Fragile X Syndrome in a Colombian Family / Sindrome X frágil en una Familia Colombiana

RESUMEN Se realizó un estudio descriptivo a una familia de Cali, Colombia, en el cual se evaluaron nueve pacientes, tres de los cuales presentaban discapacidad intelectual sin diagnóstico etiológico anterior. El caso índice fue diagnosticado con el síndrome X frágil mediante pruebas moleculares de ADN. Se realizaron pruebas en cascada a todos los miembros de la familia disponibles, identificando dos individuos adicionales con la mutación completa y cuatro portadores del alelo con pre mutación. Con este informe pretendemos contribuir a la epidemiología colombiana del síndrome y destacamos la importancia del diagnóstico etiológico de la discapacidad intelectual y proporcionar un tratamiento integral y específico a las personas afectadas. Además se busca identificar a los portadores de la pre mutación o mujeres con mutación completa sin fenotipo clásico para el asesoramiento genético y la educación sobre posibles patologías asociadas.

SUMMARY A study was performed on a family from Cali, Colombia in which nine patients were evaluated, three of which presented with intellectual disability with no previous etiological diagnosis. The proband was diagnosed with Fragile X syndrome by DNA molecular testing and, cascade testing, performed on all available family members, identifying two additional individuals with the full mutation and four carriers of a premutation allele. With this report we seek to contribute to Colombian epidemiology of the syndrome and emphasize the importance of diagnosis to provide a comprehensive and specific treatment to those affected. Further we seek to identify premutation carriers in their families or women with a full mutation without the classic phenotype for genetic counseling and education about potential associated pathologies.

Genetic cluster of fragile X syndrome in a Colombian district.

BACKGROUND: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and autism. The reported prevalence of the full mutation (FM) gene FMR1 in the general population is 0.2-0.4 per 1000 males and 0.125-0.4 per 1000 females. Population screening for FMR1 expanded alleles has been performed in newborns and in an adult population. However, it has never been carried out in an entire town. Ricaurte is a Colombian district with 1186 habitants, with a high prevalence of FXS, which was first described by cytogenetic techniques in 1999. METHODS: Using a PCR-based approach, screening for FXS was performed on blood spot samples obtained from 926 (502 males and 424 females) inhabitants from Ricaurte, accounting for 78% of total population. RESULTS: A high prevalence of carriers of the expanded allele was observed in all FXS mutation categories. Using the Bayesian methods the carrier frequency of FM was 48.2 (95% Credibility Region CR: 36.3-61.5) per 1000 males and 20.5 (95% CR:13.5-28.6) per 1000 females; the frequency of premutation carrier was 14.1 (95% RC: 8.0-21.7) per 1000 males (95% RC: 8.0-21.7 per 1000 males) and 35.9 (95% RC: 26.5-46.2) per 1000 for females (95% RC: 26.5-46.2 per 1000 females), and gray zone carrier was 13.4 (95% RC: 7.4-20.7) per 1000 males (95% RC: 7.4-20.7 per 1000 males) and 42.2 (95% RC: 32.2-53.8) per 1000 for females (95% RC: 32.2-53.8 per 1000 females). Differences in carrier frequencies were observed for premutation and FM alleles between natives and non-natives. CONCLUSIONS: This study shows that in Ricaurte the carrier frequencies of FMR1 expanded alleles (premutations and FMs) are higher than those reported in the literature, suggesting that Ricaurte constitutes a genetic cluster of FXS.

Clinical and molecular correlates in fragile X premutation females.

The prevalence of the fragile X premutation (55-200 CGG repeats) among the general population is relatively high, but there remains a lack of clear understanding of the links between molecular biomarkers and clinical outcomes. In this study we investigated the correlations between molecular measures (CGG repeat size, FMR1 mRNA, FMRP expression levels, and methylation status at the promoter region and in FREE2 site) and clinical phenotypes (anxiety, obsessive compulsive symptoms, depression and executive function deficits) in 36 adult premutation female carriers and compared to 24 normal control subjects. Premutation carriers reported higher levels of obsessive compulsive symptoms, depression, and anxiety, but demonstrated no significant deficits in global cognitive functions or executive function compared to the control group. Increased age in carriers was significantly associated with increased anxiety levels. As expected, FMR1 mRNA expression was significantly correlated with CGG repeat number. However, no significant correlations were observed between molecular (including epigenetic) measures and clinical phenotypes in this sample. Our study, albeit limited by the sample size, establishes the complexity of the mechanisms that link the FMR1 locus to the clinical phenotypes commonly observed in female carriers suggesting that other factors, including environment or additional genetic changes, may have an impact on the clinical phenotypes. However, it continues to emphasize the need for assessment and treatment of psychiatric problems in female premutation carriers.

