Ataxina-2, nuevo blanco en enfermedades genéticas complejas / Ataxin-2, a new target in complex genetic diseases

Resumen El gen de la ataxina-2 es un blanco en la patogénesis de enfermedades complejas, entre ellas los factores de riesgo cardiovascular y enfermedades neurodegenerativas. El gen ATXN2 tiene un VNTR en el exón 1, cuya expansión por encima de las 30 repeticiones provoca al desarrollo de ataxia espinocerebelosa tipo 2; las repeticiones en rango menor se asocian con diabetes tipo 2 o esclerosis lateral amiotrófica. También este locus está ligado con fenotipos metabólicos e inflamatorios. En conclusión, el gen puede ser utilizado como marcador clínico de fenotipos metabólicos y neurológicos, lo cual está relacionado con su efecto pleiotrópico.

Abstract The ataxin 2 gene is a target in the pathogenesis of complex diseases, including cardiovascular risk factors and neurodegenerative diseases. ATXN2 gen has VNTR in exon 1, whose expansion exceeding 30 repetitions leads to the development of spinocerebellar ataxia type 2; lower-range repetitions are associated with type 2 diabetes or amyotrophic lateral sclerosis. This locus is also linked with metabolic and inflammatory phenotypes. In conclusion, this gene can be used as a clinical marker of metabolic and neurological phenotypes, which is related to its pleiotropic effect.

Hipertricosis cervical anterior: caso dínico / Anterior cervical hypertrichosis: case report

La hipertricosis cervical anterior no sindrómica (OMIM N° 600457) es un desorden genético caracterizado por un parche de pelo a nivel de la prominencia laríngea. Se presenta a un niño de 12 años de edad con hipertricosis cervical anterior e hipertricosis generalizada leve, sin alteraciones neurológicas, oftalmológicas ni esqueléticas, en seguimiento clínico por un lapso de 10 años.

The non-syndromic anterior cervical hypertrichosis (OMIM N° 600457) is a genetic disorder characterized by a patch of hair at the level of the laryngeal prominence. We present a 12-year-old boy with anterior cervical hypertrichosis and mild generalized hypertrichosis. He has no neurological, ophthalmological or skeletal anomalies. The clinical follow up is 10 years.

Adiposidade corporal, mas não resistência insulínica, associa-se ao polimorfismo -675 4G/5G no gene PAI-1 em uma amostra de crianças mexicanas / Body adiposity but not insulin resistance is associated with -675 4G/5G polymorphism in the PAI-1 gene in a sample of Mexican children

OBJETIVO: Elaboramos este estudo para avaliar se o polimorfismo -675 4G/5G no gene inibidor 1 do ativador do plasminogênio se associa à obesidade e à resistência insulínica em crianças mexicanas. MÉTODOS: Foi realizado um estudo transversal em 174 crianças, 89 delas com peso normal e 85 obesas, variando sua idade de 6 a 13 anos. Todas as crianças eram do estado de Guerrero e foram recrutadas de três escolas primárias na cidade de Chilpancingo, México. Os níveis de insulina foram determinados por prova imunoenzimática. Foi usado o modelo de avaliação da homeostase para determinar resistência insulínica. O polimorfismo -675 4G/5G no gene PAI-1 foi analisado pelo método reação de polimerase em cadeia-polimorfismo no comprimento dos fragmentos de restrição. RESULTADOS: A prevalência de resistência insulínica no grupo obeso foi mais alta (49,41%) do que no grupo com peso normal (16,85%). O polimorfismo 4G/5G do PAI-1 foi encontrado em equilíbrio de Hardy Weinberg. O genótipo 4G/5G contribuiu para um aumento significativo da relação cintura-quadril (β = 0,02, p = 0,006), da circunferência da cintura (β = 4,42, p = 0,009) e da espessura da prega subescapular (β = 1,79, p = 0,04), mas não se relacionou com a resistência insulínica. CONCLUSÃO: O genótipo -675 4G/5G do gene PAI-1 se associou a aumento da adiposidade corporal em crianças mexicanas.

OBJECTIVE: To assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. METHODS: A cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β = 0.02, p = 0.006), waist circumference (β = 4.42, p = 0.009), and subscapular skinfold thickness (β = 1.79, p = 0.04); however, it was not related with insulin resistance. CONCLUSION: The -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.

