Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain.

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.

Diet and Leukocyte Telomere Length in a Population with Extended Longevity: The Costa Rican Longevity and Healthy Aging Study (CRELES).

Elderly Costa Ricans have lower mortality rates compared to their counterparts from developed countries. Reasons for this survival advantage are not completely known. In the present study, we aimed to identify dietary factors associated with leukocyte telomere length (LTL), a marker of biologic aging, in the elderly population of Costa Rica. We conducted prospective analysis in 909 participants aged 60+ years from the Costa Rican Longevity and Healthy Aging Study (CRELES). We used a food frequency questionnaire to assess usual diet. We calculated dietary patterns using Principal Component Analysis (PCA). We used generalized linear models to examine the association of dietary patterns and food groups with leukocyte telomere length. We found two major dietary patterns explaining 9.15% and 7.18% of the total variation of food intake, respectively. The first dietary pattern, which represents a traditional Costa Rican rice and beans pattern, was more frequent in rural parts of the country and was positively associated with baseline LTL: ß (95% CI) = 42.0 base-pairs (bp) (9.9 bp, 74.1 bp) per one-unit increase of the traditional dietary pattern. In analysis of individual food groups, intake of grains was positively associated with baseline LTL: ß (95% CI) = 43.6 bp (13.9 bp, 73.3 bp) per one-serving/day increase of consumption of grains. Our results suggest that dietary factors, in particular a traditional food pattern, are associated with telomere length and may contribute to the extended longevity of elderly Costa Ricans.

The impact of immigration on tuberculosis and HIV burden between Colombia and Venezuela and across frontier regions.

Historically, human migrations have determined the spread of many infectious diseases by promoting the emergence of temporal outbreaks between populations. We aimed to analyze health indicators, expenditure, and disability caused by tuberculosis (TB) and HIV/AIDS burden under the Colombian-Venezuelan migration flow focusing on the Northeastern border. A retrospective study was conducted using TB and HIV/AIDS data since 2009. We consolidated a database using official reports from the Colombian Surveillance System, World Health Organization, Indexmundi, the Global Health Observatory, IHME HIV atlas, and Joint United Nations Programme on HIV/AIDS (UNAIDS). Disability metrics regarding DALYs (disability adjusted life years) and YLDs (years lived with disability), were compared between countries. Mapping was performed on ArcGIS using official migration data of Venezuelan citizens. Our results indicate that TB profiles from Colombia and Venezuela are identical in terms of disease burden, except for an increase in TB incidence in the Colombian-Venezuelan border departments in recent years, concomitantly with the massive Venezuelan immigration since 2005. We identified a four-fold underfunding for the TB program in Venezuela, which might explain the low-testing rates for cases of multidrug-resistant TB (67%) and HIV/AIDS (60%), as well as extended hospital stays (150 days). We found a significant increase in DALYs of HIV/AIDS patients in Venezuela, specifically, 362.35 compared to 265.37 observed in Colombia during 2017. This study suggests that the Venezuelan massive migration and program underfunding might exacerbate the dual burden of TB and HIV in Colombia, especially towards the Colombian-Venezuelan border.

Performance Metric Analysis for a Jamming Detection Mechanism under Collaborative and Cooperative Schemes in Industrial Wireless Sensor Networks.

The emergence of Industry 4.0 technologies, such as the Internet of Things (IoT) and Wireless Sensor Networks (WSN), has prompted a reconsideration of methodologies for network security as well as reducing operation and maintenance costs, especially at the physical layer, where the energy consumption plays an important role. This article demonstrates through simulations and experiments that, while the cooperative scheme is more efficient when a WSN is at normal operating conditions, the collaborative scheme offers more enhanced protection against the aggressiveness of jamming in the performance metrics, thus making it safer, reducing operation and maintenance costs and laying the foundations for jamming mitigation. This document additionally offers an algorithm to detect jamming in real time. Firstly, it examines the characteristics and damages caused by the type of aggressor. Secondly, it reflects on the natural immunity of the WSN (which depends on its node density and a cooperative or collaborative configuration). Finally, it considers the performance metrics, especially those that impact energy consumption during transmission.

