[Fragile X syndrome]. / Síndrome X frágil.

INTRODUCTION AND DEVELOPMENT: Fragile X syndrome is the main inheritable genetic cause of mental retardation. It is a dynamic mutation and is due to the increase in the number of CGG triplets in exon 1 of the FMR1 gene, located in Xq27.3, and to the hypermethylation of the corresponding genomic region, which impedes production of messenger RNA and, therefore, of FMRP protein. Three types of alleles can be established, according to the number of repetitions: normal, with premutation and with full mutation. Only individuals with full mutation have fragile X syndrome. Two sub-phenotypes of the syndrome, associated to premutation, have recently been reported and are seen to appear from the fourth decade of life onwards. CONCLUSIONS: The number of female carriers of a premutation with early ovarian failure has increased, while reports have also appeared describing a neurological picture of intentional trembling and ataxia among carriers of the premutation (FXTAS).

[Monogenic causes of X-linked mental retardation]. / Causas monogénicas de retraso mental ligado a X.

INTRODUCTION AND DEVELOPMENT: The term X-linked mental retardation (XLMR) refers to a heterogeneous group of conditions that, on the basis of their presenting symptoms, have traditionally been classified as being syndromic (SMR) and non-syndromic or non-specific (XMR). The prevalence of XLMR in males is estimated to be 10%, excluding fragile X syndrome, which is the most common monogenic cause. There are over 100 genes involved in XLMR. In this work we review some of the phenotypes and genes involved in SMR. A small stature and coarse features indicate a suspected case of Coffin-Lowry syndrome, which is secondary to mutations of the RPS6KA3 or RSK2 genes. Cerebellar hypoplasia points towards alterations of the OPHN1 gene. In males with coarse features and genital abnormalities screening for alpha thalassemia must be carried out; this association results from mutations in the ATRX gene. Of the genes involved in mental retardation and epilepsy, the most notable are SLC6A8 (which triggers a deficit in creatine transport when altered and which is easily detected with respect to its biochemistry) and ARX (also associated to lissencephaly and dystonia of the hands). Mutations in the PQBP1 and JARID1C genes have been identified in patients with mental retardation associated to microcephaly and short stature. A high level of T3 hormone points towards defects in the SLC16A2 gene. Some of these genes have also been implicated in XMR, which makes this distinction less clear molecularly speaking. CONCLUSIONS: Systematic screening of all the genes involved in XLMR is not possible in clinical praxis today. It is important to search for differential phenotypic features in males with mental retardation that guide the study towards specific genes. Identification of the molecular defect will allow for correct genetic counselling. DNA microarrays for the study of different mutations in a large number of genes involved in mental retardation are the great hope for the future.

Causas monogénicas de retraso mental ligado a X / Monogenic causes of X-linked mental retardation

Introducción y desarrollo. El retraso mental ligado a X(RMLX) constituye un grupo heterogéneo de entidades que, basándoseen su presentación clínica, tradicionalmente se ha clasificadoen sindrómico (RMS) y no sindrómico o inespecífico (RMX). La prevalencia de RMLX en varones se estima en un 10%, excluido el síndromeX frágil, causa monogénica más frecuente. Existen más de100 genes implicados en el RMLX. En este trabajo se revisan algunosfenotipos y genes implicados en el RMS. La talla baja y rasgostoscos hace sospechar el síndrome de Coffin-Lowry, que es secundarioa mutaciones del gen RPS6KA3 o RSK2. La hipoplasia cerebelosaorienta a alteraciones del gen OPHN1. En varones con rasgostoscos y anomalías genitales se ha de hacer despistaje de alfa talasemia;esta asociación es el resultado de mutaciones en el genATRX. De los genes implicados en el retraso mental y la epilepsia,destacan SLC6A8 (cuya alteración provoca un déficit en el transportede la creatina, fácilmente detectable en cuanto a la bioquímica)y ARX (también asociado a lisencefalia y distonía de las manos).Mutaciones en los genes PQBP1 y JARID1C se han identificadoen pacientes con retraso mental asociado a microcefalia y tallabaja. La hormona T3 elevada orienta a defectos del gen SLC16A2.Algunos de estos genes también se han implicado en el RMX, por loque esta distinción es menos clara molecularmente. Conclusiones.El cribado sistemático de todos los genes implicados en RMLX no esposible hoy en la práctica clínica. Es importante buscar rasgos fenotípicosdiferenciales en los varones con retraso mental que dirijan elestudio a genes específicos. La identificación del defecto molecularpermitirá un asesoramiento genético certero. Los microarrays deADN para el estudio de diversas mutaciones de un gran número degenes implicados en el retraso mental son una gran esperanza parael futuro

