Aspectos genómicos, transcriptómicos y del diagnóstico en el síndrome de Down / Genomic, transcriptomic, and diagnostic features of Down syndrome

El síndrome de Down es causado por la presencia de una tercera copia del cromosoma 21 y fue descrito por primera vez en 1838 por Jean-Etienne-Dominique, y más tarde por John Langdon Haydon Down en 1866, mientras trabajaba como superintendente médico en el Asilo Real de Earlswood. Desde ese momento, la comunidad científica puso grandes esfuerzos en tratar de elucidar diversos aspectos que influyen en la naturaleza de esta condición, y que determinan su incidencia y factores de riesgo. De igual manera, se ha puesto interés en los genes involucrados en esta enfermedad, la relación genotipo-fenotipo, la expresión del fenotipo, la variabilidad del material genético y las consecuencias transcripcionales que se producen al tener una tercera copia, ya sea parcial o total, del cromosoma 21. Además, se han invertido esfuerzos en identificar biomarcadores y en diseñar metodologías de diagnóstico prenatal no invasivo que sean altamente eficientes para un mejor diagnóstico del síndrome de Down, y así reducir su impacto negativo en las madres gestantes, al proveerlas de información neutral y precisa acerca de vivir con un hijo con síndrome de Down, y darles autonomía en la decisión de la continuación de su embarazo

Down syndrome is caused by the presence of a third copy of chromosome 21 and was first described by Jean-Etienne-Dominique in 1838, and later by John Langdon Haydon Down in 1866, while working as a medical superintendent in the Royal Earlswood Asylum. Since, the scientific community has placed great efforts in trying to elucidate different influencing features in the nature of this condition that determine their incidence and risk factors. In addition, especial attention has been given to the genes involved in this disease, the genotype-phenotype relationship, the expression of the phenotype, the variability of the genetic material and the transcriptional consequences that are produced by having a third copy, either partial or total, of chromosome 21. Additionally, efforts have been invested in identifying biomarkers and designing noninvasive prenatal methodologies that are highly efficient for a better diagnosis of Down syndrome, in order to reduce its negative impact in pregnant mothers, by providing them with neutral and accurate information about life with a child with Down syndrome, as well as providing the autonomy in the decision to continue their pregnancy

Efeito da fisioterapia aquática na força muscular respiratória de crianças e adolescentes com Síndrome de Down / Effect of aquatic physioterapy on the respiratory muscle strength of children and teenagers with Down Syndrome

A força muscular respiratória em crianças e adolescentes com Síndrome de Down é comprometida pela hipotonia generalizada que os acometem. Analisar os efeitos da fisioterapia aquática na força muscular respiratória em crianças e adolescentes com síndrome de Down. Estudo de intervenção, quasi-experimental, com amostra constituída de oito crianças e adolescentes diagnosticados com SD e média de idade de 12 anos (± 3,8). Foram realizadas 10 sessões de fisioterapia aquática, com 50 minutos de duração cada, em piscina com água aquecida. A força muscular respiratória foi avaliada a partir da pressão inspiratória máxima (PImáx) e pressão expiratória máxima (PEmáx) com auxílio do manuvacuômetro, sendo obtido seus valores antes do primeiro atendimento e após o último. Analisou-se ainda a saturação periférica de oxigênio e frequência cardíaca. Para comparação das médias antes e depois da intervenção foi utilizado o Teste T pareado. Amostra de indivíduos predominantemente do sexo feminino (75,0%), pardos (75,0%) e residentes em zona urbana (87,5%). A comparação da PImáx e PEmáx antes e após as 10 sessões de fisioterapia aquática evidenciou melhora da força muscular inspiratória e expiratória, sendo tais diferenças estatisticamente significantes (valor de p<0,01). Também foram notadas melhorias na frequência cardíaca e saturação de oxigênio (valor de p<0,05) com a intervenção. Destaca-se neste estudo que a fisioterapia aquática parece ser um recurso terapêutico eficiente para o fortalecimento da musculatura respiratória e melhora dos sinais vitais de crianças e adolescentes de com diagnóstico de Síndrome de Down.