The impact of immigration on tuberculosis and HIV burden between Colombia and Venezuela and across frontier regions / El impacto de la inmigración en la tuberculosis y la carga del VIH entre Colombia y Venezuela a través de las regiones fronterizas / O impacto da imigração sobre a tuberculose e a carga de HIV entre Colômbia e Venezuela e nas regiões de fronteira

Abstract: Historically, human migrations have determined the spread of many infectious diseases by promoting the emergence of temporal outbreaks between populations. We aimed to analyze health indicators, expenditure, and disability caused by tuberculosis (TB) and HIV/AIDS burden under the Colombian-Venezuelan migration flow focusing on the Northeastern border. A retrospective study was conducted using TB and HIV/AIDS data since 2009. We consolidated a database using official reports from the Colombian Surveillance System, World Health Organization, Indexmundi, the Global Health Observatory, IHME HIV atlas, and Joint United Nations Programme on HIV/AIDS (UNAIDS). Disability metrics regarding DALYs (disability adjusted life years) and YLDs (years lived with disability), were compared between countries. Mapping was performed on ArcGIS using official migration data of Venezuelan citizens. Our results indicate that TB profiles from Colombia and Venezuela are identical in terms of disease burden, except for an increase in TB incidence in the Colombian-Venezuelan border departments in recent years, concomitantly with the massive Venezuelan immigration since 2005. We identified a four-fold underfunding for the TB program in Venezuela, which might explain the low-testing rates for cases of multidrug-resistant TB (67%) and HIV/AIDS (60%), as well as extended hospital stays (150 days). We found a significant increase in DALYs of HIV/AIDS patients in Venezuela, specifically, 362.35 compared to 265.37 observed in Colombia during 2017. This study suggests that the Venezuelan massive migration and program underfunding might exacerbate the dual burden of TB and HIV in Colombia, especially towards the Colombian‐Venezuelan border.

Resumen: Históricamente, las migraciones humanas han determinado la expansión de muchas enfermedades infecciosas, promoviendo el surgimiento de brotes temporales en la población. Nuestro objetivo fue analizar indicadores de salud, gastos, así como la discapacidad causada por la tuberculosis (TB) y la carga del VIH/SIDA ante el flujo migratorio entre Colombia-Venezuela, centrándose en los departamentos fronterizos del nordeste. Se realizó un estudio retrospectivo usando datos sobre TB y VIH/SIDA desde 2009. Consolidamos una base de datos usando informes oficiales del Sistema de Vigilancia Colombiano, Organización Mundial de la Salud, Indexmundi, Observatorio Global de la Salud, IHME HIV atlas, y Programa Conjunto de las Naciones Unidas sobre el VIH/SIDA (ONUSIDA). Se midió la discapacidad en términos del DALYs (incapacidad ajustada por años de vida) y YLDs (años vividos con discapacidad) y se compararon entre ambos países. El mapeo se realizó en ArcGIS, usando datos oficiales de migración de ciudadanos venezolanos. Nuestros resultados indican que los perfiles de TB de Colombia y Venezuela son idénticos, en lo que se refiere a la carga de la enfermedad, excepto por el incremento en la incidencia de TB en los departamentos fronterizos de la frontera entre Colombia y Venezuela en años recientes, concomitantemente con la inmigración masiva venezolana desde 2005. Identificamos una cuadruplicación de la subfinanciación para el programa de TB en Venezuela, que podría explicar las bajas tasas de test para los casos multirresistentes a medicamentos contra la TB (67%) y VIH/SIDA (60%), al igual que las estancias prolongadas en el hospital (150 días). Hallamos un incremento significativo en DALYs de pacientes con VIH/SIDA en Venezuela, específicamente, 362,35 comparados con los 265,37 observados en Colombia durante 2017. Este estudio sugiere que la migración venezolana masiva y la subfinanciación del programa podrían haber exacerbado la doble carga de la TB y el VIH en Colombia, especialmente a través de la frontera entre Colombia y Venezuela.

