Mental Retardation In Males Research Articles

X-linked West Syndrome and mental retardation

X-linked infantile spasms associated with mental retardation have been recognized as a syndrome with an identified gene: ARX. We report a family with eight affected males. Mental retardation was present in all, seven also had epilepsy. In the index case, onset took place in the form of West syndrome. The index case was a boy now six years of age, born from healthy non-consanguineous parents who started at age one month with focal seizures associated with fever. His younger brother had a similar onset. We were not able to examine the other affected males of the family and diagnosis of their type of epilepsy could not be defined. In the first case, the electroencephalogram (EEG) at one month showed slow waves in fronto-temporal regions. Laboratory and imaging studies were normal. Clusters of epileptic spasms with hypsarrhythmia in the EEG appeared at six months of age. The spasms were refractory to treatment. Psychomotor development was severely delayed thereafter. His younger brother also started with focal seizures at one month of age, but a few months later he presented frequent myoclonic seizures associated with generalized spike and spike-wave paroxysms on the EEG. His laboratory work-up and brain imaging were also normal and his seizures have remained refractory to antiepileptic drugs. This child was also mentally retarded. Apparently, there are various phenotypes of epilepsy associated with mental retardation in males in this family. However, our index case seems to have a disease compatible with the diagnosis of X-linked West syndrome.

De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation

Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X-inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood.

Four sisters compound heterozygotes for the pre- and full mutation in fragile X syndrome and a complete inactivation of X-functional chromosome: implications for genetic counseling

Fragile X syndrome (FXS) is a neurodevelopmental disorder and a leading monogenic form of cognitive impairment and autism. It is the most common form of inherited mental retardation in males and a significant cause of mental retardation in females. It is caused by the instability and subsequent expansion of the CGG repeat in the promoter region of the FMR1 (fragile X mental retardation 1) gene at Xq27.3. We describe a double consanguineous family with four sisters compound heterozygotes for the full and pre-mutation CGG repeat size. The index case shows clinical features of the affected males with profound mental retardation; the other three sisters also suffer from mental retardation, ranging from mild to severe. Molecular analysis reveals very similar ranges for the CGG expansions for both chromosomes in all four sisters. The phenotypic differences observed in the index case and her sisters are the total inactivation of X premutated chromosome and the total absence of FMRP (fragile X mental retardation protein). This family case raises important issues for genetic counseling in families with consanguinity and with cases of idiopathic mental retardation.

Somatic mosaicism for Y120X mutation in the MECP2 gene causes atypical Rett syndrome in a male

Rett Syndrome (RS; MIM_312750) is a severe and progressive neurodevelopmental disorder affecting principally females. Mutations in X-Linked MECP2 gene (methyl CpG-binding protein 2; MIM_300005) have been reported as being the major cause of RS. Mutations in this gene have been described as cause of wide spectrum of neurological disorders and mental retardation in males. In some cases, mutations in MECP2 in males produce clinical picture similar to RS. Here we report the identification of the novel truncating mutation Y120X in a 4-year-old child with atypical RS phenotype. Chromosome analysis showed a normal karyotype, and blood DNA and tissue DNA analysis reveal a mosaic for the mutation. Patient’s mother DNA analysis showed that this is a de novo mutation, that has never been described before in any female or male case of RS.

High Frequency of Nonrecurrent MECP2 Duplications Among Brazilian Males with Mental Retardation

Structural variations that affect the copy number of the MECP2 gene were shown to cause mental retardation in males by driving the overexpression of this gene. To access the impact of these rearrangements in males with unexplained mental retardation, we have performed a quantitative real-time polymerase chain reaction assay using SYBR Green I chemistry to quantify MECP2 gene copy number in 145 Brazilian males with mental retardation of unknown cause. Three patients carrying MECP2 duplications (approximately 2%) were identified. The analysis of additional markers flanking the MECP2 region showed that the duplications observed are nonrecurrent. Expression studies in two of these patients revealed the overexpression of the MECP2 gene compared to the expression level observed in controls. These findings corroborate other recent reports in the literature and highlight that the overexpression of MECP2 caused by duplications involving this gene is a relatively frequent genetic cause of mental retardation in males, highlighting the importance of MECP2 gene dosage for diagnostic purposes in such cases.

Aetiology of premature ovarian failure

Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhoea in women under the age of 40 years. POF is idiopathic in 74-90% of cases but can be familial (4-33%) or sporadic. The known causes are: genetic aberrations; autoimmune ovarian damage; iatrogenic following surgery, radiotherapy or chemotherapy; environmental factors (viruses, toxins, etc.); and metabolic (galactosaemia, 17 OH deficiency, etc.) Genetic aberrations could involve the X chromosome (monosomy, trisomy or translocations) or be autosomal. Genetic mechanisms include reduced gene dosage and non-specific chromosome effect impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. The genes for POF-1 are localized to Xq 21.3-Xq27 and for POF-2 to Xq13.3-21.1. The FMR1 gene is responsible for the fragile X syndrome. It occurs due to CGG expansion of more than 55 repeats at the 5'UTR (Xq 27.3), which is associated with gene silence resulting in mental retardation in males, and POF in female carriers. Autoimmune ovarian damage is caused by the alteration of T-cell subsets and T-cell-mediated injury, increase of autoantibody producing B-cells and a low number of effector suppressor/cytotoxic lymphocyte and a decrease of number and activity of natural killer cells. POF can be associated with other non-endocrine and endocrine diseases. The mutations of AIRE gene are responsible for polyendocrinopathies (APS I-III). As the cause of POF is unknown in the majority of cases and the number of women with POF is increasing, the primary goal of scientific groups worldwide should be focused on the study of the aetiology of POF.

AETIOLOGY OF PREMATURE OVARIAN FAILURE

Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhoea in women under the age of 40 years. POF is idiopathic in 74-90% of cases but can be familial (4-33%) or sporadic. The known causes are: genetic aberrations; autoimmune ovarian damage; iatrogenic following surgery, radiotherapy or chemotherapy; environmental factors (viruses, toxins, etc.); and metabolic (galactosaemia, 17 OH deficiency, etc.) Genetic aberrations could involve the X chromosome (monosomy, trisomy or translocations) or be autosomal. Genetic mechanisms include reduced gene dosage and non-specific chromosome effect impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. The genes for POF-1 are localized to Xq 21.3-Xq27 and for POF-2 to Xq13.3-21.1. The FMR1 gene is responsible for the fragile X syndrome. It occurs due to CGG expansion of more than 55 repeats at the 5'UTR (Xq 27.3), which is associated with gene silence resulting in mental retardation in males, and POF in female carriers. Autoimmune ovarian damage is caused by the alteration of T-cell subsets and T-cell-mediated injury, increase of autoantibody producing B-cells and a low number of effector suppressor/cytotoxic lymphocyte and a decrease of number and activity of natural killer cells. POF can be associated with other non-endocrine and endocrine diseases. The mutations of AIRE gene are responsible for polyendocrinopathies (APS I-III). As the cause of POF is unknown in the majority of cases and the number of women with POF is increasing, the primary goal of scientific groups worldwide should be focused on the study of the aetiology of POF.

The AGG interruption pattern within the CGG repeat of the FMR1 gene among Taiwanese population

The fragile X syndrome is the most common form of inherited mental retardation and is mainly due to an expansion of a (CGG)n trinucleotide repeat located in the 5′UTR of the fragile X mental retardation 1 (FMR1) gene at Xq27.3 (Kremer et al. 1991; Yu et al. 1991; Fu et al. 1991). In healthy individuals, the (CGG)n repeat in FMR1 is highly polymorphic, with allele sizes ranging from 5 to 50 repeats (Fu et al. 1991; Mandel and Biancalana 2004). However, two other stages of fragile X syndrome exist: the premutation stage of 50 to 200 repeats; and a full mutation, which is a massive expansion beyond 200 repeats, that causes mental retardation in males and in about 50% of female carriers. Apart from the length of the repeat, other factors, including AGG interruption pattern, length of uninterrupted CGG, and DXS548-FRAXAC1 markers, also have impact on the stability of the FMR1 gene and exert influence on the syndrome (Mandel and Biancalana 2004). The AGG interruptions in CGG triple repeat occur once in every nine or ten CGG repeats. Most normal alleles have two or more AGG interruptions in five to 50 CGG repeats, while most permutation alleles (50 to 200 repeats) have only a single or no interruption (Eichler et al. 1995; Zhong et al. 1995). The interruption is associated with certain haplotypes and is related to instability, which can lead to an expansion and eventually, the fragile X syndrome (Eichler et al. 1995; Zhong et al. 1995; Larsen et al. 2000). Because the total length of the repeat is not a clear predictor of expansion, it is important to determine both the length and the interruption pattern of the repeats to evaluate the tendency of instability. Therefore, this study was conducted to evaluate the pattern of CGG repeats in Taiwan.

Mutaciones en el gen ARX y retraso mental no filiado: tres nuevos casos en España

Mental retardation has an approximated prevalence of 2% in the general population and its most frequent cause is X-fragile syndrome. This genetic disorder predominantly affects males and it is mainly caused by the expansion of CGG in FMR1 gene. Recently has been demonstrated that mutations in a new called ARX gene (aristaless-related homeobox) can also cause a similar form of X linked mental retardation, as well as other neurological disorders (autism, Partington or West syndrome). The most frequent mutation that has been reported is the c.428_451 dup24, which comprises almost 60% of all described. It causes an expansion of a polyalanine tract of ARX protein. We report three cases of mental retardation in two different families where the mutation in ARX gene c.428_451 dup24 was found while X-fragile syndrome screening was made. Personal and familiar history, phenotype and evolution are described. The molecular analysis of this mutation should be considered as a routine for the genetic diagnosis of mental retardation in males of nondrafted cause.

