A novel developmental encephalopathy with epilepsy and hyperkinetic movement disorders associated with a deletion of the sodium channel gene cluster on chromosome 2q24.3

We reported a 21 months-old boy with a complex epilepsy phenotype, developmental delay, and hyperkinetic movement disorders, associated with a deletion of the whole sodium channel gene cluster. Whether this unusual phenotype results from leading to haploinsufficiency of either SCN1A or SCN2A, or the combination of both, remains subject of speculation. However, nobody of the numerous reported patients with truncating mutations in SCN1A has ever manifested such a clinical phenotyp

Plasma and CSF Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Cross-Sectional and Longitudinal Study

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course. Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit. Results: ALS patients (n = 171) showed significantly higher pNfL (p < 0.0001) and cNfL (p < 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course. Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials

Tracking Zebu Introgression in Mediterranean Cattle Breeds

A recent work investigating genetic origin, admixture and population history of primitive European cattle highlighted, by using genome-wide single nucleotide polymorphisms, zebu gene flow in the Balkan and Italian Podolic cattle populations. Haemoglobin protein polymorphism analysis in Italian breeds highlighted the presence of zebuine markers in both Italian Podolic and Alpine Grey cattle. Based on the above evidences, we here specifically look for genomic regions of zebuine ancestry in a different dataset of 50K genotypes from Mediterranean breeds including 29 Marismena (Spain); 30 Bazadaise and 30 Gasconne (France); 24 Alpine Grey, 97 Piemontese, 51 Chianina, 5 Marchigiana, 121 Romagnola, 24 Podolica, 24 Modenese, 30 Reggiana, 30 Cinisara and 30 Modicana (Italy); 24 Guelmoise (Algeria); 24 Cika (Slovenia), 43 Illyrian Mountain Bu\u161a (Albania). Additional taurine and zebuine breeds from previously published studies are also included in the analyses. Special emphasis in genetic analyses is also given to the identification of genomic regions potentially associated with a phenotypic trait observed in several taurine breeds as well as in some zebuine breeds, characterized by calves having a fawn coat at birth, while turning to various shades of grey in adult animals. The obtained results contribute to a better characterization of history and genetic structure of Mediterranean cattle breeds

High-density single nucleotide polymorphism markers reveal the population structure of 2 local chicken genetic resources

Italy counts a large number of local chicken populations, some without a recognized genetic structure, such as Val Platani (VPL) and Cornuta (COS), which represent noteworthy local genetic resources. In this study, the genotype data of 34 COS and 42 VPL, obtained with the Affymetrix Axiom600KChicken Genotyping Array, were used with the aim to investigate the genetic diversity, the runs of homozygosity (ROH) pattern, as well as the population structure and relationship within the framework of other local Italian and commercial chickens. The genetic diversity indices, estimated using different approaches, displayed moderate levels of genetic diversity in both populations. The identified ROH hotspots harbored genes related to immune response and adaptation to local hot temperatures. The results on genetic relationship and population structure reported a clear clustering of the populations according to their geographic origin. The COS formed a nonoverlapping genomic cluster and clearly separated from the other populations, but showed evident proximity to the Siciliana breed (SIC). The VPL highlighted intermediate relationships between the COS-SIC group and the rest of the sample, but closer to the other Italian local chickens. Moreover, VPL showed a complex genomic structure, highlighting the presence of 2 subpopulations that match with the different source of the samples. The results obtained from the survey on genetic differentiation underline the hypothesis that Cornuta is a population with a defined genetic structure. The substructure that characterizes the Val Platani chicken is probably the consequence of the combined effects of genetic drift, small population size, reproductive isolation, and inbreeding. These findings contribute to the understanding of genetic diversity and population structure, and represent a starting point for designing programs to monitor and safeguard these local genetic resources, in order to define a possible official recognition program as breeds

The Girgentana Goat Breed: A Zootechnical Overview on Genetics, Nutrition and Dairy Production Aspects

In recent years, there has been a great interest in recovering and preserving local livestock breeds. An interesting situation is represented by the Girgentana goat, an ancient local breed reared in Sicily. Over recent years, this breed has become almost extinct, in part as a consequence of the marked decrease in fresh goat milk consumption. On the basis of these considerations, several studies on its genetic structure and management aspects have been conducted in order to protect the Girgentana goat from the risk of extinction and recover its genetic and economic value. In this context, information on genetics, nutrition and dairy production aspects may have a crucial role in the improvement and management of the breed. Thus, this chapter describes some points of these applications through recent investigations on this goat breed

Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged

Genome-wide characterization of local cattle breeds from central and western Mediterranean

Following-up on previous studies that investigated genetic relationships among several world-wide cattle breeds using genome-wide SNP data, we focus here on the central and western part of the Mediterranean. Notably, 50K genotypes from 30 Marisme\uf1a (Spain); 24 Guelmoise (Algeria); 46 Brune de l\u2019Atlas Fauve, 15 Brune de l\u2019Atlas Grise, and 15 Blonde du Cap (Tunisia); 29 Modicana and 30 Cinisara (Sicily); 24 Podolica Italiana (Southern continental Italy); 34 Chianina and 24 Romagnola (Central Italy); 23 Modenese, 24 Reggiana, 23 Alpine Grey and 50 Pezzata Rossa Italiana (Northern Italy); 50 Bruna Italiana and 50 Frisona Italiana were considered. When included in a world-wide dataset, the three Tunisian, the Algerian, the two Sicilian, the Podolica, the Chianina and the Romagnola were the taurine breeds showing the highest closeness to the Indian zebu group in the MDS plot of the IBS distance. These results were also confirmed by ADMIXTURE analysis (K = 2). This relatively lower influence of zebu material into cattle breeds from Northern Italy suggests a major maritime-mediated route of dispersal of zebu material into Southern Europe and Northern Africa. Interestingly, breeds from the Iberian peninsula showed lower evidence of zebu introgression, suggesting that zebu introgression was likely not mediated by Moors, and possibly occurred at earlier times. Clear evidence of more recent introgression of material from improved dairy cattle breeds (Bruna Italiana and Brown Swiss) into the two Brune de l\u2019Atlas populations from Tunisia highlights the need for urgent conservation of this cross-border cattle

Possible pro-carcinogenic association of endotoxin on lung cancer among Shanghai women textile workers

Background: Endotoxin (lipopolysaccharide) is a widespread contaminant in many environmental settings. Since the 1970s, there has been generally consistent evidence indicating reduced risks for lung cancer associated with occupational endotoxin exposure. Methods: We updated a case–cohort study nested within a cohort of 267 400 female textile workers in Shanghai, China. We compared exposure histories of 1456 incident lung cancers cases diagnosed during 1989–2006 with those of a reference subcohort of 3022 workers who were free of lung cancer at the end of follow-up. We applied Cox proportional hazards modelling to estimate exposure–response trends, adjusted for age and smoking, for cumulative exposures lagged by 0, 10, and 20 years, and separately for time windows of ⩽15 and \u3e15 years since first exposure. Results: We observed no associations between cumulative exposure and lung cancer, irrespective of lag interval. In contrast, analyses by exposure time windows revealed modestly elevated, but not statistically significant relative risks (∼1.27) at the highest three exposure quintiles for exposures that occurred \u3e15 years since first exposure. Conclusions: The findings do not support a protective effect of endotoxin, but are suggestive of possible lung cancer promotion with increasing time since first exposure

Extended Glasgow Outcome Scale to Evaluate the Functional Impairment of Patients With Subcortical Band Heterotopia: A Multicentric Cross-sectional Study

Background: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy. Purpose: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH). Method: Cross-sectional multicenter study of a cohort of 49 patients with SBH (female n = 30, 61%), recruited from 23 Italian centers. Results: Thirty-nine of 49 (80%) cases showed high functional disability at EGOS-ped assessment. In the poor result subgroup (EGOS-ped >3) motor deficit, language impairment, and lower intelligence quotient were more frequent (P < 0.001, P = 0.02, and P = 0.01, respectively); the age at epilepsy onset was remarkably lower (P < 0.001); and the prevalence of epileptic encephalopathy (West syndrome or Lennox-Gastaut-like encephalopathy) was higher (P = 0.04). The thickness and the extension of the heterotopic band were associated with EGOS-ped score (P < 0.01 and P = 0.02). Pachygyria was found exclusively among patients with poor outcome (P < 0.01). Conclusions: The EGOS-ped proved to be a reliable tool for stratifying the functional disability of patients with SBH. According to this score, patients could be dichotomized: group 1 (80%) is characterized by a poor overall functionality with early epilepsy onset, thick heterotopic band, and pachygyria, whereas group 2 (20%) is characterized by a good overall functionality with later epilepsy onset and thinner heterotopic band

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Background: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies. Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients