A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.

Germline EGFR c.2527G > A (p.V843I) variant and familial lung cancer.

BACKGROUND: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported. CASE PRESENTATION: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants. CONCLUSION: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.

Portrait of autosomal recessive diseases in the French-Canadian founder population of Saguenay-Lac-Saint-Jean.

The population of the Saguenay-Lac-Saint-Jean (SLSJ) region, located in the province of Quebec, Canada, is recognized as a founder population, where some rare autosomal recessive diseases show a high prevalence. Through the clinical and molecular study of 82 affected individuals from 60 families, this study outlines 12 diseases identified as recurrent in SLSJ. Their carrier frequency was estimated with the contribution of 1059 healthy individuals, increasing the number of autosomal recessive diseases with known carrier frequency in this region from 14 to 25. We review the main clinical and molecular features previously reported for these disorders. Five of the studied diseases have a potential lethal effect and three are associated with intellectual deficiency. Therefore, we believe that the provincial program for carrier screening should be extended to include these eight disorders. The high-carrier frequency, together with the absence of consanguinity in most of these unrelated families, suggest a founder effect and genetic drift for the 12 recurrent variants. We recommend further studies to validate this hypothesis, as well as to extend the present study to other regions in the province of Quebec, since some of these disorders could also be present in other French-Canadian families.

Benefits of Newborn Screening for Vitamin D-Dependant Rickets Type 1A in a Founder Population.

Background: Vitamin D-dependant rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27B1 gene. This gene is essential for vitamin D activation. Although VDDR1A is a rare condition worldwide, its prevalence is high in the Saguenay-Lac-Saint-Jean (SLSJ) region due to a founder effect. Daily intake of calcitriol before the onset of clinical manifestations can prevent them in affected children. Methods: A genetic screening test was developed and validated for the CYP27B1 gene c.262del pathogenic variant. Newborn screening was implemented in the SLSJ region for this variant, and the feasibility and acceptability were assessed. Sixteen medical records of children affected with VDDR1A were reviewed to document the consequences of the disease at diagnosis. Results: A total of 2000 newborns were tested for VDDR1A. Most families (96.5%) accepted the genetic test. We found a carrier rate of 1/29 for the c.262delG variant in our cohort, which is suggestive of a founder effect. We identified one child affected with VDDR1A and treatment was initiated before the onset of clinical manifestations. On average, children with VDDR1A were diagnosed at 13.8 ± 5 months of age, they had a significant failure to thrive at diagnosis, among other harmful health consequences. Conclusion: Our study showed that in our population, the newborn genetic screening program is safe and feasible, it has high acceptability, and it is efficient to identify affected children. VDDR1A health consequences can be prevented by early initiation of treatment. Therefore, screening programs should be available for populations where it is deemed as beneficial from a public health perspective.

French-Canadian families from Saguenay-Lac-Saint-Jean: a new founder population for APECED.

PURPOSE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is more prevalent in some founder populations, but relatively unexplored in Canada. This study aimed at investigating the French-Canadian patients through phenotypic and genotypic characterization. METHOD: Phenotype and demographic characterization were done for 12 affected individuals belonging to eight unrelated families. Samples from 11 cases were analyzed in a molecular clinical laboratory, and muscle biopsies were reviewed for two individuals with a limb-girdle muscle dystrophy. RESULTS: The clinical phenotype was similar to that observed in European Caucasian populations but differed in the non-endocrine spectrum from the American-reported series of cases. Two cases exhibited a limb-girdle muscle dystrophy, and we found preliminary evidence of a mitochondrial dysfunction, since all three biopsies examined showed COX-deficient fibers in excess of what would be expected for age. Electron microscopy showed mitochondrial accumulation without abnormal cristea or inclusions. The c.1616C > T variant in the AIRE gene was responsible for 100% of APECED cases in the French-Canadian population of Saguenay-Lac-Saint-Jean in Quebec, Canada. CONCLUSIONS: We report the first series of French-Canadian cases affected with APECED. The Saguenay-Lac-Saint-Jean region was uncovered as a new founder population for this condition. Muscle biopsy findings expanded the range of previously described APECED-related myopathology. Long term follow-up of our genetically homogeneous French-Canadian cases may help determine if the c.1616C > T variant increases the risk of muscle involvement. A neonatal screening program is under consideration to prevent undesired life-threatening endocrine manifestations.

First glance at the molecular etiology of hearing loss in French-Canadian families from Saguenay-Lac-Saint-Jean's founder population.

The French-Canadian population of Saguenay-Lac-Saint-Jean is known for its homogenous genetic background. The hereditary causes of hearing loss were previously unexplored in this population. Individuals with hearing loss were referred from the otorhinolaryngology, pediatrics and family physicians' clinics to the medical genetics service at the Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean between June 2015 and March 2021. A regional clinical evaluation strategy was developed. Samples from 63 individuals belonging to 41 families were sent independently to different molecular clinical laboratories and index cases were analyzed through comprehensive multigene panels, with a diagnostic rate of 54%. Sixteen hearing loss causal variants were identified in 12 genes, with eight of these variants not been previously reported in the literature. Recurrent variants were present in four genes, suggesting a possible founder effect, while GJB2 gene variants were scarce. A comprehensive multigene panel approach as part of the proposed clinical evaluation strategy offers a high diagnostic yield for this population.

A Collaborative Model to Implement Flexible, Accessible and Efficient Oncogenetic Services for Hereditary Breast and Ovarian Cancer: The C-MOnGene Study.

Medical genetic services are facing an unprecedented demand for counseling and testing for hereditary breast and ovarian cancer (HBOC) in a context of limited resources. To help resolve this issue, a collaborative oncogenetic model was recently developed and implemented at the CHU de Québec-Université Laval; Quebec; Canada. Here, we present the protocol of the C-MOnGene (Collaborative Model in OncoGenetics) study, funded to examine the context in which the model was implemented and document the lessons that can be learned to optimize the delivery of oncogenetic services. Within three years of implementation, the model allowed researchers to double the annual number of patients seen in genetic counseling. The average number of days between genetic counseling and disclosure of test results significantly decreased. Group counseling sessions improved participants' understanding of breast cancer risk and increased knowledge of breast cancer and genetics and a large majority of them reported to be overwhelmingly satisfied with the process. These quality and performance indicators suggest this oncogenetic model offers a flexible, patient-centered and efficient genetic counseling and testing for HBOC. By identifying the critical facilitating factors and barriers, our study will provide an evidence base for organizations interested in transitioning to an oncogenetic model integrated into oncology care; including teams that are not specialized but are trained in genetics.

Severe epidermolysis bullosa simplex phenotype caused by codominant mutations p.Ile377Thr in keratin 14 and p.Gly138Glu in keratin 5.

Epidermolysis bullosa simplex (EBS) is a rare skin disease usually inherited in an autosomal dominant pattern. EBS is resulting from mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes encoding the keratins 5 and 14 proteins expressed in the keratinocytes of the basal layer of the epidermis. To date, seven pathogenic mutations have been reported to be responsible for EBS in the Canadian population from the province of Quebec: p.Pro25Leu, p.Leu150Pro, p.Met327Thr and p.Arg559X in KRT5; p.Arg125Ser, p.Ile377Thr and p.Ile412Phe in KRT14. Here, we present a novel French-Canadian patient diagnosed with EBS confined to the soles but presenting a severe complication form including blisters, hyperkeratosis, skin erosions and toenail abnormalities. Mutation screening was performed by direct sequencing of the entire coding regions of KRT5 and KRT14 genes and revealed the previously reported missense heterozygous mutation c. 1130T > C in KRT14 (p.Ile377Thr). Furthermore, this patient is carrying a second mutation in KRT5, c.413G > A (p.Gly138Glu), which has been linked to an increased risk of basal cell carcinoma in the literature. We suspect an impact of the p.Gly138Glu variant on the EBS phenotype severity of the studied patient. The pathogenicity and consequences of both genetic variations were simulated by in silico tools.

