Mental Retardation In Patients Research Articles

William John Little (1810-1894).

William John Little (1810-1894).

1q25.2-q31.3 Deletion in a female with mental retardation, clinodactyly, minor facial anomalies but no growth retardation

The reports of 1q25-32 deletion cases are rare. We reported here an 11-year-old Chinese Han female with an interstitial 1q25 deletion displaying mental retardation, clinodactyly of the 5th finger and minor facial anomalies. Notably, the patient did not present growth retardation which is quite common in patients with 1q25-32 deletion encompassing LHX4. The heterozygous deletion in this patient was characterized as 46,XX,del(1)(q25.2-q31.3) with a length of 20.5 Mb according to SNP-array test results. STRP (Short Tandem Repeat Polymorphism) analysis of the family trio indicated the genomic abnormality was de novo with paternal origin. After a genotype-phenotype analysis, we proposed here the loss of a 3.1 Mb critical region including 24 genes within 1q25.2 (chr1:174.5-177.6 Mb, build 36) may account for the mental retardation in patients with 1q25-32 deletion.

Xp22.3 interstitial deletion: A recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation

X-linked ichthyosis is a genetic disorder affecting the skin and caused by a deficit in the steroid sulfatase enzyme (STS), often associated with a recurrent microdeletion at Xp22.31. Most of the STS deleted patients have X-linked ichthyosis as the only clinical feature and it is believed that patients with more complex disorders including mental retardation could be present as a result of contiguous gene deletion. In fact, VCX3A gene, a member of the VCX (variable charge, X chromosome) gene family, was previously proposed as the candidate gene for X-linked non-specific mental retardation in patients with X-linked ichthyosis.We report on a boy with familial ichthyosis, dysmorphic features and moderate mental retardation with approximately 2Mb interstitial deletion on Xp22.3 involving VCX3A and STS genes.

Relative study on neuroendocrine changes and clinical characteristics in depression patients

Objective To discuss the correlation between neuroendocrine changes and clinical features in patients with depression. Methods The neuroendocrine data in patients with depression were collected and analyzed by Hamilton Depression Scale (HAMD) and Hamilton anxiety scale (HAMA). Results ①There were significant differences between the weight factor(normal group: 0.87±0.87; abnormal group: 1.09±0.87) and the sleep factor(normal group: 4.22±1.82; abnormal group: 4.54±1.84) of hypothalamic-pituitary-thyroid axis (HPT). ②There were significant differences between somatic anxiety factor(lower than the normal group: 7.87±4.65; normal group: 6.27±3.03; higher than the normal group: 6.44±2.46) and retardation factor(lower than the normal group: 9.22±4.27; normal group: 8.01±2.9; higher than the normal group: 7.41±1.92)of thyroid-stimulating hormone (TSH). ③There were significant differences between the weight factor and the retardation factor of serum free three iodine gland of the original acid(FT3). ④The weight factor of 3, 5, 3-three triiodothyronine (TT3) was significant.⑤There was no significant statistically difference in the rest groups. Conclusions The hormone abnormality of HPT axis can lead to sleep disorders and loss of weight in patients with depression.The reduction of TSH and FT3 can increase the symptoms of mental retardation in patients with depression.The decrease of TSH and FT3 can lead to weight loss in patients with depression and the decrease of TSH can increases somatic anxiety in patients with depression. Key words: Depression; Neuroendocrine; Clinical characteristics

CGG repeat in the FMR1 gene: size matters

The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The absence of FMR1 protein, FMRP, seen in FM is the cause of the mental retardation in patients with FXS. The premutation (PM) is defined as 55-200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome (FXTAS). Although arising from the mutations in the same gene, distinct mechanisms lead to FXS (absence of FMRP), FXTAS (toxic RNA gain-of-function) and FXPOI. The pathogenic mechanisms thought to underlie these disorders are discussed. This review gives insight on the implications of all possible repeat length categories seen in fragile X families.

Cortical Tubers, Cognition, and Epilepsy in Tuberous Sclerosis

Tuberous sclerosis complex is an autosomal-dominant genetic disorder characterized by hamartomatous growth in various organs. Patients who have this disorder exhibit a high rate of epilepsy and cognitive problems. We investigated number of tubers, location, seizure types, and cognitive outcome, and we analyzed the relationships among them in our tuberous sclerosis patients in the Comprehensive Epilepsy Program at the University of Alberta. We also examined the seizure outcome after tuber resection. Our study cohort included 24 patients with tuberous sclerosis complex. We obtained seizure history, electroencephalogram, and neuropsychologic parameters. Magnetic resonance imaging was used to examine tuber numbers and locations. Ten patients underwent surgical removal of tubers responsible for intractable epilepsy. A negative correlation was found between the number of tubers and intelligent quotient score. Epilepsy surgery led to freedom from seizures in this patient group. We demonstrated that the total number and location of cortical tubers play a significant role in the extent of mental retardation in patients with tuberous sclerosis complex. In addition, patients with intractable seizures and well-defined epileptic focus had excellent surgical outcome.

