Familly with two different cases of post- and pre-natal L1 syndrome; When hydrocephaly become "multidisciplinary headache"

open11openBukvic, Nenad; Boaretto, Francesca; Loverro, Giuseppe; Susca, Francesco C.; Lovaglio, Rosaura; Patruno, Margherita; Bukvic, Dragoslav; Starcevic, Srdjan; Vazza, Giovanni; Mostaciuollo, Maria Luisa; Resta, NicolettaBukvic, Nenad; Boaretto, Francesca; Loverro, Giuseppe; Susca, Francesco C.; Lovaglio, Rosaura; Patruno, Margherita; Bukvic, Dragoslav; Starcevic, Srdjan; Vazza, Giovanni; Mostaciuollo, Maria Luisa; Resta, Nicolett

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas

Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp(-) somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load

The Northern Cross fast radio burst project–I: overview and pilot observations at 408 MHz

Fast radio bursts (FRBs) remain one of the most enigmatic astrophysical sources. Observations have significantly progressed over the last few years, due to the capabilities of new radio telescopes and the refurbishment of existing ones. Here, we describe the upgrade of the Northern Cross radio telescope, operating in the 400–416 MHz frequency band, with the ultimate goal of turning the array into a dedicated instrument to survey the sky for FRBs

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivoInfrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesEuropean Union’s Horizon 2020 research and innovation programm

NEURO(NO)PATIE MOTORIE DISTALI FAMILIARI

Le neuro(no)patie motorie distali (dHMN), anche conosciute come CMT (Charcot-Marie-Tooth) spinali o SMA (Spinal Muscular Atrophy) distali, sono malattie che si caratterizzano per eterogeneit\ue0 clinica e genetica. Harding nel 1993 ha fornito una classificazione delle dHMN basata sull\u2019et\ue0 di insorgenza, sulla modalit\ue0 di trasmissione e sulla presenza di caratteristiche aggiuntive. Sono state definite quattro varianti autosomiche dominanti (dHMN-I, dHMN-II, dHMN-V, dHMN-VII) e tre autosomiche recessive (dHMN-III, dHMN-IV, dHMNVI). Pi\uf9 recentemente, con l\u2019introduzione degli studi di linkage sull\u2019intero genoma, sono state indagate famiglie con dHMN, e sono stati portati alla luce tre nuovi sottotipi clinico-genetici di cui due autosomici dominanti (dHMN con segni piramidali e SMA distale congenita) ed uno recessivo (dHMN Jerash). Vengono presentati i loci ed i geni attualmente noti che rendono conto delle diverse varianti cliniche e che permettono di fornire diagnosi differenziale

Identification and characterization of C3orf6, a new conserved human gene mapping to chromosome 3q28

This study reports the characterization of a novel human gene, chromosome 3 open reading frame 6 (C3orf6), mapped to chromosome 3q28, within the critical region of hereditary spastic paraplegia SPG14 locus. Based on computational "spliced" EST alignment and RT-PCR, two C3orf6 transcript variants were identified. The longer C3orf6 transcript contains a 1449-nt ORF, encoding a protein of 482 aa, while the shorter variant contains a 921-nt ORF, encoding for a protein of 306 aa. C3orf6 gene is organised on 12 exons and the shorter transcript comes from an alternative splicing event skipping exon 6. The two mRNA are differentially expressed in brain and in several other human tissues with a predominant level for the shorter transcript. By database analysis, EST assembling and RT-PCR, we identified the transcripts of mouse and rat C3orf6 orthologous genes. The involvement of C3orf6 in the spastic paraplegia was investigated by sequencing all coding exons and flanking sequences in the SPG14 family, excluding the presence of causative mutations

A novel 9-bp insertion in the GJB1 gene causing a mild form of X-linked CMT with late onset

X-linked Charcot-Marie-Tooth disease is the second most common variant of CMT. CMTX1 is caused by mutations in the GJB1 gene encoding for connexin 32. We describe an Italian family with an intermediate CMTX phenotype with late onset. Mutation screening of the GJB1 gene revealed a 9-bp duplication leading to the insertion of three aminoacids (Thr-Val-Phe) between the end of the second extracellular domain and the beginning of the fourth transmembrane domain. This is the third in-frame insertion in the GJB1 gene identified so far and, like the previous ones, it consists in the duplication of the flanking sequence which is repeated in tandem in the wild-type gene