Epidemiological, clinical, and molecular characterization of Cuban families with spinocerebellar ataxia type 3/Machado-Joseph disease.

BACKGROUND: Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD) is a hereditary neurodegenerative disorder resulting from the expansion of CAG repeats in the ATXN3 gene. It is the most common autosomal dominant ataxia in the world, but its frequency prevalence in Cuba remains uncertain. We undertook a national study in order to characterize the ATXN3 gene and to determine the prevalence of SCA3/MJD in Cuba. RESULTS: Twenty-two individuals belonging to 8 non-related families were identified as carriers of an expanded ATXN3 allele. The affected families come from the central and western region of the country. Ataxia of gait was the initial symptom in all of the cases. The normal alleles ranged between 14 and 33 CAG repeats while the expanded ones ranged from 63 to 77 repeats. The mean age at onset was 40 ± 9 years and significantly correlated with the number of CAG repeats in the expanded alleles. CONCLUSIONS: This disorder was identified as the second most common form of spinocerebellar ataxia (SCA) in Cuba based on molecular testing, and showing a different geographical distribution from that of SCA2. This research constitutes the first clinical and molecular characterization of Cuban SCA3 families, opening the way for the implementation of predictive diagnosis for at risk family members.

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/10(5) inhabitants) of SCA2 in the world. The existence of 753 affected individuals and 7173 relatives at risk prompted the development in 2001 of the first predictive testing program in the country. The medical records of over 1193 individuals, who requested the test within a 13-year period, were analyzed retrospectively. The presymptomatic and the prenatal tests had uptake rates of 43.4 and 23.9 %, respectively. Several ethical challenges resulted from this program. These include the following: (1) withdrawal due to the initial protocol's length; (2) the request to participate by 16 at-risk adolescents; (3) the decision made by ten out of 33 couples with a test-positive fetus to carry the pregnancy to term, leading to de facto predictive testing of minors; (4) the elevated frequency of the ATXN2 gene large normal alleles (≥23 to 31 repeats) in the reference population. These issues have led to major changes in the guidelines of the predictive testing protocol: (1) the protocol length was shortened; (2) the inclusion criteria were expanded to reach at-risk adolescents with an interest in prenatal diagnosis; (3) interdisciplinary follow-up was offered to families in which test-positive fetuses were not aborted; (4) prenatal testing was made available to carriers of large normal alleles with ≥27 CAG repeats. The profiles of the participants were similar to those reported for other predictive testing programs for conditions like Huntington disease and familial adenomatous polyposis. The genetic counseling practices at the community level, the ample health education provided to the at-risk population, together with multidisciplinary and specialized attention to the affected families, are lessons from the Cuban experience that can be relevant for other international teams conducting predictive testing for other late-onset neurodegenerative disorders.

Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

Large normal and intermediate alleles in the context of SCA2 prenatal diagnosis.

In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them.

Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report.

Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder characterized by degeneration of the cerebellum, brainstem, and retina that is caused by abnormal expansion of a CAG repeat located in the ATXN7 gene encoding sequence on chromosome 3p21.1. Although SCA7 is an uncommon autosomal dominant ataxia, we previously found increased prevalence of the disease in a Southeastern Mexican population. In this study, we described to our knowledge for the first time a marriage of consanguineous SCA7 mutation carriers and their offspring effect. We characterized a severely affected infantile-onset female patient whose parents and two siblings exhibited no symptoms of the disease at time of diagnosis. A comprehensive clinical analysis of the proband showed a progressive cerebellar syndrome, including gait ataxia, movement disorders, and saccadic movements, as well as hyperreflexia, visual deterioration, urinary and cardiovascular dysfunction, and impaired nerve conduction. The SCA7 mutation was detected in the proband patient. Subsequently, genetic examination using four ATXN7 gene-linked markers (three centromeric microsatellite markers [D3S1228, D3S1287, and D3S3635] and an intragenic Single Nucleotide Polymorphism [SNP-3145G/A]) revealed that the proband descends from a couple of consanguineous SCA7 mutation carriers. Genotyping analysis demonstrated that all offspring inherited only one mutant allele, and that the severe infantile-onset phenotype is caused by germinal expansion (from 37 to 72 CAG repeats) of the paternal mutant allele. Interestingly, the couple also referred a miscarriage. Finally, we found no CAA interruptions in the ATXN7 gene CAG repeats tract in this family, which might explain, at least in part, the triplet instability in the proband.