Respiratory muscle strength in children and adolescents with Down syndrome is compromised by the generalized hypotonia that affects them. This study aims to analyze the effects of aquatic physical therapy on respiratory muscle strength in children and adolescents with Down syndrome. Material and method: A quasi-experimental study with a sample consisting of eight children and adolescents diagnosed with DS and mean age of 12 years (± 3.8). Ten sessions of aquatic physiotherapy were performed, each with a duration of 50 minutes, in a pool with heated water. Respiratory muscle strength was assessed from maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) using a manuvacuometer, and its values were obtained before the first session and after the last one. Peripheral oxygen saturation and heart rate were also analyzed. The paired T-test was used to compare the means before and after the intervention. Sample of predominantly female (75.0%), brown (75.0%) and urban residents (87.5%). The comparison of MIP and MEP before and after the 10 sessions of aquatic physiotherapy showed an improvement in inspiratory and expiratory muscle strength, and these differences were statistically significant (p <0.01). Improvements in heart rate and oxygen saturation (p value <0.05) were also noted with the intervention. In this study, aquatic physiotherapy seems to be an efficient therapeutic resource for the strengthening of respiratory muscles and improvement of the vital signs of children and adolescents diagnosed with Down's Syndrome.

A Case of Transient Myeloproliferative Disorder Associated with Clonal Trisomy 21 in a Chromosomally Normal Newborn / 임상소아혈액종양

Transient myeloproliferative disorder (TMD) is similar to congenital leukemia, with leukocytosis, increased peripheral blast cells, and hepatomegaly in the neonatal period. Although TMD occurs only in patients with Down syndrome and trisomy 21 mosaicism, there have been reports of congenital leukemia with trisomy 21 limited to hematopoietic cells showing spontaneous resolution. We identified trisomy 21 in the leukemic cells in a patient with congenital leukemia. As there was no other gene abnormality, we stopped chemotherapy, and the disease resolved spontaneously. We reviewed the cases of clonal trisomy 21 TMD and found that their clinical features were similar to those of TDM associated with Down syndrome. In conclusion, in a phenotypically normal patient with suspected congenital leukemia, it is necessary to confirm the presence of 21 trisomy. If the neonate has only trisomy 21 without other gene abnormalities, intensive chemotherapy may not be required.

A eficácia da estimulação cortical no desenvolvimento perceptivo motor de adolescentes com síndrome de Down / The efficacy of cortical stimulation in the motor perceptual development of adolescents with Down syndrome

Objetivo: Avaliar a eficácia da estimulação cortical no desenvolvimento perceptivo motor de adolescentes com Síndrome de Down (SD). Métodos: Realizou-se um estudo experimental, com 36 adolescentes com idade compreendida entre 13 a 17 anos de idade, estudantes da Associação de Pais e Amigos dos Excepcionais, divididos em grupo controle (GA) e grupo experimental (GB). Foram avaliados pelo teste de processamento mental e como procedimento de intervenção utilizou-se o programa de estimulação cortical que foi realizado através de estímulos auditivos por vias de batidas. Resultados: Obteve-se para GBXGA um valor significativo entre os blocos F= 21.08 um p <0.01, portanto o melhor desempenho dos participantes do GB, não foi ao acaso, pois para dirimir qualquer dúvida aplicou-se o teste de Turkey, que revelou para uma variância Q= 0.08 um p<0.01. Conclusão: Dessa forma a presente pesquisa constatou a eficácia que a estimulação cortical proporcionou na melhora significativa no desenvolvimento perceptivo motor dos adolescentes com SD.

Objective: To evaluate the efficacy of cortical stimulation in the motor perceptive development of adolescents with Down syndrome (DS). Methods: An experimental study was carried out with 36 adolescents between the ages of 13 and 17, students of the Association of Parents and Friends of the Exceptional, divided into control group (GA) and experimental group (GB). They were evaluated by the mental processing test and as an intervention procedure the cortical stimulation program was performed through auditory stimuli by beat pathways. Results: A significant value was found for GBXGA between the F= 21.08 and p<0.01 blocks, so the best performance of the participants in GB was not random, since the Turkey test was used to resolve any doubts. Revealed for a variance Q= 0.08 a p <0.01. Conclusion: In this way the present research verified the effectiveness that the cortical stimulation provided in the significant improvement in the motor perceptive development of the adolescents with DS.

