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Contains fulltext : 166935.pdf (Publisher’s version ) (Closed access), Nonsyndromic X-linked mental retardation (MRX) is a highly heterogeneous condition in which mental retardation appears to be the only consistent manifestation. According to the most recent data, 77 MRX families with a lod score of >2 have been mapped and eight genes have been cloned. We hereby report on a linkage analysis performed on a Greek family with apparently nonsyndromic MRX. The affected males have moderate to severe mental retardation, severe speech problems, and aggressive behavior. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 27 Mb interval in Xq12-Xq21.33. The maximum LOD score was found for markers DXS1225, DXS8114, and DXS990 at 2.36, 2.06, 2.06, respectively at theta = 0.00. Recombination was observed for DXS983 at the proximal side and DXS6799 at the distal side. Nineteen other MRX families have been described with a partial overlapping disease gene interval in proximal Xq. No mutations were found in the MRX77 family for three known or candidate MRX genes, from this region OPHN1, RSK4, and ATR-X. These data indicate that the Xq12-Xq21.33 interval contains at least one additional MRX gene.

Contains fulltext : 166906.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 186352.pdf (Publisher’s version ) (Closed access), Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.

Item does not contain fulltext, Analysis of linkage intervals from 125 unrelated families with nonsyndromic X-linked mental retardation (NS-XLMR) has revealed that the respective gene defects are conspicuously clustered in defined regions of the human X-chromosome, with approximately 30% of all mutations being located on the proximal Xp. In 83% of these families, underlying gene defects are not yet known. Our observations should speed up the search for mutations that are still missing and pave the way for the molecular diagnosis of this common disorder.

Contains fulltext : 166896.pdf (Publisher’s version ) (Closed access), We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.

Contains fulltext : 166912.pdf (Publisher’s version ) (Closed access), Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene, with apparent lethality in male embryos. However, recent studies indicate that mutations in the MECP2 gene can cause congenital encephalopathy, an Angelman-like phenotype and even nonspecific mental retardation in males. We report on a 10-year-old boy with moderate mental retardation, hypotonia, obesity and gynaecomastia and a de novo 2-bp deletion in the MECP2 gene that resulted in a frameshift and premature stop codon. As some of the clinical features were suggestive of the Prader-Willi syndrome, it might be worthwhile screening for MECP2 mutations in patients with an atypical Prader-Willi phenotype but without the characteristic abnormalities on chromosome 15q. This report contributes to the phenotypic knowledge of male patients with MECP2 mutations. Moreover, this is the first reported male case of a de novo MECP2 mutation.

Item does not contain fulltext, X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.

Item does not contain fulltext, Mutations in the XNP gene have been reported in alpha thalassemia/mental retardation (MR) syndrome (ATR-X) and other severe X-linked MR conditions with facial dysmorphisms. In this report, we describe a missense mutation in exon 18 in a family with borderline to moderate MR. Like other disorders associated with an XNP mutation, skewed X-inactivation was found in all carrier females in this family. Only retrospective examination revealed childhood facial hypotonia and HbH inclusions in some of the affected males. These results expand the spectrum of clinical phenotypes known to be due to mutations in the XNP gene, and indicate that XNP mutation analysis should not be restricted to patients with severe MR and characteristic facial features.

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Item does not contain fulltext, OBJECTIVE: To report the familial occurrence of severe oligoasthenoteratozoospermia in a man and five male relatives related through their mothers. DESIGN: Case report. SETTING: University medical center. PATIENT(S): Six affected family members. MAIN OUTCOME MEASURE(S): Blood and semen samples were collected from all affected males and some of their healthy male relatives. Pedigree analysis and exclusion of X-linked disorder were done. RESULT(S): Analysis suggested that familial nonsyndromic male factor infertility was present. CONCLUSION(S): The family described in this report suggests the existence of an autosomal dominant trait of male infertility with sex-limited expression.

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Item does not contain fulltext, A high frequency of mutations in the methyl CpG-binding protein 2 (MECP2) gene has recently been reported in males with nonspecific X-linked mental retardation. The results of this previous study suggested that the frequency of MECP2 mutations in the mentally retarded population was comparable to that of CGG expansions in FMR1. In view of these data, we performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for FMR1 CGG repeat expansion. Five novel changes, detected in seven patients, were predicted to change the MECP2 coding sequence. Except for one, these changes were not found in a control population. While this result appeared to suggest a high mutation rate, this conclusion was not supported by segregation studies. Indeed, three of the five changes could be traced in unaffected male family members. For another change, segregation analysis in the family was not possible. Only one mutation, a frameshift created by a deletion of two bases, was found to be de novo. This study clearly shows the importance of segregation analysis for low frequency mutations, in order to distinguish them from rare polymorphisms. The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475).

Item does not contain fulltext, Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.

KUN, 07 november 2001, Promotor : Brunner, H.G., Item does not contain fulltext

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Contains fulltext : 20720___.PDF (publisher's version ) (Open Access)