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

BackgroundAproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects.ResultsKnown genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%).ConclusionThis tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

Normal intelligence and social interactions in a male patient despite the deletion of NLGN4X and the VCX genes

Xp22.3 deletion in males can be associated with short stature ( SHOX), chondrodysplasia punctata ( ARSE), mental retardation (MRX49 locus), ichthyosis ( STS), Kallmann syndrome ( KAL1) and ocular albinism ( OA1), according to the size of the deletion. Studies of terminal and interstitial deletions in male patients with a partial nullisomy of the X chromosome have led to the identification of the VCX-3A gene at the MRX49 locus on Xp22.3. The NLGN4X gene has then been identified less than 350 kb away from VCX-3A. Nonsense mutations in NLGN4X have been associated with autism and/or moderate mental retardation in males. We report a 17-year old male patient presenting with severe ichthyosis and Kallmann syndrome related to a 3.7 Mb interstitial Xp22.3 deletion, encompassing STS and KAL1 genes, respectively. However, despite the deletion of NLGN4X and all VCX genes, including VCX-3A, our patient did not manifest any learning disabilities or behavioural problems. Therefore, our case argues against a major role of NLGN4X and the VCX genes alone in cognitive development and/or communication processes.

ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal

Introduction:We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X...

An Origin of DNA Replication in the Promoter Region of the Human Fragile X Mental Retardation (FMR1) Gene

Fragile X syndrome, the most common form of inherited mental retardation in males, arises when the normally stable 5 to 50 CGG repeats in the 5' untranslated region of the fragile X mental retardation protein 1 (FMR1) gene expand to over 200, leading to DNA methylation and silencing of the FMR1 promoter. Although the events that trigger local CGG expansion remain unknown, the stability of trinucleotide repeat tracts is affected by their position relative to an origin of DNA replication in model systems. Origins of DNA replication in the FMR1 locus have not yet been described. Here, we report an origin of replication adjacent to the FMR1 promoter and CGG repeats that was identified by scanning a 35-kb region. Prereplication proteins Orc3p and Mcm4p bind to chromatin in the FMR1 initiation region in vivo. The position of the FMR1 origin relative to the CGG repeats is consistent with a role in repeat maintenance. The FMR1 origin is active in transformed cell lines, fibroblasts from healthy individuals, fibroblasts from patients with fragile X syndrome, and fetal cells as early as 8 weeks old. The potential role of the FMR1 origin in CGG tract instability is discussed.

Low significance of MECP2 mutations as a cause of mental retardation in Brazilian males

MeCP2 is a protein that selectively binds to methylated cytosines through its methyl-CpG-binding domain (MBD) and connects DNA methylation to transcriptional repression. Mutations in MECP2 gene, located in Xq28, have been reported as being the major cause of Rett syndrome and are also associated with some cases of X-linked mental retardation in both males and females. In this study, we present the first screening in the MECP2 gene in a Brazilian cohort of 239 unrelated males with idiopathic mental retardation. Eight sequence variations were observed in 10 patients: one novel putative pathogenic variant, two never described variants of unknown pathogenic value and five non-pathogenic variations. We conclude that in mentally retarded Brazilian males, non-pathogenic variants in the MECP2 gene are more common than actual pathogenic mutations, and therefore alterations in this gene have a weak relationship with mental retardation in males.

A truncating mutation in the IL1RAPL1 gene is responsible for X‐linked mental retardation in the MRX21 family

X-linked mental retardation (XLMR) is a genetically heterogeneous condition, due to mutations in at least 50 genes, involved in functioning of the central nervous system and located on the X chromosome. Nonspecific XLMR (MRX) is characterized essentially by mental retardation transmitted by X-linked inheritance. More than 80 extended MRX pedigrees have been reported to date, which have been distinguished exclusively by physical position of the corresponding gene on the X chromosome, established by linkage analysis. One such family, MRX21, which was described by us in 1993 and localized to Xp11.4-pter, has now been reanalyzed with additional markers and after one more affected individual had became available. This extra information allowed a significant reduction of the linkage interval and, eventually, identification of the mutant gene. A stop mutation in exon 10 of the IL1RAPL1 gene (in Xp21) was found in the four affected males and in obligate carriers, allowing conclusive counseling of other family members of uncertain carrier status. The W487X mutation results in the production of a truncated IL1RAPL protein, comprised of the extracellular Ig-like domain and transmembrane tract, but lacking the last 210 aminoacids of the cytoplasmic domain. MRX21 is the first extended MRX family with a point mutation in IL1RAPL1 and the second with a stop mutation, which had been previously found only in a small family. Our report confirms the role of the IL1RAPL1 gene in causing nonspecific mental retardation in males and underlines the importance of detailed linkage analysis before candidate gene mutational screening.

