Reduced cortical thickness in mental retardation

Mental retardation is a developmental disorder associated with impaired cognitive functioning and deficits in adaptive behaviors. Many studies have addressed white matter abnormalities in patients with mental retardation, while the changes of the cerebral cortex have been studied to a lesser extent. Quantitative analysis of cortical integrity using cortical thickness measurement may provide new insights into the gray matter pathology. In this study, cortical thickness was compared between 13 patients with mental retardation and 26 demographically matched healthy controls. We found that patients with mental retardation had significantly reduced cortical thickness in multiple brain regions compared with healthy controls. These regions include the bilateral lingual gyrus, the bilateral fusiform gyrus, the bilateral parahippocampal gyrus, the bilateral temporal pole, the left inferior temporal gyrus, the right lateral orbitofrontal cortex and the right precentral gyrus. The observed cortical thickness reductions might be the anatomical substrates for the impaired cognitive functioning and deficits in adaptive behaviors in patients with mental retardation. Cortical thickness measurement might provide a sensitive prospective surrogate marker for clinical trials of neuroprotective medications.     

Chromosomal rearrangements in children with idiopathic mental retardation using subtelomeric fluorescent in situ hybridization

To screen a selected group of children with idiopathic mental retardation for subtelomeric abnormalities using the fluorescent in situ hybridization (FISH), which has been reported to be cost-effective in routine applications. We also aimed to assess the availability of the scoring system which is used for selection of those children for FISH analysis. A total of 30 children aged 3-16 years with idiopathic mental retardation (moderate to severe) and normal karyotypes were included in this study. The children whose parents had consanguineous marriages were excluded from the study. All cases were evaluated using the scoring system published by de Vries et al. (5) Forty-one subtelomeric regions for each case were analyzed by fluorescent in situ hybridization. One case with a score value 5 presented terminal deletion of chromosome 9p by FISH (3.3 %). Analyzing chromosomes of the same case with higher resolution G-banding showed the same abnormality. The frequency of subtelomeric abnormalities in our study group was much lower than the frequencies reported in other studies and the scoring criterions suggested by de Vries et al. have not effectively increased our subtelomeric deletion detection rates. Autosomal recessive disorders may be a more common reason compared to subtelomeric abnormalities in this group of patients in the countries where consanguinity rate is high. Laboratories may be encouraged to analyze high-resolution G-banded karyotypes in those cases. Moreover more effective selection criteria for FISH are suggested by establishing thorough genotype-phenotype correlations besides case reports with different subtelomeric abnormalities.     

A Turkish case of subcortical/subependymal heterotopia associated with corpus callosum dysgenesis, craniofacial dysmorphism, severe eye abnormalities, and growth-mental retardation

The patient is a 12-year-old boy with a history of learning disability, growth retardation, and strabismus. Weight, height and head circumference were below the 3rd percentile. A café-au-lait spot, 1x1 cm a diameter, on the back region and pectus excavatum deformity were diagnosed. He had facial asymmetry, a broad nose, sparse eyebrows and eyelashes, a rudimentary frontal sinus, deviation of the nasal septum, and bilateral small maxillary bones. The left orbital fossa was also mildly rudimentary. On eye examination the movements of the left globe to the upward and lateral side were limited and internal strabismus was noted at this side. Visual acuity was 1/10, bilaterally. Bilateral choroid coloboma, glaucoma, vertical and horizontal nystagmus were diagnosed. Fundoscopic examination revealed bilateral optic atrophy and macular and paramacular granulation tissues on the left side. Intelligence quotient was 46. Electroencephalography revealed bilateral frontal slow-wave activity. Visual evoked potential revealed prolonged p100 wave latencies bilaterally. Magnetic resonance imaging of the brain demonstrated corpus callosum dysgenesis, bilateral subcortical heterotopia in the frontal lobes and subependymal heterotopia in the posterior horn of the left ventricle. Chromosomal analysis revealed a normal male karyotype, 46, XY. Although several cases of heterotopia in association with mental retardation, craniofacial dysmorphism, cerebral, and eye abnormalities have been described the combination of abnormalities diagnosed in our case has not previously been reported. We hypothesize that the combination of subcortical/subependymal heterotopia, corpus callosum dysgenesis, craniofacial dysmorphism, severe eye abnormalities, and growth-mental retardation may be a new syndrome.     

Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation

The clinical implementation of array comparative genomic hybridization has revolutionized the diagnosis of patients with syndromic or nonsyndromic mental retardation. Multiple studies of hundreds of patients with idiopathic mental retardation, and normal karyotype and/or subtelomeric testing using genome-wide microarray platforms with approximately 2000 to >30,000 (tiling-path) interrogating BAC/PAC probes have detected chromosome abnormalities in up to 17% of cases. Surprisingly, some of the pathogenic changes are mosaic and not detectable in conventional karyotyping. Commercially available genome-wide microarrays with >300,000 synthesized oligonucleotide probes enable higher resolution and sensitivity and will probably replace the BAC/PAC arrays in clinical laboratories.     

Rho GTPases, dendritic structure, and mental retardation

A consistent feature of neurons in patients with mental retardation is abnormal dendritic structure and/or alterations in dendritic spine morphology. Deficits in the regulation of the dendritic cytoskeleton affect both the structure and function of dendrites and synapses and are believed to underlie mental retardation in some instances. In support of this, there is good evidence that alterations in signaling pathways involving the Rho family of small GTPases, key regulators of the actin and microtubule cytoskeletons, contribute to both syndromic and nonsyndromic mental retardation disorders. Because the Rho GTPases have been shown to play increasingly well-defined roles in determining dendrite and dendritic spine development and morphology, Rho signaling has been suggested to be important for normal cognition. The purpose of this review is to summarize recent data on the Rho GTPases pertaining to dendrite and dendritic spine morphogenesis, as well as to highlight their involvement in mental retardation resulting from a variety of genetic mutations within regulators and effectors of these molecules.     

X-linked recessively inherited non-specific mental retardation. Report of a large family.

A large kindred is described in which 22 males and 3 females show non-specific mental retardation with impaired speech. An X-linked recessive is the most likely mode of inheritance of this condition. Similar families have been described in the literature, characteristic physical abnormalities are absent and performance I.Q. tends to be higher than verbal I.Q. This possible heterogenous condition may be a major individual cause of mental deficiency in males, and may account for the excess of male retardates in the population.     

A novel 7.4 kb mitochondrial deletion in a patient with congenital progressive external ophthalmoplegia, muscle weakness and mental retardation.

We present a patient with external ophthalmoplegia, bilateral ptosis, progressive muscle weakness with "ragged-red fibres" and mental retardation. Mitochondrial DNA analysis by Southern blot revealed heteroplasmy in muscle for a 7.4 kb deletion. In white blood cells, the deletion was only detectable by PCR. There was no evidence for duplications, nor for multiple deletions in the proband or siblings. PCR analysis did not reveal the presence of a mitochondrial DNA defect in the parents and siblings. Thus, there is no experimental support for a maternally inherited mitochondrial DNA deletion. We consider this a sporadic case with a de novo deletion. Diabetes and complaints of fatigue, also seen in this family, are probably coincidental. Mental retardation has been reported occasionally in patients with mitochondrial deletions, but is not common.     

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).     

Molecular basis of X-linked non-specific mental retardation

Mental retardation (MR) is a common disorder, affecting 1-3% of the total population. This condition results from failure to develop cognitive abilities and intelligence level appropriate for the age group. Mental retardation is basically a clinically as well as etiologically heterogeneous type of condition and both genetic and non-genetic factors have been found to be involved. There are more than 1000 entries in Online Mendelian Inheritance in Man (OMIM) database under the name of mental retardation. In recent years 15 genes for X linked non-specific mental retardation have been identified which provide important clues regarding molecular and cellular processes involved in signal transduction cascade in central nervous system. Recent advancements in identification and characterization of X-linked non-specific mental retardation genes have been discussed in this review. Understanding of the molecular pathways of disease causing genes would be helpful in developing effective therapeutic approaches for mental retardation.     

