Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the alpha II-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative alpha II-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes

Bibliographical Search Fasciola hepatica Cases in Humans in Argentina

La casuística publicada en Argentina referida a casos humanos que presentaron fasciolosis es escasa. Al no ser una enfermedad de denuncia obligatoria solo se comunican casos aislados y no se investigan los pormenores epidemiológicos y del ecosistema. Quien detecte un caso no esta obligado a informarlo, y por otro lado no todos los casos que se diagnostican se publican. Además la falta de técnicas diagnosticas en la mayoría de las redes de salud complica la detección de la infección y favorece el subregistro. El objetivo del presente estudio fue reportar el número de casos humanos publicados con fasciolosis en la República Argentina desde 1950 al 2010. Se realizó una búsqueda bibliográfica en las bases de datos de la Secretaria de Ciencia y Técnica, en bibliotecas de universidades y en los principales institutos científicos del país. Se hallaron presentaciones sobre 218 personas infectadas desde la primera descripción realizada en Resistencia, Chaco, hasta la publicación sobre casos en Catamarca. En los casos discriminados, el género femenino (54,66%) fue significativamente más frecuente que el masculino. Del total encontrado, seis pacientes (4%) presentó un proceso agudo, 144 corresponden a cursos crónicos. Seis provincias registran enfermos, siendo Catamarca la que presenta mayor número de casos. El arqueo bibliográfico realizado, con excepción hecha de algunos datos imprecisos en la provincia de Córdoba, el número de pacientes diagnosticados es bajo, A pesar que el número de casos totales denunciados en el país confirman que es una zoonosis secundaria u ocasional y que no existe relación estrecha entre la alta incidencia animal y humana, el notable incremento del número de infectados amerita un cambio de categoría transformándola en serio problema de salud pública en algunas regiones.The case series published in Argentina referred to human cases that presented fasciolosis is scarce. As a cause of not being a notificable disease, only isolated cases are reported and epidemiological and ecosystem details are not investigated. Who detected a case is not required to inform it, and on the other hand not all cases diagnosed are published. Besides the lack of diagnostic techniques in most health networks complicates the detection of infection and promotes the understated. The aim of this study was to report the number of published human cases with fascioliasis in Argentina from 1950 to 2010. It was performed a bibliographical search in the databases of the Science and Technology Secretary, in libraries of universities and major scientific institutes of the country. There were found presentations of 218 infected people since the first description made in Resistencia, Chaco until the publication of cases in Catamarca. In discrimination cases, female gender (54,66%) was significantly more frequent than among men. Of the total found, six patient (4%) had an acute process, and 144 correspond to chronic illness. Six provinces reported sick; Catamarca is that with greater number of cases. In the bibliographic tonnage carried, with exception of some imprecise data in the province of Cordoba, the number of diagnosed patients is low. Despite the number of total cases reported in the country confirm that it is a secondary or occasional zoonosis, and that it does not exist a close relationship between animal and human high incidence, the substantial increase in the number of infected warrants a change in category transforming it in a serious public health problem in some regions.Fil: Malandrini, J. B.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Carnevale, Silvana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Soria, C. C. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Velásquez, Jorge Néstor. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Molina, V. E.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentin

Evaluation of Pax6 Mutant Rat as a Model for Autism

Autism is a highly variable brain developmental disorder and has a strong genetic basis. Pax6 is a pivotal player in brain development and maintenance. It is expressed in embryonic and adult neural stem cells, in astrocytes in the entire central nervous system, and in neurons in the olfactory bulb, amygdala, thalamus, and cerebellum, functioning in highly context-dependent manners. We have recently reported that Pax6 heterozygous mutant (rSey2/+) rats with a spontaneous mutation in the Pax6 gene, show impaired prepulse inhibition (PPI). In the present study, we further examined behaviors of rSey2/+ rats and revealed that they exhibited abnormality in social interaction (more aggression and withdrawal) in addition to impairment in rearing activity and in fear-conditioned memory. Ultrasonic vocalization (USV) in rSey2+ rat pups was normal in male but abnormal in female. Moreover, treatment with clozapine successfully recovered the defects in sensorimotor gating function, but not in fear-conditioned memory. Taken together with our prior human genetic data and results in other literatures, rSey2/+ rats likely have some phenotypic components of autism

Current management of the gastrointestinal complications of systemic sclerosis.

