Syndromic Form Of X-linked Mental Retardation Research Articles

A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25–q26

X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25–Xq27 encompassing 13.7 Mb with a maximum LOD score of 1.1 for marker DXS8038 at θ = 0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.

A new detection method for ATRX gene mutations using a mismatch‐specific endonuclease

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X, OMIM 301040) is a syndromic form of X-linked mental retardation (XLMR). It is caused by a mutation in the ATRX gene, which is also involved in other syndromic forms of XLMR as well as in non-syndromic XLMR, both in males and in females. To analyze the full range of disease-causing mutations for genetic counseling and to establish phenotype-genotype correlations, we have established a new screening method for mutations in the ATRX gene, which uses mismatch-specific endonuclease. We applied this method to confirm 13 known mutations in our patients, some of which have been difficult to be demonstrated by conventional denaturing high-performance liquid chromatography. Furthermore, we found four additional mutations in four ATR-X patients whose clinical diagnosis had not been confirmed at the molecular level. In this method, experimental conditions do not need to be altered depending on mutation sites, and it should be the alternative method for mutation screening.

X-linked mental retardation, short stature, microcephaly and hypogonadism maps to Xp22.1-p21.3 in a Belgian family

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at θ = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.

X-linked mental retardation: vanishing boundaries between non-specific (MRX) and syndromic (MRXS) forms.

This review covers the history and nosology of X-linked mental retardation (XLMR) in which the following, largely clinically based, subclassification was used: fragile X syndrome (FRAXA), syndromic forms (MRXS) and non-specific forms (MRX). After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been identified in the last 6 years. A short description is given of the strategies used to identify the genes that cause mental retardation (MR). Furthermore, their potential functions and the association with MR will be discussed. It is emphasized that mutations in several of these MR genes can result in non-specific, as well as in syndromic forms of XLMR. Present findings stress the importance of accurate clinical evaluation. Most considerably, genotype-phenotype correlation studies of affected individuals in XLMR families with MRX gene mutations are necessary to define the criteria of MRX vs MRXS subclassification.