Resumo: Historicamente, as migrações humanas determinaram a propagação de muitas doenças infecciosas ao facilitar surtos temporais entre populações. O estudo buscou analisar os indicadores sanitários e os gastos e taxas de incapacidade relacionados à tuberculose (TB) e à carga de HIV/aids no fluxo migratório entre Colômbia e Venezuela, com destaque para os departamentos (estados) da fronteira nordeste. Foi realizado um estudo retrospectivo de dados sobre TB e HIV/aids desde 2009. Consolidamos uma base de dados a partir de relatórios do Sistema de Vigilância da Colômbia, Organização Mundial da Saúde, Indexmundi, Observatório de Saúde Global, IHME HIV Atlas e Programa Conjunto das Nações Unidas sobre HIV/AIDS (UNAIDS). As métricas de incapacidade em termos de AVAIs (anos de vida ajustados para incapacidade) e AVIs (anos vividos com incapacidade) foram comparadas entre os dois países. O mapeamento foi realizado no ArcGIS, com dados oficiais sobre migração de cidadãos venezuelanos. Nossos resultados indicam que os perfis de TB da Colômbia e da Venezuela são idênticos em termos de carga de doença, exceto por um aumento da incidência de TB nos departamentos na fronteira entre os dois países em anos recentes, concomitantemente com a imigração venezuelana maciça desde 2005. Identificamos um subfinanciamento (por um fator de quatro) no programa de tuberculose da Venezuela, o que pode explicar as baixas taxas de testagem para casos de TB multirresistente (67%) e HIV/aids (60%), além das internações hospitalares prolongadas (150 dias). Encontramos um aumento significativo de AVAIs em pacientes de HIV/aids na Venezuela, especificamente 362,35 comparado com 265,37 na Colômbia em 2017. O estudo sugere que a migração maciça venezuelana e o subfinanciamento podem exacerbar a carga dupla de TB e HIV na Colômbia, principalmente na fronteira com a Venezuela.

Mutational survivorship bias: The case of PNKP.

The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term "Wald's domain" for future studies analyzing the possible survivorship bias in multidomain proteins.

Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair.

Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

Correlates of longitudinal leukocyte telomere length in the Costa Rican Longevity Study of Healthy Aging (CRELES): On the importance of DNA collection and storage procedures.

The objective is to identify cofactors of leukocyte telomere length (LTL) in a Latin American population, specifically the association of LTL with 36 socio-demographic, early childhood, and health characteristics, as well as with DNA sample collection and storage procedures. The analysis is based on longitudinal information from a subsample of 1,261 individuals aged 60+ years at baseline from the Costa Rican Study of Longevity and Healthy Aging (CRELES): a nationally representative sample of elderly population. Random effects regression models for panel data were used to estimate the associations with LTL and its longitudinal changes. Sample collection procedures and DNA refrigerator storage time were strongly associated with LTL: telomeres are longer in blood collected in October-December, in DNA extracted from <1-year-old blood cells, and in DNA stored at 4°C for longer periods of time up to five years. The data confirmed that telomeres are shorter at older ages, as well as among males, and diabetic individuals, whereas telomeres are longer in the high-longevity Nicoya region. Most health, biomarkers, and early childhood indicators did not show significant associations with LTL. Longitudinal LTL variation over approximately two years was mainly associated with baseline LTL levels, as found in other studies. Our findings suggest that if there is unavoidable variability in season of sample collection and DNA storage time, these factors should be controlled for in all demographic and epidemiologic studies of LTL. However, due to unobserved components of measurement variation, statistical control may be inadequate as compared to standardization of data collection procedures.

DNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria.

Mutations in DNA repair enzymes can cause two neurological clinical manifestations: a developmental impairment and a degenerative disease. Polynucleotide kinase 3'-phosphatase (PNKP) is an enzyme that is actively involved in DNA repair in both single and double strand break repair systems. Mutations in this protein or others in the same pathway are responsible for a complex group of diseases with a broad clinical spectrum. Besides, mitochondrial dysfunction also has been consolidated as a hallmark of brain degeneration. Here we provide evidence that supports a shared role between mitochondrial dysfunction and DNA repair defects in the pathogenesis of the nervous system. As models, we analyze PNKP-related disorders, focusing on Charcot-Marie-Tooth disease and ataxia. A better understanding of the molecular dynamics of this relationship could provide improved diagnosis and treatment for neurological diseases.

The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

Amerindian ancestry and extended longevity in Nicoya, Costa Rica.

OBJECTIVES: The aim of this study was to address the hypothesis that Amerindian ancestry is associated with extended longevity in the admixed population of Nicoya, Costa Rica. The Nicoya Peninsula of Costa Rica has been considered a "longevity island," particularly for males. METHODS: We estimated Amerindian ancestry using 464 ancestral informative markers in 20 old Nicoyans aged ≥99 years, and 20 younger Nicoyans (60-65 years). We used logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of the association of Amerindian ancestry and longevity. RESULTS: Older Nicoyans had higher Amerindian ancestry compared to younger Nicoyans (43.3% vs 36.0%, P = .04). Each 10% increase of Amerindian ancestry was associated with more than twice the odds of being long-lived (OR = 2.32, 95% CI = 1.03-5.25). CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first time that ancestry is implicated as a likely determinant of extended longevity. Amerindian-specific alleles may protect against early mortality. The identification of these protective alleles should be the focus of future studies.

Wideband phantoms of different body tissues for heterogeneous models in body area networks.

One of the key issues about wireless technologies is their interaction with the human body. The so-called internet of things will comprise many devices that will transmit either around or through the human body. These devices must be tested either in their working medium, when possible, or in the most realistic one. For this purpose, tissue-like phantoms are the best alternative to carry out realistic analyses of the performance of body area networks. In addition, they are the conventional way to certify the compliance of commercial standards by these devices. However, the number of phantoms that work in large bandwidths is limited in literature. This work aims at presenting chemical solutions that will be useful to prepare a variety of wideband tissue phantoms. Besides, the colon was mimicked in two ways, the healthy tissue and the malignant one, taking into account studies that relate changes on the relative permittivity with cancer. They were designed on the basis of acetonitrile in aqueous solutions as described in a previous work. Thus, many scenarios could be developed such as multilayers which imitate parts of the heterogeneous body.

A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica.

Intellectual disability is a highly heterogeneous disease that affects the central nervous system and impairs patients' ability to function independently. Despite multiples genes involved in the etiology of disease, most of the genetic background is yet to be discovered. We used runs of homozygosity and exome sequencing to study a large Costa Rican family with four individuals affected with severe intellectual disability and found a novel homozygous missense mutation, p. 96G>R, c. 286G>A, in all affected individuals. This gene encodes for a pyridoxal enzyme involved in the production of the neurotransmitter glutamate and is highly expressed in the white matter of brain and cerebellum. Protein modeling of GPT2 predicted that the mutation is located in a loop where the substrate binds to the active site of the enzyme, therefore, suggesting that the catalytic activity is impaired. With our report of a second mutation we fortify the importance of GPT2 as a novel cause of autosomal recessive nonsyndromic intellectual disability and support the premise that GPT2 is highly important for the neurodevelopment of the central nervous system. SYNOPSIS: The mutation p. 96G>R c. 286G>A in GPT2, located in a loop where the substrate binds to the active site of the enzyme, fortifies the importance of GPT2 in the pathogenesis of nonsyndromic intellectual disability.

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.

