Bianca Curotto L

Caracterización clínico-genético-molecular de 45 pacientes chilenos con Síndrome de Prader Willi

Background: Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by neonatal hypotonia, retarded mental and motor development, hypogonadism, hyperphagia, morbid obesity and dysmorphic facial features. It has an incidence of 1:12.000-15.000 newborns and is caused by abnormalities in genes located in 15q11q13. PWS is one of the most frequent genetic disorders and microdeletion syndromes. It is also the most common cause of obesity from genetic origin and it was the first disease in which imprinting and uniparental disomy were recognized as cause of genetic disorders. Seventy to seventy five percent of PWS cases are due to 15q11q13 deletions, 20-25% to uniparental disomy and 1% to mutations in the imprinting center. Aim: To analyze the clinical, genetic and molecular features of patients with PWS, seen at one institution. Patients and methods: Retrospective review of 45 patients (27 males) with PWS seen at the Genetics Outpatient Clinic at INTA. Results: Twenty three (51.1%) patients had a delection, 13 (28.9%) patients did not have a deletion. In nine patients, fluorescence in situ hybridization (FISH) study was not performed, therefore the presence of deletion was unknown. The clinical score was 8 points for patients younger than 3 years (n=11) and 11.5 points for patients older than 3 years (n=34); for patients aged 12 months or less, the clinical score was 7 points. Mean clinical score was 11 points for patients with deletion and 10 points for patients without deletion. Conclusions: Most patients with PWS have a deletion; the phenotype depends on age and the clinical score is useful for Chilean patients with PWS (Rev Med Chile 2005; 133: 33-41).

Tamizaje clínico y análisis de mutaciones en el gen FMR1 en 99 varones con características clínicas del síndrome de X-frágil

Introduccion: El sindrome de X fragil (SXF) es una causa frecuente de retraso mental (RM), se presenta en 1 de 4 000 hombres y en 1 de 8 000 mujeres. A nivel molecular existen principalmente tres tipos de alteraciones: premutacion, mutacion completa y mosaicos, todas las cuales corresponden a amplificacion del trinucleotido CGG localizado en el primer exon del gen FMR1: las premutaciones presentan entre 52 y 200 repetidos; las mutaciones completas, sobre 200 CGG, presentan hipermetilacion de la region promotora del gen FMR1 e inhibicion de la expresion de la proteina FMRP, causante del RM y dismorfias caracteristicas de este sindrome. Los mosaicos presentan mutacion completa y premutacion o metilacion parcial del gen FMR1. Los pacientes con SXF son diagnosticados clinicamente segun un protocolo de tamizaje que considera 15 caracteristicas clinicas que entrega un puntaje maximo de 30 puntos en individuos afectados. Objetivo: Definir criterios clinicos especificos para poblacion chilena que ayuden a identificar a los individuos que deban ser sometidos a estudios moleculares confirmatorios de SXF. Pacientes y Metodo: Se consideraron 99 pacientes varones referidos al INTA por presentar retraso mental y caracteristicas clinicas sugerentes del SXF; a todos se les realizo evaluacion clinica utilizando el protocolo descrito por Buttler y estudio molecular con analisis directo del gen FMR1 por Southern blot. Resultados: 23 de los 99 pacientes estudiados presentaron una mutacion en FMR1 y puntaje clinico entre 16 y 27 puntos; los 76 casos restantes con puntajes clinicos entre 10 y 26 puntos, no presentaron mutacion en el gen FMR1. Se evaluaron las caracteristicas clinicas en ambos grupos y se observo que 4 de ellas se asocian significativamente a la mutacion, siendo tres de ellas independientes de la edad de los pacientes. Conclusiones: Con estos resultados y a fin de optimizar el estudio molecular directo del gen FMR1, proponemos que el criterio de seleccion de pacientes sea a traves del examen clinico y que todo individuo con puntaje ³ 15 puntos debe ser sometido al estudio molecular

Diagnóstico molecular de los síndromes de Prader-Willi y de Angelman: análisis de metilación, citogenética y FISH

Background: The diagnosis of Prader-Willi and Angelman syndromes is difficult, since their phenotypic manifestations are variable and unspecific. The study of the methylation state of DNA in l5(q11-q13) using polymerase chain reaction, called methylation test, allows the diagnosis of most patients with Prader-Willi and Angelman syndromes, irrespective if the underlying molecular alteration is a deletion, uniparental disomy or a punctual imprinting mutation. Aim: To assess the effectiveness of methylation test in the diagnosis of Prader-Willi and Angelman syndromes. Patients and methods: Thirty seven cases with a presumptive diagnosis of Prader-Willi syndrome and 25 with the presumptive diagnosis of Angelman syndrome were studied. Methylation test was done in genomic DNA obtained from peripheral Iymphocytes. Results: Methylation test confirmed the clinical diagnosis in 11 of 37 patients with PraderWilli (30%) and 6 of 25 patients with Angelman syndrome (24%). Conclusions: Clinical criteria overestimate the diagnosis of Prader-Willi and Angelman syndromes. The initial diagnosis should be confirmed with the methylation test and, if necessary, with FISH that will detect most deletions in the region. (Rev Med Chile 2001, 129: 367-374)

Hallazgos citogenéticos en pacientes con síndrome de Down

In order to describe the frequency of non classical forms of 21 trisomy in patients with Downs syndrome at the cytogenetics laboratory of our institution (Instituto de Nutricion y Tecnologia de los Alimentos, Universidad de Chile) 201 chromosomal studies from peripheral blood lymphocytes of patients referred with a clinical diagnosis of Downs syndrome were analyzed. Among them 22 (11%) cases showed no chromosomal abnormalities, 161 (80%) had classic 21 trisomy, 7 (3.5%), showed 21 trisomy by translocation, 5 (2.5%) had 21 trisomy mosaicism, 6 (3%) showed 21 trisomy plus an autosomic balanced translocation. Male to female rate was 1.18:1 and diagnosis was done at the neonatal period in 26.8% of cases. Early recognition of the different kinds of chromosomal abnormalities in Downs syndrome is important if appropriate genetic council is the goal.