Inversión inusual del cromosoma 21 en una paciente abortadora habitual / Chromosome 21 Inversioninusual in a Recurrent Abortion Patient

Las inversiones pericéntricas están entre los reordenamientos cromosómicos balanceados más usuales, con una frecuencia de un 1-2 %. Al laboratorio de citogenética del Centro Nacional de Genética Médica se remite una paciente con múltiples abortos del primer trimestre del embarazo. Se realizó el cariotipo en sangre periférica a una resolución de 450 bandas. La paciente presentó una inusual inversión pericéntrica del cromosoma 21 con la fórmula cromosómica 46,XX,inv (21) (p11.2 q21.1). Se discuten los posibles gametos resultantes de la segregación meiótica en esta paciente y se valoran los riesgos de abortos e hijos malformados teniendo en cuenta los puntos de ruptura en el 21.

Pericentric inversions are among the most frequent chromosomal rearrangements with a frequency of 1-2 %. A woman with repeated first trimester pregnancy loss was referred to cytogenetic laboratory of The National Center of Human Genetics. A karyotype conventional banding technique at resolution of ~450 was made. The patient presented an unusual pericentric inversion 46,XX,inv (21)(p11.2 q21.1). The possible gametes as result of crossover events (during the pachytene stage of meiosis I) were discussed. The risk of miscarriages and malformed children were evaluated according the breakpoint in 21 chromosome.

Extracellular chromosome 21-derived microRNAs in euploid & aneuploid pregnancies.

Background & objectives: Trisomy 21 is the most common chromosomal aneuploidy in live born infants. Recently, the over expression of chromosome 21-derived microRNAs (miR-99a, let-7c, miR-125b-2, miR-155 and miR-802) in human fetal hippocampus and heart samples from individuals with Down syndrome was observed. Therefore, concentrations and expression profile of extracellular chromosome 21-derived microRNAs were studied to verify their ability to distinguish noninvasively between pregnancies bearing euploid fetuses and those affected with Down syndrome. Methods: RNA enriched for small RNAs was isolated from plasma samples of 12 pregnant women with high risk of bearing Down syndrome foetuses (median gestation 18.5 wk), 12 women with normal course of gestation and 10 non-pregnant women. MicroRNA transcribed into cDNA using specific stem-loop primer was detected using real-time PCR assay. Simulation experiments using RNA pools of healthy non-pregnant individuals and aneuploid amniotic fluid samples in descending dilution ratio ranging from 1:1 to 1000:1 were used to test the detection limit of the technique for overexpressed chromosome 21-derived microRNAs specific for Down syndrome. The expression profile of the gene encoding microRNA was studied through the relative gene expression using the comparative Ct (threshold cycle) method. Concentrations of individual microRNAs were subtracted from the calibration curves in the course of analyses and expressed as pg of total RNA per milliliter of plasma. Results: Four of the five extracellular chromosome 21-derived microRNAs (miR-99a, let-7c, miR-125b-2 and miR-155) were reliably detected in plasma samples. Simulation experiments revealed the detection limit of aneuploidy at a ratio 100:1 for let-7c, miR-125b-2 and miR-155, and a ratio of 1000:1 for miR-99a. Overexpression of extracellular miR-99a, miR-125b-2 and miR-155 was observed in pregnant women compared to non-pregnant women. Similarly, increased concentrations of extracellular miR-99a and miR-125b-2 were detected in pregnant women than in non-pregnant women. The concentrations and relative gene expression of extracellular chromosome 21-derived microRNAs did not differ between the cohorts of pregnancies bearing euploid foetuses and those affected with Down syndrome. Interpretation & conclusions: Analysis of extracellular chromosome 21-derived microRNAs has no benefit for screening programmes and non-invasive diagnosis of Down syndrome.

Dyslipidemia and Superoxide Dismutase Activity in Children with Down Syndrome.