Calibración y validación de la Razón Internacional Normatizada (RIN) en pacientes cirróticos / Calibration and Validation of the International Normalized Ratio (INR) in Cirrhotic Patients

El MELD es un modelo pronóstico de score matemático usado para priorizar los pacientes en lista de espera para trasplante hepático, incluye resultados de creatinina, bilirrubina y tiempo de protrombina expresado como RIN. La disparidad en el score MELD como resultado de la variabilidad interlaboratorio de los componentes de la formula nos lleva a cuestionar la validez del mismo como herramienta de medición objetiva para la locación del órgano. El motivo de utilizar el MELD se basa en la presunción que el score debería ser igual en distintos lugares, si los métodos utilizados para medir las distintas variables llegaran al mismo resultado numérico. La evidencia muestra que la metodología utilizada para las mediciones puede influenciar en el cálculo del MELD identificando al RIN como la variable más importante. Esta variabilidad está dada por la distinta procedencia biológica de las tromboplastinas y de su ISI el cual refleja la capacidad de respuesta de la tromboplastina a la disminución de los factores de coagulación dependientes de la vitamina k. El RIN estandariza el tiempo de protrombina durante la anticoagulación oral, su uso se extendió para estandarizar el tiempo de protrombina en la enfermedad hepática y se incluyó en los modelos pronósticos como el MELD. Sin embrago los mecanismos de prolongación del tiempo de protrombina en la enfermedad hepática difieren de aquellos implicados en la anticoagulación oral y las tromboplastinas difieren en su sensibilidad para detectar las variaciones en los diferentes mecanismos. Tripodi y Velez han propuesto que los valores de ISI para las distintas tromboplastinas deberían ser calculados con plasmas de pacientes cirróticos y así calcular el RIN hepático lo que resolvería la variabilidad relacionada al RIN en el cálculo del MELD.

MELD is a prognostic model from amathematical score used to prioritize patients on a waiting list for liver transplantation and includes creatinine, bilirubin and prothrombin time expressed as an INR. The disparity in the MELD score, as a result of interlaboratory variability of the formula components, has lead us to question its validity as an objective measuring tool to localize the organ. The reason to use the MELD is based on the assumption that the score should be the same through different places, if methods used to measure the different variables reached the same numerical results. The evidence shows that the methods used in measuring can affect the MELD assessment by identifying the INR as the most important variable. This variability is caused by the different biological origin of the thromboplastins and their ISI, which reflects the thromboplastin's capacity of response to the decrease of vitamin K-dependent coagulation factors. The INR standardizes the prothrombin time during oral coagulation; its use was extended to standardize the prothrombin time in liver disease and was included in prognostic models like MELD. However, the mechanisms to extend the prothrombin time in liver disease are different from those involved in oral anticoagulation and the sensitivity of thromboplastins differ when detecting the variations in the different mechanisms. Tripodi and Velez have proposed that the ISI values for the different thromboplastins should be calculated on the basis of plasma from cirrhotic patients and thus the liver IRN should be calculated as well, which would resolve the variability associated to the IRN in calculating the MELD.

Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome.

OBJECTIVES: Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS. METHODS: Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24-72months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models. RESULTS: A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P=0.008) and the cognitive T score (P=0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study. CONCLUSION: This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings.

Phenobarbital use and neurological problems in FMR1 premutation carriers.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55-200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital. Here we present a study of three sisters with the premutation who were exposed differentially to phenobarbital therapy throughout their lives, allowing us to compare the neurological effects of this drug in these patients.

Ultrasonographic assessment of enthesitis in HLA-B27 positive patients with rheumatoid arthritis, a matched case-only study.