Tamizaje clínico y análisis de mutaciones en el gen FMR1 en 99 varones con características clínicas del síndrome de X-frágil

Background: Fragile X syndrome (FXS) is the most prevalent cause of inherited mental retardation in males, with an incidence of 1/4 000 males and 1/8 000 females. 3 molecular alterations have been identified: permutation, full mutation and mosaics, where expanded CGG repeats in the 5´ region surrounding FMR1 gene promoter. Individuals with permutation present between 52 and 200 repeats, whereas full mutations with more than 200 repeats show impaired gene transcription by hypermethylation of FMR1 gene promoter region and absence of FMRP protein, producing mental retardation and specific FXS clinical characteristics. Objective: The FXS clinical diagnosis is performed using a protocol that considers 15 characteristics; however, the phenotypical differences difficult the exact identification. Method: 99 male patients referred to INTA with mental retardation and clinical characteristics suggesting FXS were evaluated. Results: 23 cases present FMR1 full mutation with clinical score 16 to 27 points and 76 cases without mutation with clinical score 10 to 26 points. Comparing both groups, 4 clinical characteristics were significantly different and 3 of them were frequently associated with full mutation, independent of age. Conclusions: In order to optimize the molecular study of FMR1 gene, the selection of patients should include a clinical screening, so that the study is performed in individuals with clinical score ³ 15 points.

Fragile X Screening Likely to Be Requested by Patients

Fragile X syndrome, a common cause of mental retardation in males, is caused by an expansion of three nucleotides (CGG) at the 5′ end of the familial mental retardation gene ( FMR1 ). Normal individuals have fewer than 40 such repeats, and individuals with between 55 and 200 repeats are clinically asymptomatic but said to have a “premutation.” Those with more than 200 repeats have the full mutation, often resulting in mental retardation due to transcriptional silencing. These repeats …

XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless related homeobox) gene

BackgroundX-linked mental retardation (XLMR) is the leading cause of mental retardation in males. Mutations in the ARX gene in Xp22.1 have been found in numerous families with both nonsyndromic and syndromic XLMR. The most frequent mutation in this gene is a 24 bp duplication in exon 2. Based on this fact, a panel of XLMR families linked to Xp22 was tested for this particular ARX mutation.MethodsGenomic DNA from XLMR families linked to Xp22.1 was amplified for exon 2 in ARX using a Cy5 labeled primer pair. The resulting amplicons were sized using the ALFexpress automated sequencer.ResultsA panel of 11 families with X-linked mental retardation was screened for the ARX 24dup mutation. Four nonsyndromic XLMR families – MRX29, MRX32, MRX33 and MRX38 – were found to have this particular gene mutation.ConclusionWe have identified 4 additional XLMR families with the ARX dup24 mutation from a panel of 11 XLMR families linked to Xp22.1. This finding makes the ARX dup24 mutation the most common mutation in nonsyndromic XLMR families linked to Xp22.1. As this mutation can be readily tested for using an automated sequencer, screening should be considered for any male with nonsyndromic MR of unknown etiology.

Mutations in exon 1 of MECP2B are not a common cause of X-linked mental retardation in males

Mutations in exon 1 of MECP 2 B are not a common cause of X-linked mental retardation in males

The A140V mutation in the MECP2 gene is not a common etiological factor among Brazilian mentally retarded males

In mammals, methyl-CpG binding proteins play a significant role in the control of gene expression through their association with chromatin-remodeling complexes. Mutations in the gene coding for methyl-CpG-binding protein 2 ( MECP2) cause Rett syndrome and have also been reported in a number of X-linked mental retardation diseases. In this study, DNA samples from 363 male individuals with syndromic and non-syndromic mental retardation and other psychiatric diseases were screened for A140V (419C>T) mutation in the MECP2 gene, considered the most frequent MECP2 mutation in males. No 419C>T was found suggesting that the A140V mutation in the MECP2 gene is not a common cause of mental retardation in males. Recently, a new and abundant isoform of MECP2 was described, which has an alternative N-terminus, translated from exon 1, that was previously thought to be non-coding and has been excluded from many mutational screening, as well, the 5′ and 3′ UTR regions. We consider essential proceeding further screening in the whole extension of the MECP2 gene using clinically well-documented and larger sized sample to assure the overall contribution of MECP2 to mental retardation.