Introduction: Down Syndrome (trisomy 21) provides an interesting natural model to study atherosclerosis, since these individuals appear to be protected from plaque formation. Methodology: We assessed the lipid levels, and superoxide dismutase (SOD) activity in 32 clinically diagnosed children of Down syndrome and 34 children matched for age and sex as controls. Results: SOD activity was found to be significantly higher (p=0.004) in children with Down Syndrome (mean=313.7 IU/ml) than in controls (mean140.2 IU/ ml). Significantly higher levels of serum triglyceride (154.7 mg/dl) and VLDL (33.9 mg/dl) were observed in Down Syndrome as compared to healthy controls (119.6 mg/dl and 23.9 mg/dl respectively; p<0.05 for each). However, the two groups did not show any significant difference in levels of serum HDL-C, LDL-C. Conclusion: The raised antioxidant activity of SOD, because of over expression of genes situated non chromosome 21, probably offers some protection against the development of atherosclerosis despite the occurrence of dyslipidemia.

Diagnóstico molecular de cromosomopatías fetales en Costa Rica / Molecular diagnosis of fetal chromosomal defects in Costa Rica

En Costa Rica, el diagnóstico de anomalías cromosómicas fetales se realiza solo mediante el análisis citogenético convencional de cromosomas obtenidos de cultivos celulares. Además de que la espera por los resultados puede ser larga, con alguna frecuencia fracasa el cultivo, por contaminación o por mala calidad de la muestra, o las figuras mitóticas no se pueden analizar, por lo que es necesario disponer de una metodología sencilla y barata, para obtener un diagnóstico prenatal rápido y fiable de trisomía 21, 18 ó 13, en embarazos de alto riesgo genético sometidos a amniocentesis o cordocentesis. Métodos: Se diseñaron tres PCRs multiplex para amplificar cuatro distintas repeticiones cortas en tándem, de cada uno de los cromosomas 21, 18 y 13. Se colectaron 93 muestras (88 líquidos amnióticos y 5 sangres fetales), recibidas en el laboratorio entre 2006 y 2008, con solicitud de análisis cromosómico. Los resultados de la reacción en cadena de la polimerasa cuantitativa fluorescente, fueron comparados con el cariotipo obtenido de las mismas muestras para demostrar la fiabilidad del ensayo. Resultados: Para este grupo de datos, la exactitud del ensayo fue del 100 por ciento y se consiguió obtener resultados en 48 horas. Se logró realizar el análisis de repeticiones cortas en tándem en el 77 por ciento de las muestras en las que no se pudo obtener crecimiento celular. Conclusión: La reacción en cadena de la polimerasa cuantitativa fluorescente demostró ser una metodología sencilla, fiable y rápida, por lo que podría convertirse en una herramienta complementaria del análisis cromosómico convencional. La obtención de resultados rápidos en casos de diagnóstico prenatal podría disminuir el periodo de ansiedad parental por la espera de los resultados, así como permitir un mejor abordaje terapéutico de los fetos afectados.

In Costa Rica, the diagnosis of chromosomal fetal anomalies is realizedonly by conventional cytogenetic analysis of chromosomes obtained from cellular cultures. The waiting for the results can be long. Moreover with some frequency culture fails due tocontamination or bad quality of the sample or they cannot be analyzed. This makes it necessary to have a simple and cheap methodology to obtain an accurate and rapid fetal diagnosis of trisomy 21, 18 or 13, in pregnancies of high genetic risk submitted to amniocentesis or cordocentesis. Materials and methods: Three multiplex PCRs were designed to amplify four different short tandem repeats of each of the chromosomes 21, 18 and 13. There were collected 93 samples (88amniotic fluids and 5 fetal bloods), received in the laboratory between 2006 and 2008 with request ofor chromosomal analysis. The results of the quantitative fluorescent PCR werecompared with the obtained cariotype of the same samples to stablish the accuracy demonstrate the reliability of the assay. Results: Accuracy of the assay was 100% and it was possible to obtain results within 48 hours.STRs analysis could be made in 77% of the samples where the cellular culture could not be done. Conclusion: The quantitative fluorescent PCR demonstrated to be a simple, accurate and rapid methodology, from what it might turn into a complementary tool of the chromosomal conventional analysis. The securing of rapid results in cases of antenatal diagnosis might diminish the period of anxiety parental for the waiting of the results, as well as to allow a better therapeutic management of the affected fetuses.