Systemic sclerosis is a multisystem autoimmune disorder that involves the gastrointestinal tract in more than 90% of patients. This involvement can extend from the mouth to the anus, with the oesophagus and anorectum most frequently affected. Gut complications result in a plethora of presentations that impair oral intake and faecal continence and, consequently, have an adverse effect on patient quality of life, resulting in referral to gastroenterologists. The cornerstones of gastrointestinal symptom management are to optimize symptom relief and monitor for complications, in particular anaemia and malabsorption. Early intervention in patients who develop these complications is critical to minimize disease progression and improve prognosis. In the future, enhanced therapeutic strategies should be developed, based on an ever-improving understanding of the intestinal pathophysiology of systemic sclerosis. This Review describes the most commonly occurring clinical scenarios of gastrointestinal involvement in patients with systemic sclerosis as they present to the gastroenterologist, with recommendations for the suggested assessment protocol and therapy in each situation

Bibliographical Search Fasciola hepatica Cases in Humans in Argentina

La casuística publicada en Argentina referida a casos humanos que presentaron fasciolosis es escasa. Al no ser una enfermedad de denuncia obligatoria solo se comunican casos aislados y no se investigan los pormenores epidemiológicos y del ecosistema. Quien detecte un caso no esta obligado a informarlo, y por otro lado no todos los casos que se diagnostican se publican. Además la falta de técnicas diagnosticas en la mayoría de las redes de salud complica la detección de la infección y favorece el subregistro. El objetivo del presente estudio fue reportar el número de casos humanos publicados con fasciolosis en la República Argentina desde 1950 al 2010. Se realizó una búsqueda bibliográfica en las bases de datos de la Secretaria de Ciencia y Técnica, en bibliotecas de universidades y en los principales institutos científicos del país. Se hallaron presentaciones sobre 218 personas infectadas desde la primera descripción realizada en Resistencia, Chaco, hasta la publicación sobre casos en Catamarca. En los casos discriminados, el género femenino (54,66%) fue significativamente más frecuente que el masculino. Del total encontrado, seis pacientes (4%) presentó un proceso agudo, 144 corresponden a cursos crónicos. Seis provincias registran enfermos, siendo Catamarca la que presenta mayor número de casos. El arqueo bibliográfico realizado, con excepción hecha de algunos datos imprecisos en la provincia de Córdoba, el número de pacientes diagnosticados es bajo, A pesar que el número de casos totales denunciados en el país confirman que es una zoonosis secundaria u ocasional y que no existe relación estrecha entre la alta incidencia animal y humana, el notable incremento del número de infectados amerita un cambio de categoría transformándola en serio problema de salud pública en algunas regiones.The case series published in Argentina referred to human cases that presented fasciolosis is scarce. As a cause of not being a notificable disease, only isolated cases are reported and epidemiological and ecosystem details are not investigated. Who detected a case is not required to inform it, and on the other hand not all cases diagnosed are published. Besides the lack of diagnostic techniques in most health networks complicates the detection of infection and promotes the understated. The aim of this study was to report the number of published human cases with fascioliasis in Argentina from 1950 to 2010. It was performed a bibliographical search in the databases of the Science and Technology Secretary, in libraries of universities and major scientific institutes of the country. There were found presentations of 218 infected people since the first description made in Resistencia, Chaco until the publication of cases in Catamarca. In discrimination cases, female gender (54,66%) was significantly more frequent than among men. Of the total found, six patient (4%) had an acute process, and 144 correspond to chronic illness. Six provinces reported sick; Catamarca is that with greater number of cases. In the bibliographic tonnage carried, with exception of some imprecise data in the province of Cordoba, the number of diagnosed patients is low. Despite the number of total cases reported in the country confirm that it is a secondary or occasional zoonosis, and that it does not exist a close relationship between animal and human high incidence, the substantial increase in the number of infected warrants a change in category transforming it in a serious public health problem in some regions.Fil: Malandrini, J. B.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Carnevale, Silvana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Soria, C. C. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Velásquez, Jorge Néstor. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Molina, V. E.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentin

Identification and characterization of a highly conserved protein absent in the Alport S. (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome

We recently described a novel contiguous gene deletion syndrome (AMME) in Xq22.3 that includes Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene. In our effort to isolate additional genes from the deleted region, we have identified the gene named AMMECR1 (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1). RACE experiments and screening of cDNA libraries enabled us to obtain the entire ORF of the gene (1002 bp) followed by about 2 kb of 3'UTR. AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa. Sequence analysis revealed that this gene is conserved in several species ranging from Caenorhabditis elegans and yeast to micro-organisms. Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown. Analysis of the predicted protein product using ExPAsy tools raises the possibility that the gene may code for a regulatory factor potentially involved in the development of AMME contiguous gene deletion syndrome

Identification and characterization of a highly conserved protein absent in the Alport (A), Mental retardation (M), Midface hypoplasia (M) and Elliptocytosis (E) contiguous gene deletion syndrome

We recently described a novel contiguous gene deletion syndrome (AMME) in Xq22.3 that includes Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene. In our effort to isolate additional genes from the deleted region, we have identified the gene named AMMECR1 (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1). RACE experiments and screening of cDNA libraries enabled us to obtain the entire ORF of the gene (1002 bp) followed by about 2 kb of 3'UTR. AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa. Sequence analysis revealed that this gene is conserved in several species ranging from Caenorhabditis elegans and yeast to micro-organisms. Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown. Analysis of the predicted protein product using ExPAsy tools raises the possibility that the gene may code for a regulatory factor potentially involved in the development of AMME contiguous gene deletion syndrome

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263. © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Associatio

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263. © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Associatio