Estudio de agregación familiar en gemelos afectados por Adicción al Alcohol en Holguín / Familial aggregation study in twins affected by alcohol addiction in Holguin

La adicción al alcohol es una enfermedad reconocida por la OMS y ha sido la drogodependencia más estudiada desde el punto de vista genético. Conocer la contribución de los factores genéticos y ambientales en la adicción al alcohol. Se realizó un estudio epidemiológico analítico transversal, mediante un análisis de agregación familiar a partir de gemelos probando, para ello se escogió el total de parejas de gemelos (21) contenidas en el Registro Cubano de Gemelos pertenecientes al municipio Holguín (independientemente de su cigocidad), donde al menos uno de sus miembros presentara adicción al alcohol, en el período de enero a marzo del 2009. Se efectuó un estudio clásico de concordancia con el caso índice, se comparó la agregación familiar en monocigóticos versus dicigóticos y se exploraron factores de riesgo ambientales asociados con la enfermedad. La proporción de co gemelos afectados para parejas monocigóticas fue 5/7 y para dicigóticas 1/14. La concordancia para el caso índice monocigóticos fue del 83 (percent) y en dicigóticos 13 (percent). El 33 (percent) de los familiares de primer grado de un gemelo monocigótico presenta adicción al alcohol, en los dicigóticos fue el 19,5(percent). En el caso de los familiares de segundo grado de gemelos monocigóticos se observó la presencia de la enfermedad en el 18(percent) y para los dicigóticos el 8,5(percent). Los factores de riesgos no genéticos más frecuentes fueron: hábito de fumar materno durante el embarazo, traumas psicológicos y complicaciones perinatales. Una mayor proporción de concordancia en parejas de gemelos monocigóticos, seguida de una historia familiar de la enfermedad, aporta evidencias de la posible participación de factores genéticos en la adicción al alcohol…(AU)

Couples at risk for spinocerebellar ataxia type 2: the Cuban prenatal diagnosis experience.

Cuba reports the highest worldwide prevalence of spinocerebellar ataxia type 2 (SCA2) and the greatest number of descendants at risk. A protocol for genetic counseling, presymptomatic testing, and prenatal diagnosis of hereditary ataxias has been under development since 2001. Considering that the revision of the experience with prenatal diagnosis for SCA2 in Cuba would enable comparison of ours with international findings, we designed a descriptive study, based on the retrospective revision of the medical records belonging to the 58 couples that requested their inclusion in the program, during an 11-year period (2001-2011). Most of the participants in the prenatal diagnosis program were known presymptomatic carriers, diagnosed through the presymptomatic testing in the same period of study, for an uptake among them of 22.87 % (51 out of 223). In 28 cases, the fetuses were carriers, 20 of these couples (71.43 %) decided to terminate the pregnancy; the rest continued the pregnancy to term, this resulting in a predictive test for their unborn children. A predominance of females as the at-risk progenitor was observed. Except for a slightly lower average age, the results attained in the Cuban SCA2 prenatal diagnosis program resulted similar to the ones reported for Huntington disease in other countries. It is necessary to have easy access to the Cuban program through its expansion to other genetic centers along the island. Future research is needed to evaluate the long-term impact of both the predictive testing in unborn children and the selection of other reproductive options by the at-risk couples.