Introduction and development. The term X-linked mental retardation (XLMR) refers to a heterogeneous group ofconditions that, on the basis of their presenting symptoms, have traditionally been classified as being syndromic (SMR) andnon-syndromic or non-specific (XMR). The prevalence of XLMR in males is estimated to be 10%, excluding fragile X syndrome,which is the most common monogenic cause. There are over 100 genes involved in XLMR. In this work we review some of thephenotypes and genes involved in SMR. A small stature and coarse features indicate a suspected case of Coffin-Lowrysyndrome, which is secondary to mutations of the RPS6KA3 or RSK2 genes. Cerebellar hypoplasia points towards alterationsof the OPHN1 gene. In males with coarse features and genital abnormalities screening for alpha thalassemia must be carriedout; this association results from mutations in the ATRX gene. Of the genes involved in mental retardation and epilepsy, themost notable are SLC6A8 (which triggers a deficit in creatine transport when altered and which is easily detected with respectto its biochemistry) and ARX (also associated to lissencephaly and dystonia of the hands). Mutations in the PQBP1 andJARID1C genes have been identified in patients with mental retardation associated to microcephaly and short stature. A highlevel of T3 hormone points towards defects in the SLC16A2 gene. Some of these genes have also been implicated in XMR,which makes this distinction less clear molecularly speaking. Conclusions. Systematic screening of all the genes involved inXLMR is not possible in clinical praxis today. It is important to search for differential phenotypic features in males with mentalretardation that guide the study towards specific genes. Identification of the molecular defect will allow for correct geneticcounselling. DNA microarrays for the study of different mutations in a large number of genes involved in mental retardationare the great hope for the future

Síndrome X frágil / Fragile X syndrome

Introducción y desarrollo. El síndrome X frágil constituyela mayor causa genética heredable de retraso mental. Se tratade una mutación dinámica y se debe al incremento del número detripletes CGG en el exón 1 del gen FMR1, localizado en Xq27.3, ya la hipermetilación de la región genómica correspondiente, queimposibilita la producción del ARN mensajero y, por tanto, de laproteína FMRP. Según el número de repeticiones se pueden establecertres tipos de alelos: normal, con premutación y con mutacióncompleta. Sólo los individuos con mutación completa presentan elsíndrome X frágil. Recientemente se han descrito dos subfenotiposen el síndrome, asociados a la premutación, que se presentan a partirde la cuarta década. Conclusión. Se ha producido un incrementode mujeres portadoras de premutación con fallo ovárico precoz,a la vez que se ha descrito un cuadro neurológico de temblores intencionalesy ataxia entre portadores de la premutación (FXTAS)

Introduction and development. Fragile X syndrome is the main inheritable genetic cause of mental retardation. It isa dynamic mutation and is due to the increase in the number of CGG triplets in exon 1 of the FMR1 gene, located in Xq27.3,and to the hypermethylation of the corresponding genomic region, which impedes production of messenger RNA and, therefore,of FMRP protein. Three types of alleles can be established, according to the number of repetitions: normal, with premutationand with full mutation. Only individuals with full mutation have fragile X syndrome. Two sub-phenotypes of the syndrome,associated to premutation, have recently been reported and are seen to appear from the fourth decade of life onwards.Conclusions. The number of female carriers of a premutation with early ovarian failure has increased, while reports have alsoappeared describing a neurological picture of intentional trembling and ataxia among carriers of the premutation (FXTAS)

[Congenital bilateral agenesis of the vas deferens associated with cystic fibrosis. A molecular genetic study]. / Agenesia congénita bilateral de vasos deferentes asociada a fibrosis quística. Estudio genético molecular.

OBJECTIVE: To analyze the association of congenital bilateral agenesis of the vas deferens and cystic fibrosis. METHODS: Three azoospermic patients with surgically confirmed congenital agenesis of the vas deferens in whom a molecular genetics study had been performed to discard the more common mutations of cystic fibrosis are described and the literature reviewed. RESULTS: All patients showed azoospermia. The molecular genetics study showed one of the patients to be a heterozygotic carrier of G542X and no other mutations like the remaining patients. CONCLUSIONS: 15% of patients with azoospermia have chromosomal anomalies. Recently, it has been reported that 50%-65% of patients with congenital bilateral agenesis of the vas deferens have mutations for the CFTR gene, with more than 400 reported. Patients with bilateral agenesis and their partners should be screened for cystic fibrosis prior to any in vitro fertilization techniques.

[A genetic and molecular study of 85 families affected with the fragile X syndrome]. / Estudio genético y molecular de 85 familias afectas del síndrome del cromosoma X frágil.

The objective of this study was to analyze clinically, cytogenetically and molecularly 85 Spanish families with fragile X syndrome. Clinical studies were based on the score proposed by Hagerman, cytogenetic studies were made by adding. 5-fluorodeoxiuridine and molecular studies were performed by using a StB12.3 probe and the polymerase chain reaction (PCR). The results of the molecular studies in 620 individuals at risk confirmed the clinical diagnosis of fragile X syndrome in 126 affected males. In addition, 197 carrier females were detected (48 with mental retardation) and 246 "at risk" individuals and 36 non-related members were found not to have the expansion. Fifteen cases of normal transmitting males (NTM) were detected. We found one non-mentally retarded male where the CpG island of the FMR-1 gene was not methylated, but with more than 200 (CGG)n repeats (high functioning male). In the sample studied, no de novo mutations were found and all of the mutations detected were (CGG)n expansions. PCR analysis of the (CGG)n repeat in 297 normal chromosomes showed an allele distribution that ranged from 17 to 54 repeats, with an allele of 29 (CGG)n repeats accounting for 24% of the chromosomes. In conclusion, molecular genetic study of fragile X provides accurate diagnosis and facilitates genetic counselling in families with affected members. Southern blot analysis and PCR of the (CGG)n repeat provides efficient diagnosis, compared to cytogenetic techniques, for the detection of female carriers, NTMs, and prenatal diagnosis.