Molecular screening of FRAXA and FRAXE in Indian patients with unexplained mental retardation

Fragile-X mental retardation is the commonest form of inherited mental retardation. We have studied 146 Indian patients (174 X chromosomes) with unexplained mental retardation by molecular methods. All study subjects were unrelated. Three of the 118 males were found to have the FMR1 full mutation. None of the patients tested were positive for the FMR2 full mutation. The Fragile X prevalence was 2.5% among males, which is lower than previously reported in Indian mentally retarded patients. Screening for Fragile X among patients with nonspecific mental retardation is important, even if there is no family history of mental retardation or typical behavioral or physical features associated with the Fragile-X phenotype. Identification of positive cases is also very important for the families, because of the high recurrence risk of the disease. Large multicenter screening programs with uniform criteria would be worthwhile to determine the prevalence of Fragile-X mental retardation in the Indian population.     

Molecular investigation of mental retardation locus gene PRSS12 by linkage analysis

The present study was carried out to determine the prevalence of families having mental retardation in Pakistani population. We enrolled seven mentally retarded (MR) families with two or more affected individuals. Family history was taken to minimize the chances of other abnormalities. Pedigrees were drawn using the Cyrillic software (version 2.1). The structure of pedigrees shows that all the marriages are consanguineous and the families have recessive mode of inheritance. All the families were studied by linkage analysis to mental retardation locus (MRT1)/gene PRSS12. Three STR markers (D4S191, D4S2392, and D4S3024) in vicinity of mental retardation (MR) locus (MRT1)/gene PRSS12 were amplified on all the sample of each family by PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). The Haplotype were constructed to determine the pattern of inheritance and also to determine that a family was linked or unlinked to gene PRSS12. One out of the seven families was potentially linked to gene PRSS12, while the other six families remain unlinked.     

SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome

Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na(+)/H(+) exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations.     

Familial 13p+ chromosome with mental retardation and dysmorphic features in two children

Summary Chromosomal studies of two brothers with mental retardation and dysmorphic features showed a 13p+chromosome. The same 13p+chromosome was found in the father and the other sib, who were both phenotypically normal. The relationship between the physical abnormalities and the chromosomal findings are discussed.     

Microencephalic nanism, severe retardation, hypertonia, obesity, and hypogonadism in two brothers: a new syndrome?

Two brothers are described with a severe syndrome of postnatal growth and mental retardation which includes extreme microcephaly, obesity developing during infancy, microgonadismsm, and a characteristic amphora-shaped facies. The neurological exam is highly abnormal, with hypertonia and hyperreflexia, nystagmus, and an extremely irritable and agitated behavior. The first child, who died at 4/1/2 years, also presented neonatal hypoglycemia and chronic constipation. Although the etiology of this syndrome is unknown, it is tempting to consider an X-linked recessive gene, given the importance of the X chromosome in mental retardation. Among the over 70 syndromes of X-linked mental retardation already described, our patients resemble individuals with the B?rjeson-Forssman-Lehmann (BFL) syndrome the most. However, the severity of their dwarfism and mental retardation is much greater than described in any BFL patient to date, and the neurological and dysmorphic features vary significantly from those described in the BFL. Although a particularly severe variant, perhaps allelic, is a possibility, an as yet undescribed disorder is also plausible, the etiology of which would probably be recessive, either autosomal or X-linked.     

Linkage to Xq28 in a family with nonspecific X-linked mental retardation

Linkage analysis was performed in a family with nonspecific X-linked mental retardation (MRX). Affected individuals had no clinical characteristics other than mental retardation. Linkage was detected to the marker loci DXS477, DXS465, DXS52, DXS15 and F8C with maximum lod scores of 1.70, 1.32, 2.52, 1.70, and 1.09, respectively ( = 0.0). The results strongly indicate that the gene for mental retardation in the family studied maps close to DXS52.     