INTRODUCTION: HLA-B27 has a modifier effect on the phenotype of multiple diseases, both associated and non-associated with it. Among these effects, an increased frequency of clinical enthesitis in patients with Rheumatoid Arthritis (RA) has been reported but never explored again. We aimed to replicate this study with a sensitive and quantitative assessment of enthesitis by using standardized ultrasonography (US). METHODS: The Madrid Sonography Enthesitis Index (MASEI) was applied to the US assessment of 41 HLA-B27 positive and 41 matched HLA-B27 negative patients with longstanding RA. Clinical characteristics including explorations aimed to evaluate spondyloarthrtitis and laboratory tests were also done. RESULTS: A significant degree of abnormalities in the entheses of the patients with RA were found, but the MASEI values, and each of its components including the Doppler signal, were similar in HLA-B27 positive and negative patients. An increase of the MASEI scores with age was identified. Differences in two clinical features were found: a lower prevalence of rheumatoid factor and a more common story of low back pain in the HLA-B27 positive patients than in the negative. The latter was accompanied by radiographic sacroiliitis in two HLA-B27 positive patients. No other differences were detected. CONCLUSION: We have found that HLA-B27 positive patients with RA do not have more enthesitis as assessed with US than the patients lacking this HLA allele. However, HLA-B27 could be shaping the RA phenotype towards RF seronegativity and axial involvement.

Influencia de las hormonas sexuales en mujeres con esclerosis múltiple durante la memoria de trabajo y la activación cerebral medida con mapeo electroencefalográfico / Influence of sex hormones in women with MS during the working memory and brain activation measured by electroencephalogram mappin

La Esclerosis Múltiple es una enfermedad inflamatoria desmielinizante del Sistema Nervioso Central, que se presenta con más frecuencia en mujeres, lo cual sugiere que las hormonas sexuales parecen modular la manifestación de la sintomatología. La actividad electroencefalografíca no ha sido evaluada en mujeres con Esclerosis Múltiple durante el procesamiento de Memoria de Trabajo y su estado hormonal. Los registros se realizaron en las fases folicular y lútea del ciclo menstrual de manera simultánea la tarea cognitiva y el electroencefalograma, además se correlacionaron con los niveles hormonales. La fase lútea mostró una ejecución mejor con un mayor número de categorías alcanzadas (p<0.004), un menor número de errores perseverativos (p<0.003) y un mayor número de ensayos para alcanzar una categoría (p<0.011), se asoció con un aumento de la actividad de Theta (p<0.018) y Alfa 2 (p<0.000). El 92 por ciento de la variabilidad en el número de ensayos de la tarea, fue explicada por la actividad de Theta y Alfa 2, Hormona Luteinizante y Estrona en la fase folicular, en la fase lútea el 90 por ciento de la variabilidad fue explicada por la actividad de Theta, Hormona Luteinizante, Progesterona y Estradiol. La Memoria de trabajo mejora en la fase lútea del ciclo menstrual, sugiriendo que la progesterona parece facilitar actividad de Theta.

Multiple Sclerosis is an inflammatory demyelinating CNS disease that occurs most often in women, suggesting that sex hormones appear to modulate the manifestation of symptoms. EEG activity has not been evaluated in women with MS during the processing of MT and hormonal status. The recordings were made in the follicular and luteal phases of the menstrual cycle a simultaneous cognitive task and EEG also were correlated with hormone levels. The luteal phase showed a better performance with a greater number of categories achieved (p <0.004), fewer perseverative errors (p <0.003) and greater number of trials to reach a category (p <0.011) was associated with increased theta activity (p <0.018) and Alpha 2 (p <0.000). 92 percent of the variability in the number of trials of the task was explained by the activity of Theta and Alpha 2, LH and estrone levels in the follicular phase, luteal phase, 90 percent of the variability was explained by the activity of theta, LH, progesterone and stradiol. The MT improvement in the luteal phase of the menstrual cycle, suggesting that progesterone seems to facilitate Theta activity.

¿Por qué solicitamos estudios diagnósticos de síndrome antifosfolípido? / Why do we request diagnostic studies of antiphospholipid syndrome?