BACKGROUND: Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum. METHODS: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy. RESULTS: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one. CONCLUSIONS: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.

Experimental Path Loss Models for In-Body Communications Within 2.36-2.5 GHz.

Biomedical implantable sensors transmitting a variety of physiological signals have been proven very useful in the management of chronic diseases. Currently, the vast majority of these in-body wireless sensors communicate in frequencies below 1 GHz. Although the radio propagation losses through biological tissues may be lower in such frequencies, e.g., the medical implant communication services band of 402 to 405 MHz, the maximal channel bandwidths allowed therein constrain the implantable devices to low data rate transmissions. Novel and more sophisticated wireless in-body sensors and actuators may require higher data rate communication interfaces. Therefore, the radio spectrum above 1 GHz for the use of wearable medical sensing applications should be considered for in-body applications too. Wider channel bandwidths and smaller antenna sizes may be obtained in frequency bands above 1 GHz at the expense of larger propagation losses. Therefore, in this paper, we present a phantom-based radio propagation study for the frequency bands of 2360 to 2400 MHz, which has been set aside for wearable body area network nodes, and the industrial, scientific, medical band of 2400 to 2483.5 MHz. Three different channel scenarios were considered for the propagation measurements: in-body to in-body, in-body to on-body, and in-body to off-body. We provide for the first time path loss formulas for all these cases.

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype / Una familia costarricense afectada por la enfermedad de Charcot-Marie-Tooth, debido a la mutación p.thr124Met en la proteína mielina cero (MPZ) compartida con el haplotipo belga

The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4): 1285-1293. Epub 2014 December 01.

La mutación p.thr124Met en la proteína mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatía periférica con síntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, Bélgica, Japón, Italia y Norteamérica, entre otras. Aquí reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutación. Se realizaron análisis clínico, electrofisiológico y molecular de pacientes y controles, incluyendo secuenciación del gen y de marcadores ligados a éste. Estos pacientes comparten casi por completo el haplotipo con dos pacientes belgas no emparentados. Como resultado del análisis de los haplotipos, basado en diez marcadores (siete SNPs, dos microsatélites y un elemento poli-A intrónico), se sugiere que se ha dado un efecto fundador en la migración de este alelo.

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype.

The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers' sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive.

Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal X-linked musculodegenerative condition consisting of an underlying genetic defect whose manifestation is augmented by inflammatory mechanisms. Previous treatment approaches using gene replacement, exon-skipping or allogeneic cell therapy have been relatively unsuccessful. The only intervention to mediate improvement in survival, albeit minor, is glucocorticoid treatment. Given this modality appears to function via suppression of underlying inflammation; we focus this review on the inflammatory response as a target for mesenchymal stem cell (MSC) therapy. In contrast to other cell based therapies attempted in DMD, MSC have the advantages of (a) ability to fuse with and genetically complement dystrophic muscle; (b) possess anti-inflammatory activities; and (c) produce trophic factors that may augment activity of endogenous repair cells. We conclude by describing one practical scenario of stem cell therapy for DMD.

Frecuencia del alelo causante de la enfermedad de Charcot-Marie-Tooth (tipo axonal con herencia autosómica recesiva) en Palmares, Costa Rica / Frequency of the allele causing Charcot-Marie-Tooth disease (axonal type with autosomal recessive inheritance) in Palmares, Costa Rica

Frecuency of the allele causing the axonal form of autosomal recessive Charcot-Marie-Tooth in Palmares, Costa Rica. The Charcot-Marie-Tooth disease constitutes is among the most frequent hereditary peripheral neuropathies world-wide. We identified a family from Palmares (Alajuela, Costa Rica) with 18 affected members. Their neuropathy is axonal, with an autosomal recessive pattern of inheritance; the responsible gene is at the 19q13.33 chromosomal region. Later the mutation was identified in gene MED25. We studied the frequency and geographic distribution of the mutant allele. In a random sample of 103 individuals, six were heterozygote and were widely distributed in Palmares. There was no person in homozigote state for the mutant allele. Clinical characteristics do not differ significantly between individuals that are homozygous for the wildtype allele and individuals hetero zygous for the mutation. A 5.83 % of the population is heterozygote and the frequency of the Ala335Val allele is 0.029, six times higher than in a sample of the Costa Rican population. Werecommend a molecular analysis of carriers to detect additional cases in the region. Rev. Biol. Trop. 57 (Suppl.1): 381-387. Epub 2009 November 30.