Therapeutic applications of organosulfur compounds as novel hydrogen sulfide donors and/or mediators

Hydrogen sulfide, once considered as toxic gas, is now recognized as an important biological mediator. The deficiency of hydrogen sulfide could lead to various pathological changes, such as arterial and pulmonary hypertension, Alzheimer’s disease, gastric mucosal injury and liver cirrhosis. However, excessive production of hydrogen sulfide, by using inorganic hydrogen sulfide donors such as NaHS, may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome. Therefore, an increasing interest in organic molecules that are capable of regulating the formation of hydrogen sulfide has extended in recent years. Allium vegetables are one natural source of organic sulfur-containing compounds and have been widely investigated regarding their therapeutic applications, and it has been proven that the ingredients of garlic, such as diallyl disulfide, diallyl trisulfide and S-ally cysteine act as hydrogen sulfide donors or mediators in pharmaceutical studies. In addition, S-propargyl cysteine (ZYZ-802) and S-propyl cysteine, two synthetic cysteine analogs, have been examined and could be used to treat ischemic heart disease via modulation of the hydrogen sulfide pathway. In addition, drugs containing hydrogen sulfide-releasing moieties have been synthesized and widely reported in recent years, such as S-nonsteroidal anti-inflammatory drugs and the derivative of Lawesson’s reagents, which exhibit varied biological effects in experiments. As cystathionine β-synthase and cystathionine γ-lyase are the enzymes that are able to catalyze the production of endogenous hydrogen sulfide from cysteine, their inhibitors, such as dl-propylargylglycine and β-cyanoalanine, have been frequently used in studies on the biological mechanism of hydrogen sulfide. All these hydrogen sulfide donors, mediators and inhibitors have provided useful tools in the research of a variety of biological effects and are promising drug candidates of hydrogen sulfide.

A parallel SNP array study of genomic aberrations associated with mental retardation in patients and general population in Estonia

The increasing use of whole-genome array screening has revealed the important role of DNA copy-number variations in the pathogenesis of neurodevelopmental disorders and several recurrent genomic disorders have been defined during recent years. However, some variants considered to be pathogenic have also been observed in phenotypically normal individuals. This underlines the importance of further characterization of genomic variants with potentially variable expressivity in both patient and general population cohorts to clarify their phenotypic consequence. In this study whole-genome SNP arrays were used to investigate genomic rearrangements in 77 Estonian families with idiopathic mental retardation. In addition to this family-based approach, phenotype and genotype data from a cohort of 1000 individuals in the general population were used for accurate interpretation of aberrations found in mental retardation patients. Relevant structural aberrations were detected in 18 of the families analyzed (23%). Fifteen of those were in genomic regions where clinical significance has previously been established. In 3 families, 4 novel aberrations associated with intellectual disability were detected in chromosome regions 2p25.1–p24.3, 3p12.1–p11.2, 7p21.2–p21.1 and Xq28. Carriers of imbalances in 15q13.3, 16p11.2 and Xp22.31 were identified among reference individuals, affirming the variable phenotypic consequence of rare variants in some genomic regions considered as pathogenic.

Detailed molecular and clinical characterization of three patients with 21q deletions

We have investigated three patients with 21q deletions, two with developmental delay, dysmorphic features and internal organ malformations, and one with cognitive function within the normal range but with some deficits in gross and fine motor development. All aberrations were characterized by array-comparative genomic hybridization (array-CGH). In addition, extensive fluorescence in situ hybridization (FISH) mapping on metaphase chromosomes and mechanically stretched chromosomes was performed on patient 1 who had an extremely complex intrachromosomal rearrangement with 16 breakpoints, four deletions and four duplications. Patients 2 and 3 had interstitial deletions comprising 21q21.1-21q22.11 and 21q11.2-21q21.3, respectively. Partial deletions of 21q are rare and these patients display a highly variable phenotype depending on the size and position of the deletion. A review of the literature identified 38 cases with pure 21q deletions. Twenty-three of these had reliable mapping data. The combined information of present and previous cases suggests that the ITSN1 gene is involved in severe mental retardation in patients with 21q deletion. In addition, a critical region of 0.56 Mb containing four genes, KCNE1, DSCR1, CLIC6 and RUNX1, is associated with severe congenital heart defects, and deletions of the most proximal 15-17 Mb of 21q is associated with mild or no cognitive impairment, but may lead to problems with balance and motor function.