Asesoramiento genético sobre el cáncer de mama / Genetic Assessment on Breast Cancer

El cáncer de mama es una neoplasia maligna, de acuerdo con su etiología, la genética lo clasifica en esporádico o hereditario. La forma hereditaria es causada por una mutación en la línea germinal en genes supresores de tumores y la más frecuente se localizada en los genes BRAC1 y BRAC2. Los individuos portadores de estos genes presentan un incremento del riesgo de desarrollar cáncer. La historia familiar es esencial para su identificación, además existen los criterios cualitativos de la American Society of Clinical Oncology (ASCO) y los diferentes modelos matemáticos que resultan útiles en el cálculo del riesgo de padecer cáncer de mama o de portar la mutación. En los individuos con probabilidad de presentar una mutación hay que valorar la realización del test genético. Además, existe la prevención convencional que por su alto riego es muy importante y debe comenzar a los 25 años. El asesoramiento genético es de gran importancia para la prevención y el manejo integral de esta enfermedad(Au)...

The breast cancer is a malignant neoplasm and according to its etiology it is classified in sporadic or hereditary. The cause of the hereditary cancer is a mutation of germline in the tumoral suppressors gene and the most frequent one is located in BRAC1 and BRAC2 gene, which are the most frequently found. The carriers of these genes show an increase of the risk in developing cancer. The family history is the essential tool for their identification; also exist the qualitative criterion of the American Society of Clinical Oncology (ASCO) and the different mathematical models which are very useful in the cancer risk estimates calculation. In the individuals with the probability of carrier a mutation its necessary value for the genetic test. The conventional prevention is very important in these cases should begin at 25 years of age. The genetic counselling is considered very necessary in preventing and management of this disease(AU)...

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles.

The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (~3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs.

The inv dup (15) or idic(15) syndrome: a case report

This report describes a patient who presented with hypotonia and epileptic seizures. She was prenatally diagnosed as a supernumerary chromosome carrier. By means of Fluorescence in Situ Hybridization (FISH) using Vysis Prader-Willi/Angelman region probes, the marker chromosome was double positive for D15Z1 and quadruple positive for SNRPN. Her karyotype was thus interpreted as 47, XX,+ idic(15)(pter→q13::q13→ pter) .ish idic (15)(D15Z1++, SNRPN++++). No sphincters control and signs of kyphoscoliosis may provide additional evidence for the spectrum of clinical manifestations in the inv dup (15) syndrome to be broader than previously considered. The mother had a history of two miscarriages and one molar pregnancy, it suggests she could have been prone to unsuccessful meiosis. The existence of genetic or environmental factors predisposing to chromosomal aberrations and its correlation with the common instability of this chromosomal region are issues to be further investigated...(AU)

Estudio de agregación familiar en gemelos afectados por esquizofrenia en el municipio Calixto García, provincia Holguín, año 2009 / Familial aggregation study in schizophrenic twins in the Calixto García municipality, Holguín province on 2009

Se realizó un estudio analítico de agregación familiar a partir de 7 gemelos probandos con esquizofrenia, en el municipio Calixto García, provincia Holguín, durante el período enero–marzo de 2009. Se calculó la frecuencia con que se presenta este trastorno mental en el otro miembro del par y en otros miembros de la familia con relación de primer o segundo grado de parentesco con el caso índice. Al mismo tiempo se exploró la co-morbilidad de otros trastornos mentales en estas familias y la asociación con factores de riesgo no genéticos. La concordancia para la esquizofrenia en el hermano gemelo del caso índice resultó mayor en gemelos monocigóticos que en dicigóticos. En todos los casos hubo presencia de agregación familiar. Se identificó co-morbilidad psiquiátrica, fundamentalmente con el alcoholismo. El antecedente de parto distócico fue el factor de riesgo no genético más frecuente. Sobre esta base se diseñó una estrategia preventiva para las familias con esquizofrenia en el municipio…(AU)

