Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mental retardation and congenital malformations in individuals with small ring X chromosomes are often due to the functional disomy that results from failure of these chromosomes to undergo X inactivation. Such chromosomes either lack the XIST locus or do not express it. We have carried out genetic analysis of the ring X chromosomes from two girls with a 45,X/46,X,r(X) karyotype, mental retardation, and a constellation of abnormalities characteristic of the severe phenotype due to X disomy. In each case the ring X chromosome included an intact XIST locus which was expressed; the breakpoints were distal to DXS128, and therefore outside the XIC region; transcription analysis of alleles at the androgen receptor locus confirmed that these were inactive chromosomes. The characteristics of the XIST RNA were similar to the wild-type. Additional studies in cultured fibroblasts showed a second ring in a small percentage of the cells. The association of severe phenotype with an inactive X chromosome most likely reflects the presence of a second ring X chromosome which was active at least in some tissues during embryogenesis, but is no longer prominent in the tissues we analyzed.
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PMID:Severe phenotypes associated with inactive ring X chromosomes. 1086 82

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.
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PMID:X linked mental retardation: a clinical guide. 1611 46

Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.
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PMID:MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. 1839 36

In a man with severe mental retardation, minor facial and genital anomalies, disproportionate short stature and a broad thorax, we identified a de novo Xq13.2q21.1 duplication by array CGH. This 7 Mb duplication encompasses 23 known genes, including the X-linked mental retardation (XLMR) genes ATRX and SLC16A2. The phenotype of this patient is similar to that described in more than 10 previously reported patients with overlapping Xq duplications. Detailed comparison of the clinical characteristics and the function of the genes located in the commonly duplicated regions of these patients led us to the hypothesis that an increased dosage of ATRX and perhaps of other genes is involved in the pathogenetic mechanism of this XLMR phenotype, including mental retardation, short stature, and genital abnormalities comprising cryptorchidism and/or a small penis.
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PMID:Xq13.2q21.1 duplication encompassing the ATRX gene in a man with mental retardation, minor facial and genital anomalies, short stature and broad thorax. 1929 73

The Allan-Herndon-Dudley syndrome (AHDS;MIM 300523) of X-linked mental retardation and hypotonia is caused by mutations in a thyroid hormone transporter gene--the monocarboxylate transporter 8 (MCT8 also known as SLC16A2) gene. A 23-month-old boy with severe developmental delay, hypotonia, recurrent emesis, and irritability is described. He was diagnosed with hypothyroidism at the age of 4 months. However, T3 level was elevated. Molecular analysis of the MCT8 gene detected a single base duplication in exon 5 c.1614dupC (p.Ile539fs), consistent with a diagnosis of AHDS. While T3 is the best marker for this disorder, elevations in TSH should alert to the diagnosis.
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PMID:