of Human GeneticsSeptember 25, 2014In BriefEmerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. Full-Text PDF Open Archive

Primary familial brain calcification (PFBC) (formerly idiopathic basal ganglia calcification; Fahr disease) is an autosomal dominant cerebral microvascular calcifying disorder with variable clinical and imaging features.(1) Four causative genes have been identified: SLC20A2,(2) PDGFRB,(3) PDGFB,(4) and XPR1.(5).

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for similar to 4% of unsolved MAE cases.

This work describes the results of the geotechnical and hydrogeological characterization of a very slow landslide involving Acero, a village in the Northern Apennine. Through boreholes and geophysical surveys, it was possible to obtain a geological profile of the landslide, while through some monitoring activities we were able to obtain information about displacements and water table. Laboratory tests completed the definition of the geotechnical and mineralogical properties of the soil. The landslide shows maximum speed values of 1.5 cm/y, with maximum accelerations during heavy rain periods. This landslide has been classified as a residual state type and can be considered as dormant or active, depending on vertical effective stress and pore pressure variations. The hydrogeological risk mitigation is carried out through the interpretation of the landslide trigger and evolution mechanisms such as the reduction of the water table level.

The Lemeglio landslide has been known since the end of nineteenth century because it represents a well-preserved coastal landslide in the Mediterranean environment. The landslide affects engineering structures: several drillings have been performed that allowed establishing the thickness and the bedrock nature; moreover they have been equipped with geotechnical and hydrogeological monitoring tools. It represents an active complex landslide, with a mean rate of movement up to 3 cm/y, whereas rapid phenomena like rockfalls occur at the landslide scarps. Recently, further information on ground movements has been collected through the radar interferometry technique PSinSAR. This monitoring activity, together with field surveys, allowed us to make a new delimitation of this large slope instability phenomenon. It now affects also the Lemeglio village and the north catchment of the hystorically-known area. On the basis of the collected data we can ascribe all the coastal area to a rock block slide or rotational sagging.

OBJECTIVE:Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders.METHODS:We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.RESULTS:We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways.INTERPRETATION:This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.

Objective: To identify the genetic cause of a familial form of late-onset action myoclonus in 2 unrelated patients. Both probands had 2 siblings displaying a similar disorder. Extensive laboratory examinations, including biochemical assessment for urine sialic acid in the 2 probands, were negative. Methods: Exome sequencing was performed in the probands using an Illumina platform. Segregation analysis of putative mutations was performed in all family members by standard Sanger sequencing protocols. Results: NEU1 mutations were detected in 3 siblings of each family with prominent cortical myoclonus presenting in the third decade of life and having a mild and slowly progressive course. They did not have macular cherry-red spot and their urinary sialic acid excretion was within normal values. Genetic analysis demonstrated a homozygous mutation in family 1 (c.200G>T, p.S67I) and 2 compound heterozygous mutations in family 2 (c.679G>A, p.G227R; c.913C>T, p.R305C). Conclusions: Our observation indicates that sialidosis should be suspected and the NEU1 gene analyzed in patients with isolated action myoclonus presenting in adulthood in the absence of other typical clinical and laboratory findings.

Christel Depienne, Eric LeGuern and colleagues report the identification of 5 de novo missense mutations in HCN1 in individuals with early-onset epileptic encephalopathy. Functional studies confirmed the pathogenic nature of these mutations. Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

Clinical GeneticsVolume 86, Issue 1 p. 99-101 LETTER TO THE EDITOR Functional characterization of the c.462delA mutation in the NDUFS4 subunit gene of mitochondrial complex I S. Assereto, S. Assereto Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorA. Robbiano, A. Robbiano Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorM. Di Rocco, M. Di Rocco Department of Paediatrics, Unit of Rare Diseases, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorA. Rossi, A. Rossi Department of Paediatric Neuroradiology, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorD. Cassandrini, D. Cassandrini Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Panicucci, C. Panicucci Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorG. Brigati, G. Brigati Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorR. Biancheri, R. Biancheri Department of Neuroscience, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Bruno, C. Bruno Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Minetti, C. Minetti Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Department of Paediatrics, University of Genova, Genoa, Italy Department of Neuroscience, University of Genova, Genoa, ItalySearch for more papers by this authorH. Trucks, H. Trucks Cologne Center for Genomics, University of Cologne, Cologne, GermanySearch for more papers by this authorT. Sander, T. Sander Cologne Center for Genomics, University of Cologne, Cologne, GermanySearch for more papers by this authorF. Zara, Corresponding Author F. Zara Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Correspondence: Elisabetta Gazzerro, MD, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 Fax: +39 010 3538265 e-mail: elisabettagazzerro@ospedale-gaslini.ge.it and Federico Zara, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 fax: +39 010 3538265 e-mail: federicozara@ospedale-gaslini.ge.itSearch for more papers by this authorE. Gazzerro, Corresponding Author E. Gazzerro Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Correspondence: Elisabetta Gazzerro, MD, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 Fax: +39 010 3538265 e-mail: elisabettagazzerro@ospedale-gaslini.ge.it and Federico Zara, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 fax: +39 010 3538265 e-mail: federicozara@ospedale-gaslini.ge.itSearch for more papers by this author S. Assereto, S. Assereto Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorA. Robbiano, A. Robbiano Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorM. Di Rocco, M. Di Rocco Department of Paediatrics, Unit of Rare Diseases, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorA. Rossi, A. Rossi Department of Paediatric Neuroradiology, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorD. Cassandrini, D. Cassandrini Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Panicucci, C. Panicucci Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorG. Brigati, G. Brigati Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorR. Biancheri, R. Biancheri Department of Neuroscience, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Bruno, C. Bruno Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, ItalySearch for more papers by this authorC. Minetti, C. Minetti Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Department of Paediatrics, University of Genova, Genoa, Italy Department of Neuroscience, University of Genova, Genoa, ItalySearch for more papers by this authorH. Trucks, H. Trucks Cologne Center for Genomics, University of Cologne, Cologne, GermanySearch for more papers by this authorT. Sander, T. Sander Cologne Center for Genomics, University of Cologne, Cologne, GermanySearch for more papers by this authorF. Zara, Corresponding Author F. Zara Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Correspondence: Elisabetta Gazzerro, MD, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 Fax: +39 010 3538265 e-mail: elisabettagazzerro@ospedale-gaslini.ge.it and Federico Zara, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 fax: +39 010 3538265 e-mail: federicozara@ospedale-gaslini.ge.itSearch for more papers by this authorE. Gazzerro, Corresponding Author E. Gazzerro Paediatric Neurology and Muscle Disease Unit, G. Gaslini Institute, Genoa, Italy Correspondence: Elisabetta Gazzerro, MD, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 Fax: +39 010 3538265 e-mail: elisabettagazzerro@ospedale-gaslini.ge.it and Federico Zara, PhD Paediatric Neurology Unit G. Gaslini Institute L.go Gaslini 5 16147 Genova Italy Tel.: +39 010 5636803 fax: +39 010 3538265 e-mail: federicozara@ospedale-gaslini.ge.itSearch for more papers by this author First published: 11 September 2013 https://doi.org/10.1111/cge.12248Citations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume86, Issue1Special Issue: Personalized Medicine and Clinical GeneticsJuly 2014Pages 99-101 RelatedInformation

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de nova mutations, including de novo mutations in DNM1 in five individuals and de nova mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de nova mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 x 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de nova mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

PURPOSE:To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). METHODS:Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. KEY FINDINGS:A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. SIGNIFICANCE:Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307, c.388delG/p.Ala130Profs 46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80-100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.