Chromosomal abnormalities associated with mental retardation in female subjects

Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR). However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150) by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120), chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025).     

Cerebellar dysgenesis and mental retardation associated with a complex chromosome rearrangement

Cerebellar hypoplasia, mild mental retardation, skeletal abnormalities, and ataxia were present in a 40 years old patient with a complex chromosome rearrangement (CCR). Chromosomes 2, 5, 16, and 17 were involved in the CCR. For the definition of the eight breakpoints leading to the rearrangement FISH with whole chromosomes paintings and specific telomeric probes was employed. Gene disruption, positional effect variegation, and sub-microscopic deletions are all possible causes for the abnormal phenotype observed in the patient.     

Moderate mental retardation and nonspecific dysmorphic syndrome associated with ring chromosome 9

Summary A ring chromosome 9 is reported in a 12-year-old, moderately mentally retarded boy. As in other ring chromosome 9 patients, the clinical stigmata are nonspecific and their expressivity is mild. The finding of two normal cells of a total of 121 cells examined favors the hypothesis of a postzygotic, mitotic origin of the ring chromosome formation.     

The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation

Idiopathic mental retardation is a common condition the origins of which are poorly understood. Following initial reports that small chromosomal rearrangements affecting telomeres could be an important aetiological contributor, several new methods for screening patients have been developed. Over the past few years, 22 studies have reported results from 2585 patients. The prevalence of abnormalities in the entire group is 5.1%; but the figure is higher (6.8%) in individuals with moderate to severe mental retardation. About half the cases are caused by a de novo deletion, and about half by a balanced translocation segregating in a patient's family. Despite the large sample size available, it is still not clear whether a combination of thorough clinical examination and assiduous cytogenetic investigation might not be as effective at detecting subtelomeric anomalies as molecular assays.     

Fetal face syndrome with mental retardation

Summary Two cases of a variant of the fetal face syndrome are described. The affected babies were born from two consecutive pregnancies to the same gypsy parents. In addition to the classical syndrome, both cases showed a severe feeding difficulties, failure to thrive and severe psychomotoric retardation and one of them cleft lip and palate.     

Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation

The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found that the Xp11.2 breakpoints disrupt the novel human KIAA1202 (hKIAA1202) gene in both cases. We also identified a missense exchange in this gene, segregating with the Stocco dos Santos XLMR syndrome in a large four-generation pedigree but absent in >1,000 control X-chromosomes. Among other phenotypic characteristics, the affected males in this family present with severe MR, delayed or no speech, seizures and hyperactivity. Molecular studies of hKIAA1202 determined its genomic organisation, its expression throughout the brain and the regulation of expression of its mouse homologue during development. Transient expression of the wild-type KIAA1202 protein in HeLa cells showed partial colocalisation with the F-actin based cytoskeleton. On the basis of its domain structure, we argue that hKIAA1202 is a new member of the APX/Shroom protein family. Members of this family contain a PDZ and two ASD domains of unknown function and have been shown to localise at the cytoskeleton, and play a role in neurulation, cellular architecture, actin remodelling and ion channel function. Our results suggest that hKIAA1202 may be important in cognitive function and/or development. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users. O. Hagens and A. Dubos contributed equally to this work.     

Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly

In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain–containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.     

X-linked mental retardation

X-linked mental retardation (XLMR) affects 1.8 per thousand male births and is usually categorized as "syndromic" (MRXS) or "non-specific" (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes.     

X-linked mental retardation

Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.     

Fragile X mental retardation protein interactions with the microtubule associated protein 1B RNA

Fragile X mental retardation syndrome, the most common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein (FMRP). FMRP has been shown to use its arginine-glycine-glycine (RGG) box to bind to a subset of RNA targets that form a G quadruplex structure. We performed a detailed analysis of the interactions between the FMRP RGG box and the microtubule associated protein 1B (MAP1B) mRNA, a relevant in vivo FMRP target. We show that MAP1B RNA forms an intramolecular G quadruplex structure, which is bound with high affinity and specificity by the FMRP RGG box. We determined that hydrophobic interactions are important in the FMRP RGG box-MAP1B RNA association, with minor contributions from electrostatic interactions. Our findings that at low protein:RNA ratios the RNA G quadruplex structure is slightly stabilized, whereas at high ratios is unfolded, suggest a mechanism by which the FMRP concentration variation in response to a neurotransmitter stimulation event could act as a regulatory switch for the protein function, from translation repressor to translation activator.     

Expression in fibroblast culture of the satellited-X chromosome associated with familial sex-linked mental retardation

Summary The satellited-X chromosome previously shown in lymphocyte culture to be associated with certain types of sex-linked mental retardation has, for the first time, been demonstrated in cultured skin fibroblasts and lymphocytes from two affected males and an obligate carrier female. These findings provide a basis for reliable diagnosis of female carriers and for the development of prenatal diagnosis.     

2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report

Pulmonary emphysema and bronchiectasis in HIV seropositive patients has been described in the presence of injection drug use, malnutrition, repeated opportunistic infections, such as Pneumocytis jirovici pneumonia and Mycobacterium tuberculosis infection, and has been linked to the presence of HIV virus in lung tissue. Given the high burden of pulmonary infections and malnutrition among people living with HIV in resource poor settings, these individuals may be at increased risk of developing pulmonary emphysema, potentially reducing the long term benefit of antiretroviral therapy (ART) if initiated late in the course of HIV infection. In this report, we describe three HIV-infected individuals (one woman and two children) presenting with extensive pulmonary cystic disease.     

Dissociation between mental retardation and fragile site expression in a family with fragile X-linked mental retardation

Summary We report an extended family in which two brothers with a fragile X chromosome are mentally retarded while a third brother with the fragile site is both phenotypically and mentally normal. The study of six probes detecting restriction fragment length polymorphisms on either sides of the fragile site Xq27 confirmed that the fragile X regions inherited by these three brothers were identical from DXS 102 to the telomere. These data highlight the heterogeneity of the fragile X syndrome, which is discussed in the framework of the different hypotheses previously proposed.     

Prenatal diagnosis of X-linked choroideremia with mental retardation,associated with a cytologically detectable X-chromosome deletion

Summary We describe a family in which an X-chromosome deletion is segregating with choroideremia, an X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86–100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq1321, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.     

X-linked non-specific mental retardation

Non-specific mental retardation is a very common and genetically heterogeneous disorder but, to date, only six genes related to this condition have been identified. Five of these six have been found in the past two years, through positional-cloning efforts of mapped X-linked families. The characteristics of the newly identified genes are providing insights into the molecular mechanisms of mental impairment and the development of cognitive functions.