Hydrogen sulfide (H2S): the new member of gasotransmitter family

Recent studies indicate that apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third gaseous mediator in mammals. H2S is synthesized from L-cysteine by either cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), vitamin B6-dependent enzymes also involved in homocysteine metabolism. H2S stimulates ATP-sensitive potassium channels (KATP) in vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic β-cells. H2S is involved in neurotransmission, regulation of vascular tone and blood pressure, regulates gastrointestinal motility and secretory function and inhibits insulin secretion. Deficiency of endogenous H2S was observed in various models of arterial and pulmonary hypertension, gastric mucosal injury and liver cirrhosis. Exogenous H2S or its donors decrease blood pressure and reduce vascular hypertrophy in spontaneously hypertensive rats, inhibit neointima formation induced by arterial injury, ameliorate myocardial dysfunction associated with ischemia/reperfusion, and reduce gastric mucosal damage induced by anti-inflammatory drugs. On the other hand, excessive production of H2S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these diseases. Biomedical Reviews 2007; 18: 75-83.

Identification of an mRNA-Decapping Regulator Implicated in X-Linked Mental Retardation

Two major decapping enzymes are involved in the decay of eukaryotic mRNA, Dcp2 and DcpS. Despite the detection of robust DcpS decapping activity in cell extract, minimal to no decapping is detected from human Dcp2 (hDcp2) in extract. We now demonstrate that one reason for the lack of detectable hDcp2 activity in extract is due to the presence of inhibitory trans factor(s). Furthermore, we demonstrate that a previously identified testis-specific protein of unknown function implicated in nonspecific X-linked mental retardation, VCX-A, can function as an inhibitor of hDcp2 decapping in vitro and in cells. VCX-A is a noncanonical cap-binding protein that binds to capped RNA but not cap structure lacking an RNA. Its cap association is enhanced by hDcp2 to further augment the ability of VCX-A to inhibit decapping. Our data demonstrate that VCX-A can regulate mRNA stability and that it is an example of a tissue-specific decapping regulator.

Deletion of distal promoter of VCXA in a patient with X-linked ichthyosis associated with borderline mental retardation

X-linked ichthyosis (XLI) is caused by deficiency of steroid sulfatase (STS) activity. About 90% XLI patients have large deletions involving the entire STS gene and flanking regions. Recently, VCXA, which is located approximately 0.7Mb telomeric to the STS gene, was reported as a candidate gene for mental retardation (MR) in patients with XLI. To delineate the X-chromosomal deletion of a XLI patient with borderline mental retardation. We carried out FISH analysis to show that the whole STS gene is deleted, and PCR analysis for fine-scale deletion mapping. The deleted segment is approximately 1.6Mb in size, and includes the entire STS and VCXB1 genes. VCXA itself is intact, but its promoter is deleted. A deletion that includes the VCXA promoter is associated with borderline mental retardation in a patient with XLI.

TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions

Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.

Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis

X-linked ichthyosis (XLI) is often associated with a recurrent microdeletion at Xp22.31 due to non-allelic homologous recombination between the CRI-S232 low-copy repeat regions flanking the STS gene. The clinical features of these patients may include mental retardation (MR) and the VCX-A gene has been proposed as the candidate MR gene. Analysis of DNA from four XLI patients with MR by array-comparative genomic hybridization (array-CGH) on a 150 kb resolution X chromosome-specific array revealed a 1.5 Mb interstitial microdeletion with breakpoints in the CRI-S232 repeat sequences, each of which harbors a VCX gene. We demonstrate that the recombination sites in all four cases are situated in the 1 kb repeat unit 2 region present at the 3' ends of the VCX-A and VCX-B genes thereby deleting VCX-A and VCX-B1 but not VCX-B and VCX-C. Array-CGH with DNA of an XLI patient with MR and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all four VCX genes and duplication of both VCY homologs. These data confirm the role of VCX-A in the occurrence of MR in XLI patients. Moreover, we propose a VCX/Y teamwork-dependent mechanism for the incidence of mental impairment in XLI patients.