El síndrome antifosfolípido (SAF) es una condición autoinmune caracterizada por trombosis arterial, venosa o de la microvasculatura, y/o patología obstétrica; asociada con la presencia de anticuerpos antifosfolípidos. Objetivos: Revisar las causas clínicas que motivan estudios de SAF en el Hospital El Cruce (HEC). Establecer el porcentaje de positividad en las muestras derivadas de la red sin datos clínicos. Metodología: serie de casos. Estudio descriptivo retrospectivo de resultados obtenidos de pacientes con rango de edad de 0 a 85 años que fueron estudiados en el HEC en el período comprendido entre el 01/05/2010 al 31/05/2011 con motivo de solicitud de estudios de SAF en historia clínica del HEC; HGZA "Mi Pueblo" de Varela y pacientes derivados de hospitales de la red sin datos clínicos. Resultados: Se analizaron resultados de 256 pacientes, 167 (65%) con datos clínicos: y 89 (35%) sin datos. En el grupo con datos los resultados fueron positivos en el 13,1 % y en el grupo sin datos el 5,6%. La diferencia entre la frecuencia de resultados positivos de los dos grupos de pacientes tiene una p: 0,06 (IC95: 0-14,2). Conclusiones: Observamos que la frecuencia de resultados positivos en el grupo con datos clínicos fue superior al doble que en el grupo sin datos clínicos. La diferencia señala la importancia de contar con una adecuada evaluación clínica previa a la solicitud de estudios de SAF.

[Variation of the lipids and fatty acids in marine shrimps consumed in Venezuela]. / Variación de lípidos y ácidos grasos en camarones marinos consumidos en Venezuela.

There are three marine shrimp species in the Venezuelan internal market, two of them are native species, from fisheries, Farfantapenaeus brasiliensis and Litopenaeus schmitti, and one is an exotic species and farmed, L. vannamei. The objectives of this paper were to determine the possible variation of lipid content and fatty acid composition of these species, even under different culture conditions (e.g. feed used). The lipid content in all the species are higher (5 to 10 times) that the data from previous papers deal with marine shrimps, ranged from 4.8 to 10.9%, suggesting that its impact in the human health should be reviewed. At the same time, there were detected differences between the lipid content and fatty acids composition of the species. Wild L. schmitti had the highest lipid content (10.9%), following by wild F. brasiliensis (9.0%), cultured L. schmitti (4.8% to 7.1%) and cultured L. vannamei (5.1% to 6.2%). On the other hand, L. schmitti fed on commercial feed had the highest proportion of EPA and/or DHA, following by L. vannamei fed on the experimental feed, wild L. schmitti and fed with the experimental feed and wild F. brasiliensis.

Variación de lípidos y ácidos grasos en camarones marinos consumidos en Venezuela / Variation of the lipids and fatty acids in marine shrimps consumed in Venezuela

En el mercado interno venezolano se consumen, fundamentalmente, tres especies de camarones marinos, dos autóctonas, encontradas en su ambiente natural, Farfantapenaeus brasiliensis y Litopenaeus schmitti, y una introducida y cultivada, L. vannamei. El objetivo del presente trabajo fue el de determinar, si existe variación en la proporción de lípidos y el perfíl de ácidos grasos de estas especies, incluso bajo diferentes condiciones de cultivo (balanceados utilizados). El total de lípidos detectado en todas las especies y condiciones de cultivo es mayor que el indicado en la bibliografía existente, superándolos en 5 a 10 veces, con valores que oscilan entre 4,8 y 10,9 por ciento, por lo que su incidencia en la salud debería ser revisada. Se evidenció una diferencia en el porcentaje de lípidos, así como en el perfíl de ácidos grasos de las especies. El mayor porcentaje de lípidos fue detectado en L. schmitti salvaje (10,9 por ciento) seguido de F. brasiliensis salvaje (9,0 por ciento),L. schmitti cultivado (4,8 por ciento a 7,1 por ciento) y L. vannamei cultivado (5,1 por ciento a 6,2 por ciento). De los camarones estudiados, L. schmitti cultivado con el balanceado comercial aparece con mayor proporción de EPA y/o DHA, seguido de L. vannamei alimentados con el balanceado experimental, L. schmitti salvaje y alimentado con el mismo balanceado y F. brasiliensis salvaje