A Case of Ring Chromosome 21 with Multiple Congenital Anomalies

Ring chromosome 21 causes a multitude of phenotypes, ranging from severe abnormalities to normal. The proposed mechanism of ring formation, breakage of both short and long arms of a chromosome with subsequent end to end fusion, remains unproven. We encountered a 4-year-old boy who presented developmental delay, microcephaly, micrognathia, hypertelorism, low-set ears, mild optic nerve hypoplasia, cleft lip and palate, scoliosis and left foot valgus, but normal brain MRI. Chromosome study from peripheral blood showed 46,XY, r(21)(p11.2q22.1) karyotype. The authors report the first case of ring chromosome 21 in Korea with a review of the literature.

The Clinical Features and Prognosis of Leukemia in Down Syndrome / 대한소아혈액종양학회지

PURPOSE: There are several reports that the risk of development of leukemias is much higher in Down syndrome (DS) children than in non DS children. But there are a few reports about the clinical features of leukemia in Down syndrome and the prognosis in Korea. The object of this study is to evaluate clinical features, treatment results and the prognosis of leukemia of Down syndrome patients. METHODS: We conducted retrospective reviews in 10 children with leukemia of Down syndrome who were admitted to the Department of Pediatrics in Yonsei University Hospital between March 1986 and December 2000. We analyzed the clinical features, laboratory findings and survival rates. RESULTS: A male to female ratio was 1:1.25. Median age at diagnosis was 2 years 8 months. Initial symptoms were hepatosplenomegaly, petechiae, fever and upper respiratory infection symptoms. The number of patients by the type was as followed:acute myeloid leukemia (AML) 7 (70%), acute lymphocytic leukemia 2 (20%), acute mixed lineage leukemia 1 (10%). There were 4 cases of M7 subtype in AML. The median peripheral blood cell counts were as followed; leukocyte was 41,000/muL, hemoglobin was 8.7 g/dL, the platelet was 103,000/muL. The five years event free survival rate after diagnosis was 87.5% (7/8). The one patient relapsed and another one patient died of cardiac anomaly. CONCLUSION: There seemed to be several differences of clinical features between DS leukemia and non DS leukemia, especially prognosis. Multi-centered well organized study should be done to confirm our observation.

Genetic polymorphism and forensic application of five novel STR loci / 中国输血杂志

0.85,and the exclusion probabilities ≥0.48.The independence test of 5 loci proved that there were no correlations between the two STRs in 5 pairs,which were LFG26 and LFG21,LFG20 and LFG24,LFG21 and LFG24,LFG24 and LFG26,LFG24 and LFG29.Therefore they could be used simultaneously.Conclusion The forensic study of 5 STRs on chromosome 21 revealed that LFG21,LFG24,LFG26 and LFG29 were good candidates as polymorphic markers for forensic DNA analysis.

Loss of Heterozygosity on the Long Arm of Chromosome 21 in Non-Small Cell Lung Cancer / 결핵

BACKGROUND: Non-small lung cancer(NSCLC) develops as a result of the accumulation of multiple genetic abnormalities. Loss of heterozygosity(LOH) is one of the most frequent genetic alterations that is found in NSCLC, and the chromosomal regions that display a high rate of LOH are though to harbor tumor suppressor genes(TSGs). This study was done to determine the frequency of LOH in 21q with the aim of identifying potential TSG loci. METHOD: Thirty-nine surgically resected NSCLCs were analysed. Patietns peripheral lymphocytes were used as the source of the normal DNA. Five microsatellite markers of 21q were used to study LOH : 21q21.1(D21S1432, and D21S1994) ; 21q21.2-21.3(D21S1442) ; 21q22.1(21S1445) ; and 21q22.2-22.3(D21S266). The fractional allelic loss(FAL) in a tumor was calculated as the ratio of the number of markers showing LOH to the number of informative markers. RESULT: LOH for at least one locus was detected in 21 of 39 tumors(53.8%). Among the 21 tumors with LOH, 5(21.8%) showed LOH at almost all informative loci. Although statistically not significant, LOH was found more frequently in squamous cell carcinomas(15 of 23, 65.2%) than in adenocarcinomas(6 of 16, 37.5%). In the squamous cell carcinomas the frequency of LOH was higher in stage II-III (80.0%) than in stage I (53.8%). The FAL value in squamous cell carcinomas(0.431±0.375) was significantly higher than that found in adenocarcinomas(0.192±0.276). CONCLUSION: These results suggest that LOH on 21q may be involved in the development of NSCLC, and that TSG(s) that contribute to the pathogenesis of NSCLC may exist on 21q.