La enfermedad de Charcot-Marie-Tooth constituye elgrupo de neuropatías periféricas hereditarias más común a nivel mundial. Una familia con 18 afectados del cantón de Palmares (Alajuela, Costa Rica) con una neuropatía de tipo axonal y herencia autosómica recesiva, permitió localizar el gen responsable en la región 19q13.33. Posteriormente se identificó la mutación causante en el gen MED25. El presente estudio determinó la frecuencia del alelo mutante, así como la distribución geográfica de este alelo. En una muestra al azar de 103 individuos se encontraron seis individuos heteroigotas para la mutación, distribuidos por todo el cantón. No se encontró ninguna persona en estado homocigota para este alelo. No hallamos algunacaracterística clínica que difiera significativamente entre los individuos homocigotos silvestres y los heterocigotos para la mutación. El 5.83% de la población es heterocigota y la frecuencia del alelo Ala335Val es de 0.029, seis veces mayor que en una muestra de toda la población costarricense. Por esta razón se recomienda un análisis molecular de portadores con el fin de alertar sobre la posibilidad de aparición de más casos en el cantón.

Distribución espacial de la enfermedad Charcot-Marie-Tooth en Costa Rica, 1990-2003 / Spatial distribution of the Charcot-Marie-Tooth disease in Costa Rica, 1990-2003

Objetivo: Evaluar la distribución espacial como indicador de la incidencia de la enfermedad de Charcot-Marie-Tooth por los egresos hospitalarios reportados en Costa Rica entre el período 1990-2003. Métodos: Se aplicó un rastreo estadístico espacial de la incidencia de la enfermedad y se evaluó la significancia estadística de los conglomerados con excesos de casos. Resultados: El exceso de casos observados de la enfermedad en la zona de Naranjo fue estadísticamente significativo (56 versus 26.3 p menor 0.05). Otras regiones en donde se presenta exceso significativo de casos de CMT, son: Tibás (33 versus 13.5), Alajuela Centro (20 versus 6), Turrialba centro (16 versus 4.5), Golfito (18 versus 5.6) y Puntarenas centro (9 versus 1.5). Discusión: Se propone este rastreo estadístico espacial como herramienta en el proceso de toma de decisiones paa disminuir la incidencia de la enfermedad, así como atender adecuadamente a los afectados por CMT y sus familias, pues el métoido identificó regiones críticas o conglomerados (clusters) en donde es necesario dirigir los esfuerzos para la evaluación de la incidencia de la enfermedad.

Objective: To evaluate the spatial distribution of Charcot- Marie-Tooth disease as indicator of incidence in Costa Rica between 1990-2003.Methods: A spatial statistical scan was performed for the CMT incidence. We evaluated the statistical significance of high rate clusters. Results: The excess of observed cases of the disease in the area of Naranjo was statistically significant (56 vs. 26.3 p <0.05). Other regions showing significant excess of cases of CMT are: Tibás (33 vs. 13.5), Alajuela Centro (20 vs. 6), Turrialba Centro (16 vs. 4.5), Golfito (18 vs. 5.6) and Puntarenas Centro (9 vs. 1.5).Discussion: Spatial statistical scan is proposed as a tool in the decision making process in order to reduce the incidence of the disease and respond appropriately to those affected by CMT and their families. The method identifies clusters where it is necessary to focus efforts in evaluating the incidence of the disease.