Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.

Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions.

Co-occurring malformations of cortical development and SCN1A gene mutations.

OBJECTIVE: To report on six patients with SCN1A mutations and malformations of cortical development (MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features. METHODS: Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging (MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children. RESULTS: The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia (PNH) in two patients and focal cortical dysplasia (FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy (SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality. SIGNIFICANCE: MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome.

Mitofusin 2: The missing link between mtDNA maintenance defects and neurotransmitter disorders.

Mitofusin (MFN) 2 belongs to the large family of mitochondrial transmembrane GTPases and has a role in dynamic mitochondrial remodeling process governed by fusion and fission. MFN2 pathogenic variants classically cause Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of CMT, but patients with complex and unusual phenotypes involving the central and peripheral nervous system have been described, with mitochondrial dysfunction proposed as the underlying pathogenic mechanism. Here, we report the first description of a neurochemical pattern of secondary alterations in the metabolism of biogenic amines linked to the de novo presence of the hotspot MFN2 pathogenic variant p.Arg104Trp. The infant presented a very early onset choreic movement disorder associated with severe axial hypotonia and fluctuating dystonia of limbs. The relationship between mitochondrial DNA (mtDNA) maintenance defects and dopaminergic neurotransmitter disorders, governed by MFN2, is discussed.

Schizophrenia in real life: courses, symptoms and functioning in an Italian population.

BACKGROUND: In the general belief, schizophrenia is associated with the concepts of seriousness, incurability, dangerousness: this is incorrect. In recent decades, the interest in course studies increased and different trends emerged, not necessarily chronic, with the possibility of remission.The plan of this research was to draw a picture of the schizophrenia syndrome in a specific geographic area, in the past and at present time: this allows to detect needs, weaknesses and strengths, for a better planning of future interventions. METHODS: The course of all cases diagnosed as schizophrenia (N = 1,759) in the period 1978-2008, was retrospectively studied in the entire population of an Italian province by observing, for a mean period of 12 years per person, age at first psychiatric consultation, number and length of admissions for both acute symptoms and residential-rehabilitation programs, number of interventions in outpatients. The cases under treatment (N = 842), were evaluated in terms of symptoms, using the Brief Psychiatric Rating Scale, and in terms of functioning, using the Personal and Social Functioning Scale. RESULTS: The disease course differs significantly between genders: males have an earlier age at first consultation (about 7 years earlier), higher admission rates, greater number of outpatient interventions and personal and social functioning significantly worse.Hospitalization resulted often unnecessary: 23.1% of cases were never hospitalized and 67.2% spent less than one week per year in hospital.A quarter of the cases meets the international criteria for remission and more than 75% are asymptomatic or mildly symptomatic; only 5.3% of cases shows severe symptoms. However, Personal and Social Functioning highlights, in about 1/3 of cases, relevant or serious problems mainly in Work and Relationships areas, whilst Aggressiveness is a serious problem only in 9%. CONCLUSIONS: In this population, schizophrenia in real life shows great individual variability in course, symptoms and functioning: in most cases nowadays it appears a less severe and chronic disease than in the past, but further improvements are needed on disability prevention and social inclusion.

Schizophrenia and quality of life: how important are symptoms and functioning?

OBJECTIVE: the relationship between Quality of life (QoL) and global functioning and symptoms in outpatients with Schizophrenia METHOD: The study was carried out on the outpatients with schizophrenia attending a Community Mental Health Centre in 2008. Each patient completed the WHO QoL Instrument - Brief and was administered the Brief Psychiatric Rating Scale-24 to assess psychiatric symptoms and the VADO Personal and social Functioning Scale to assess the level of functioning. RESULTS: subjects showed an intermediate satisfaction on the overall QoL and health; these data can be juxtaposed to the national standard sample rates. QoL resulted positively associated to personal and social functioning, while it was negatively related to psychiatric symptoms. CONCLUSION: patients showed a fairly good satisfaction in regard to their QoL. The severity of psychiatric symptoms is one of the elements influencing QoL, together with personal and social functioning that plays a relevant role.