Microdysgenesis in epilepsy

Microdysgenesis is a microscopic malformation of cortical development characterized by heterotopic neurones and abnormal cortical architecture. It has been described in primary generalized and partial epilepsy. Its significance in epileptogenesis is controversial, partly due to lack of consensus of diagnostic criteria. Different terms have also been used for the malformation. Several quantitative studies have been performed of the histopathological aberrations associated with microdysgenesis. A majority of the studies have revealed an increased number of heterotopic neurones in specimens from epilepsy patients. However, the quantitative values given for abnormal numbers of white matter neurones vary greatly between studies and there is no consensus yet on quantitative criteria for microdysgenesis. There have also been conflicting results from studies correlating microdysgenesis with clinical data. Both favourable and worse outcome after epilepsy surgery have been reported in patients with increased numbers of white matter neurones and microdysgenesis. While some studies have shown earlier seizure onset and increased frequency of mental retardation in patients with microdysgenesis, others have not. Differences in inclusion criteria and definition might contribute to the contradictory results. There is some evidence that microdysgenesis could be important in epileptogenesis, but the mechanisms involved remain unknown and difficult to investigate. A consensus on what histopathological criteria to use for the diagnosis of microdysgenesis is needed to explore this further and enable comparisons between centres. There are advantages and disadvantages both with quantitative stereological and with qualitative assessments. It is necessary to evaluate these in the decision on diagnostic criteria, if possible taking both qualitative and quantitative aspects into account.

Prognostic factors for mental retardation in patients with tuberous sclerosis complex.

To analyze the prognostic factors for mental retardation in patients with tuberous sclerosis complex (TSC). We retrospectively reviewed 35 in-patients with TSC in a medical center and analyzed the clinical features. 19 of 32 patients (59.4%) fulfilled the classical diagnosis of tuberous sclerosis. According to the diagnostic criteria of Roach et al., 30 patients had definite TSC and 5 patients possible TSC. Among the 35 patients, the mean age at diagnosis was 15.9 +/- 12.5 years, and the male-to-female ratio was 14:21. 11 of 30 patients (36.6%) had a family history of TSC. The most frequent CNS manifestations were seizures (32/35, 91.4%) and mental abnormality (12/32, 62.5%). The most common cutaneous manifestation was facial angiofibroma (27/35, 77.1%) and the most common seizure pattern was generalized tonic clonic seizures (22/32, 62.9%). Poor control of seizures (p=0.006) and the presence of cortical tubercles in imaging studies (p=0.03) were correlated statistically with mental abnormality. Poor control of seizures (15/32, 46%) was more common in generalized tonic clonic seizures than other seizure types (p=0.041). Twenty-six of 28 patients (92.8%) displayed the typical findings of cortical tubers and subependymal nodules on the brain CT or MRI. Mental retardation in TSC was correlated with poor control of seizures and the presence of CNS lesions.

A study of bone turnover markers in prepubertal children with phenylketonuria.

To investigate the effect of low-phenylalanine diets onbone mineralisation status, we compared biochemicalbone formation and resorption markers in prepubertalchildren with phenylketonuria with those of age-mat-ched healthy controls.Dietary phenylalanine (Phe) restriction is the onlyknown strategy of preventing neurological impairmentand mental retardation in patients with phenylketonuria(PKU). In general, most phenylketonuric patients on alow-Phe diet can achieve normal growth and intellectualdevelopment. It is suggested, however, that this form ofdiet may influence bone metabolism, especially inchildhood and adolescence when growth and boneturnover are at their most intensive. Some authors havedescribed decreased bone mineral density and osteope-nia in patients suffering from PKU [1, 2, 3,5].Measurements of bone mineral density (BMD) reflectonly bone mineral status but not the dynamics of boneturnover. Non-invasive biochemical markers whichshow global skeletal activity have lately been developedand validated for the assessment of bone formation andbone resorption processes. Among them, osteocalcin(OC), bone alkaline phosphatase (BALP) and collagentype 1 cross-linked C-telopeptide (CTX) are consideredto be clinically useful. Recently, the novel cytokineosteoprotegerin (OPG), belonging to the tumournecrosis factor receptor family has been established asan endogenous inhibitor of osteoclastogenesis andresorption processes.Our study population consisted of 37 childrenwith PKU under surveillance at the Department ofPaediatrics at the Institute of Mother and Child inWarsaw. Patients were divided into two groups. Thosein group A (n =12; median age 4.5 years; range 3–10years) followed their therapeutic diet strictly and hadmean serum Phe concentrations close to the referencerange (189.4±64.2 lmol/l) and those in group B(n =25; median age 6.0 years; range 3–10 years) did notadhere to their diet and had increased Phe concentra-tions (649.2±140.6 lmol/l). The mean serum Pheconcentration was calculated for the last 3 years of thelife of each patient. Children with PKU were fed with anaminoacid mixture PAM, Milupa-PKU 2 or Phenyl-free. These patients have normal values for calcium andphosphate. Healthy children sent to our laboratory forroutine analytical control (n =27; median age 5.9 years;range 4–9 years) were the reference group. The wholegroup of investigated children was ethnically homoge-nous. Venous blood samples were collected after anovernight fast, centrifuged and serum levels of Phe,calcium and phosphate were determined. Remainingserum samples were frozen and collected for measure-ment of BALP, OC, CTX and OPG. Phe was assayedfluorometrically according to McCaman and Robbins;calcium and phosphate by standard procedures with aCobas Integra analyser (Roche, Switzerland). Serum OCand CTX were measured by immuno-enzymatic ELISAassays (Osteometer, Denmark). For determination ofBALP, the Alkphase-B kit from Metra Biosystems(USA) and for OPG, the kit from Biomedica (Austria)were used. The differences were evaluated by ANOVAwith Bonferroni correction. The significance was set atP <0.05.We observed lower levels of bone formation andbone resorption markers in group A than in group B,but these differences are not statistically significant(Table 1). However, OC, CTX and OPG concentrationswere significantly lower in both groups of PKU childrenin comparison to the healthy age-matched controls.There are only a few papers presenting values of boneturnover markers in PKU subjects. Perez-Duenas et al.[6] observed the same levels of OC and BALP in a groupof younger patients and significantly lower serum BALP