Polimorfismo en el codón 72 del gen p53 y riesgo de cáncer cérvico-uterino en México / Polymorphism in codon 72 of the p53 gene and cervico-uterine cancer risk in Mexico

A polymorphism at codon 72 in the p53 gen has been reported as a potential risk factor to cervical cancer (CC) because human papillomavirus (HPV) is more effective at degrading p53 Arg-72 than p53 Pro-72, making individuals homozygous for p53 Arg-72 seven times more likely to develop HPV-associated CC. As In Mexico the CC is a health public problem, we designed this study to determinate whether the p53 codon 72 polymorphism represent a risk factor to CC in our population. A case-controls study was performed. DNA was obtained from paraffin-embedded cervical fixed tissue samples. Analysis of the p53 genotype at position 72 was performed by polymerase chain reaction using specific primers and Accll digestion. Among cases with CC the proportions of the p53 genotypes at codon 72 were 0.05 to proline homozygous, 0.5 to heterozygous, and 0.45 to arginine-homozygous. In controls the proportions were 0.08, 0.62, and 0.31. X2 test showed no significant difference In the proportions. We conclude than In our population, as other worldwide countries, the homozygous for arginine at codon 72 of the p53 gene is not a risk factor to cervical cancer.

Mucopolisacaridosis tipo I, III y VI: actividad enzimática y determinación cualitativa y cuantitativa de glucosaminoglucanos urinarios / Mucopolysaccharidoses types I, III and VI: enzimatic activity quantitative and qualiatative determination of urinary glycosaminoglycans

Introducción. Las mucopolisacaridosis (MPS) son un grupo heterogéneo de enfermedades hereditarias, originadas por la deficiencia de enzimas lisosomales que catalizan la degradación de los glucosaminoglucanos (GAGs). Actualmente se conocen 11 deficiencias enzimáticas que originan 8 fenotipos distintos y expresan una variedad de síntomas clínicos. Material y métodos. Doce pacientes con diagnóstico clínico de MPS (4 con MPS I, 2 con MPS IIIB y 6 con MPS VI) dos fueron estudiados bioquímicamente mediante la cuantificación de GAGs urinarios, su identificación a través de electroforesis en acetato de celulosa y la correlación con la actividad enzimática en leucocitos. Resultados. En todos los casos la concentración de GAGs/creatinina estuvo elevada en comparación con un grupo control. La electroforesis reveló la presencia de los GAGs esperados en cada tipo de MPS y la actividad enzimática fue deficiente en los 12 pacientes estudiados. Conclusiones. La aplicación de los métodos anteriores en pacientes con MPS, es una poderosa herramienta a utilizar como diagnóstico.

Deteccion de Mycobacterium tuberculosis mediante la reaccion en cadena de la polimerasa en una poblacion seleccionada del noroccidente de Mexico / Detection of Mycobacterium tuberculosis with polymerase chain reaction in a selected population in northwestern Mexico

Este estudio compara la detección de Mycobacterium tuberculosis mediante baciloscopia (tinción de Ziehl-Neelsen), cultivo en medio de L"wenstein-Jensen y reacción en cadena de la polimerasa (RCP) realizada con ADN extraído directamente de distintos tipos de muestras. Se analizaron 252 muestras (114 de esputo, 96 de orina, 15 de LCR y 27 de otros tipos) de 160 pacientes con sospecha de tuberculosis en cualquiera de sus formas que acudieron al Laboratorio de Patología Clínica del Hospital de Especialidades del Centro Médico Nacional de Occidente del Instituto Mexicano del Seguro Social. En todos los casos se realizó tinción de Ziehl-Neelsen, cultivo en medio de L"wenstein-Jensen y amplificación por RCP de un segmento de 285 pares de bases específico del complejo M. tuberculosis. De las 252 muestras, 18 fueron positivas para micobacterias no tuberculosas en el cultivo. De las 234 restantes, 12 (5,1 por ciento) fueron positivas en la RCP y el cultivo, 174 (74,4 por ciento) negativas en ambas pruebas, 47 (20,1 por ciento) positivas en la RCP y negativas en el cultivo y 1 (0,4 por ciento) negativa en la RCP y positiva en el cultivo; tomando el cultivo como prueba de referencia, la RCP proporcionó una sensibilidad de 92,3 por ciento, una especificidad de 78,7 por ciento, un valor predictivo positivo de 20,3 por ciento y un valor predictivo negativo de 99,4 por ciento. El límite de detección de la RCP en ADN extraído de cultivo fue de 10 fg (equivalente a 4 o 5 micobacterias). También en comparación con el cultivo, la RCP identificó correctamente a la totalidad de las micobacterias del complejo M. tuberculosis. Tomando como prueba de referencia el cultivo, al analizar únicamente las muestras de esputo, la RCP directa proporcionó una sensibilidad de 90,9 por ciento, una especificidad de 89,5 por ciento, un valor predictivo positivo de 52,6 por ciento y un valor predictivo negativo de 98,7 por ciento. La RCP es una técnica sensible y específica para detectar el complejo M. tuberculosis en muestras tanto positivas como negativas en la baciloscopia. Un procedimiento controlado de RCP permite establecer o excluir el diagnóstico de tuberculosis en un tiempo que se reduce de m s de tres semanas a tan solo 24 a 48 horas, lo cual resulta particularmente útil cuando es necesario un diagnóstico temprano para establecer el pronóstico del paciente o en casos de transplante de órganos