Caracterización integral de la ataxia espinocerebelosa 2 en Cuba y su aplicación en proyectos de intervención / Comprehensive characterization of spinocerebellar ataxia type 2 in Cuba and its application in intervention projects

Introducción Cuba es el país con mayores tasas de prevalencia e incidencia para las ataxias hereditarias, lo que constituye un problema de salud que motivó la creación del Centro para la Investigación y Rehabilitación de Ataxias Hereditarias en Holguín. Objetivos Describir los principales resultados, aportes científicos, estrategias de intervención e impactos que durante más de 10 años se han obtenido por el citado centro, como modelo para el abordaje integral de las ataxias hereditarias en Cuba. Fuente de datos Se realizó una revisión en las bases de datos Pubmed-Medline y Scopus, analizando todos los artículos relevantes, comprendidos en el periodo 1978-2011. Se utilizó el descriptor «ataxia espinocerebelar¼, de elevada especificidad y sensibilidad para el tema en análisis. Síntesis de los datos La prevalencia de la enfermedad se ha mantenido constante durante 40 años, extendiéndose a toda la isla. La mutación ataxia espinocerebelosa tipo 2 es responsable del 60 % de la variabilidad fenotípica mientras que el 40 % restante se debe a factores modificadores genéticos y/o ambientales. Se ha descrito la existencia de un daño oxidativo severo, disminución de neuroprotectores y oligoelementos. Los estudios neurofisiológicos permitieron definir etapas evolutivas desde estadios preclínicos de la enfermedad así como biomarcadores de progresión y daño genético. Estos resultados proiciaron el diseño y ejecución de varios ensayos clínicos controlados en busca de un protocolo de tratamiento contra la enfermedad. Adicionalmente se brinda un servicio de diagnostico prenatal y presintomático con un impacto positivo sobre las familias afectadas. Conclusiones Las investigaciones sobre la ataxia espinocerebelosa tipo 2 cubana, como problema de salud, han tenido un enfoque integral. Los nuevos descubrimientos sobre la patogenia, la identificación de biomarcadores, los ensayos clínicos, el diagnóstico prenatal y presintomático permitieron conformar un nuevo modelo cubano para el abordaje de las ataxias hereditarias y el estudio de otras enfermedades neurodegenerativas.

Introduction Cuba is one of the countries with high rates of prevalence and incidence of hereditary ataxias, which is a health problem that encouraged the foundation of the Center for Research and Rehabilitation of Hereditary Ataxias in Holguín province. Objectives To describe the main results, scientific achievements, intervention strategies and impacts of this institution for more than 10 years, as a sort of pattern to be followed to approach hereditary ataxias in Cuba in a more comprehensive way. Data source Pubmed-Medline and Scopus database were reviewed in which all the relevant articles published from 1978 to 2011 were analyzed. Spinocerebelar ataxia, highly specific and sensitive subject headings, were used for the topic under analysis. Data synthesis The prevalence of this disease has remained unchanged for 40 years, being extended to the whole island. Spinocerebelar ataxia type 2 mutation accounts for 60% of the phenotypical variability whereas the remaining 40% is caused by genetic and/or environmental modifying factors. Severe oxidative damage, reduction of neuroprotectors and of oligoelements have been described. The neurophysiological studies allowed defining evolutionary phases from the preclinical stagings as well as progression and genetic damage biomarkers. These results allowed designing several controlled clinical assays in search of one treatment protocol for the disease. Additionally, prenatal and pre-symptomatic diagnosis service is rendered, with positive impact on affected families. Conclusions The research studies on spinocerebelar ataxia type 2 in Cuba as a health problem have had comprehensive approach. The new breakthroughs on pathogeny, identification of biomarkers, clinical assays, prenatal and presymptomatic diagnosis allowed making a new Cuban model to approach hereditary ataxias and the study of other neurodegenerative diseases.