Correlation between cerebral MRI abnormalities and mental retardation in patients with mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are a group of inherited disorders due to lysosomal enzyme deficiencies which lead to multi-organ accumulation of glycosaminoglycans. Some forms of MPS disorders are characterized by various degrees of mental retardation. Magnetic Resonance Imaging (MRI) is the primary imaging technique to detect CNS alterations. The aim of this study is to evaluate the correlation between white matter (WM) alterations and the presence of mental retardation. We analyzed 20 patients with different forms of MPSs, 11 with mental retardation and 9 with a normal cognitive function; all of them underwent brain MRI and received a score on the basis of the alterations (WM alterations; perivascular, subarachnoid, and ventricular space enlargement; abnormalities of the basal ganglia, of the corpus callosum and of the atlanto-axial joint). All patients with mental retardation presented severe WM alterations, while only five out of the nine subjects without mental retardation showed certainly WM abnormalities. As far as the other cerebral abnormalities are concerned, no difference between the two groups has been found. These data seem to show that there is a significant correlation between the presence of WM alterations and mental retardation.

An infant with Down syndrome and retinoblastoma. A possible non-fortuitous association

Satge et al.' reported in Ophthalmic Genetics an infant with Down syndrome and retinoblastoma and presented also a review of the literature. They are to be commended with a very interesting study. As the authors stated in their article, it is unlikely that all cases with both Down syndrome and retinoblastoma are reported in the literature and included in their study. In fact, they missed at least one study' published in your journal regarding the prevalence of mental retardation in patients with hereditary retinoblastoma. We did an epidemiological study and found in the Dutch retinoblastoma Register 8.7% cumulative incidence of mental retardation in 241 patients Nith hereditary retinoblastoma born in a 5o year period between 1 9451 994 . Two patients (females) of the 241 hereditary retinoblastoma patients had both Down syndrome (trisomy 21) and sporadic bilateral retinoblastoma (no 13q deletion found)! Tliat is much higher than the Down syndrome in 690 life births reported by the WHO. In summary, our epidemiological study supports the idea of Statge et al.' that hereditary retinoblastoma patients may have an increased risk for Down syndrome.

Protein Kinase Dyrk1 Activates cAMP Response Element-binding Protein during Neuronal Differentiation in Hippocampal Progenitor Cells

Dyrk is a dual specific protein kinase thought to be involved in normal embryo neurogenesis and brain development. Defects/imperfections in this kinase have been suggested to play an important role in the mental retardation of patients with Down's syndrome. The transcriptional factor cAMP response element-binding protein (CREB) has been implicated in the formation of many types of synaptic plasticity, such as learning and memory. In the present study we show that Dyrk1 activity is markedly induced during the differentiation of immortalized hippocampal progenitor (H19-7) cells. The addition of a neurogenic factor, basic fibroblast growth factor, to the H19-7 cells results in an increased specific binding of Dyrk1 to active CREB. In addition, Dyrk1 directly phosphorylates CREB, leading to the stimulation of subsequent CRE-mediated gene transcription during the neuronal differentiation in H19-7 cells. Blockade of Dyrk1 activation significantly inhibits the neurite outgrowth as well as CREB phosphorylation induced by basic fibroblast growth factor. These findings suggest that Dyrk1 activation and subsequent CREB phosphorylation is important in the neuronal differentiation of central nervous system hippocampal cells.