This study compares the detection of Mycobacterium tuberculosis through bacilloscopy (Ziehl-Neelsen stain), growth in Lowenstein-Jensen medium, and polymerase chain reaction (PCR) carried out with DNA taken directly from various types of samples. A total of 252 samples were analyzed (114 sputum, 96 urine, 15 cerebrospinal fluid, and 27 of other types) from 160 patients with any form of suspected tuberculosis who came to the Clinical Pathology Laboratory of the Specialties Hospital of the Western National Medical Center of the Mexican Social Security Institute. In all cases ZiehlNeelsen stains were done, as were also cultures with Lowenstein-Jensen medium and PCR amplification of a segment of 285 base pairs specific to the M. tuberculosis complex. Of the 252 samples, with the culture, 18 were positive for nontuberculous mycobacteria. Of the 234 others, 12 (5.1%) were positive with the PCR and the culture, 174 (74.4%) negative in both tests, 47 (20.1%) positive with the PCR and negative with the culture, and 1 (0.4%) negative with the PCR and positive with the culture. Using the culture as the reference test, the PCR provided a sensitivity of 92.3%, a specificity of 78.7%, a positive predictive value of 20.3%, and a negative predictive value of 99.4%. The PCR detection limit with DNA taken from culture was 10 fg, equivalent to four or five mycobacteria. Also in comparison with the culture, the PCR correctly identified the totality of the mycobacteria of the M. tuberculosis complex. Taking the culture as the reference test, when analyzing just the sputum samples, the direct PCR provided a sensitivity of 90.9%, a specificity of 89.5%, a positive predictive value of 52.6%, and a negative predictive value of 98.7%. The PCR is a sensitive and specific technique for detecting the M. tuberculosis complex in both positive and negative bacilloscopy samples. A controlled PCR procedure makes it possible to establish or to exclude the diagnosis of tuberculosis in a time that is reduced from more than three weeks to just 24 to 48 hours. This is particularly useful when an early diagnosis is needed to establish a patient's prognosis or in organ transplant cases.

Linkage disequilibrium between IDUA kpnI-VNTR Haplotype in mexican patients with MPS-I

Background. The MPS-I is an autosomal recessive disorder caused by mutations in the IDUA gene that induce to a deficiency of glycosidase Ó-L-iduronidase that is required for degradation of heparan and dermatan sulfate. This disorder expresses a wide range of clinical symptoms. Methods. Kpnl (k) and VNTR (V) intragenic polymorphisms at the IDUA gene were studied in mestizo and Huichol Indian Mexican populations as well in 13 MPS-I patients. Data from Australian normal and MPS-I (2-4) individuals were also studied. Results. Genotypes for IDUA K and V sites in Mexicans were in agreement with hardy-Weinberg expectations, except for stie K in Huichols, Individually, allele frequency distributions were different (p< 0.05) in the two normal groups for the V site. K-V haplotype frequency distributions (HFDs) in these two normal groups were also different as compared with normal Australians. In Mexican MPS-I patients, HFD was different (p <0.05) with or MPS-I Australians. This can be taken as evidence of linkage disequilibrium between K-V polymorphism and MPS-I gene mutation(s) at the IDUA region. A similar finding was reported. However, disequilibrium in Mexicans was determined by haplotypes different from those in Australia. In Mexican MPS-I patients, haplotype K2-V1 is increased and K1-V3 decreades with respect to the Mexican mestizo (p < 0.05), while in Australians, MPS-I patients had an increase of haplotypes K2-V2 and K1-V2 with respect to expected frequency. Conclusions. The similar HFD between Mexican and australian MPS-I patients suggests a common genetic origin, that MPS-I mutations were introduced to Mexico by Spaniards, and that such mutations predate the dispersion between Mexican and Australian Caucasian ancestors. The differences in disequilibrium are explained rather by genetic drift

Mucopolysaccharidoses type II: Enzymatic activity and quantitative and qualitative studies of urinary glycosaminoglycans in five patients

Five patients presenting Hunter's syndrome were biochemically studied. Quantification of urinary glycosaminoglycans (GAGs), electrophoretic characterizatio and correlation with ensymatic activity in leucocytes were carried out. In all cases, urinary GAGs/creatinine ratio was increased. Electrophoresis revealed the presence of heparan sulfate (HS) and dermatan sulfate (DS) in four cases (80 perecent), but in the remaining patient, only DS was present. In all patients, deficient enzymatic activity was demonstrated. These results show evidences of biochemical differences in thys syndrome