Uniparental isodisomy for paternal 7p and maternal 7q in a child with growth retardation.

Uniparental isodisomy resulting from the simultaneous presence of isochromosomes of the p and q arms of a chromosome and absence of a normal homologue is an exceptionally rare event. We have observed a growth-retarded female infant in whom the normal chromosome 7 homologues were replaced by what appeared cytogenetically to be isochromosomes of 7p and 7q. Polymorphic microsatellite loci spanning the length of 7p and 7q were analyzed in the proband and her parents to ascertain the parental origin and extent of heterozygosity of the proband's rearranged chromosomes. These studies demonstrated that the 7p alleles of the proband were derived only from the father, the 7q alleles were derived only from the mother, and there was homozygosity for all chromosome 7 loci analyzed. The mechanisms leading to the formation of the proband's isochromosomes could reflect abnormalities of cell division occurring at meiosis, postfertilization mitosis, or both. We believe that the present case may result from incomplete mitotic interchange in the pericentromeric regions of chromosome 7 homologues, with resolution by sister-chromatid reunion in an early, if not first, zygotic division. Phenotypically, our proband resembled three previously reported cases of maternal isodisomy for chromosome 7, suggesting that lack of paternal genes from 7q may result in a phenotype of short stature and growth retardation.     

A new case of dup(1)(q21.2q12) in an individual with mild mental retardation

Proximal duplications of the long arm of chromosome 1 are rare and the few patients that have been described in literature have multiple congenital abnormalities and/or mental retardation. The present paper describes the clinical and cytogenetic findings of an adult patient with only mild mental retardation and some minor malformations. The patient carries an inverted duplication of 1q12q21.2.     

Infant C677T MTHFR polymorphism and severe mental retardation

BACKGROUND: We investigated whether infants with homozygous genotype TT of the MTHFR gene were at increased risk of severe mental retardation. METHODS: One hundred children with severe mental retardation (cases) were investigated from a large geographic-based study of infants born in California in 1992-1993. Cases were compared to 743 randomly selected nonmalformed control infants born in California during 1987-1991. DNA was extracted from newborn screening filter papers. Cases and controls were genotyped TT if homozygous for the MTHFR C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild type) allele. RESULTS: Overall, case and control infants had similar percentages of TT and CT genotypes. Percentages between cases and controls differed somewhat across race/ethnic groups. Elevated ORs of 1.9 (95% CI: 0.7-5.0) and 2.6 (95% CI: 1.1-5.8) were observed for the TT and CT genotypes, respectively, among Hispanic children. Observed results were not substantially altered for analyses that removed 41 case children who also had structural birth defects. CONCLUSIONS: Folate-related mechanisms are important to investigate for etiologies of birth defects, and such lines of inquiry may be revealing for mental retardation given the relationships between mental retardation and birth defects and potential relationships between folate, DNA methylation, and mental retardation.     

Balanced translocations in mental retardation

Over the past few decades, the knowledge on genetic defects causing mental retardation has dramatically increased. In this review, we discuss the importance of balanced chromosomal translocations in the identification of genes responsible for mental retardation. We present a database-search guided overview of balanced translocations identified in patients with mental retardation. We divide those in four categories: (1) balanced translocations that helped to identify a causative gene within a contiguous gene syndrome, (2) balanced translocations that led to the identification of a mental retardation gene confirmed by independent methods, (3) balanced translocations disrupting candidate genes that have not been confirmed by independent methods and (4) balanced translocations not reported to disrupt protein coding sequences. It can safely be concluded that balanced translocations have been instrumental in the identification of multiple genes that are involved in mental retardation. In addition, many more candidate genes were identified with a suspected but (as yet?) unconfirmed role in mental retardation. Some balanced translocations do not disrupt a protein coding gene and it can be speculated that in the light of recent findings concerning ncRNA’s and ultra-conserved regions, such findings are worth further investigation as these potentially may lead us to the discovery of novel disease mechanisms.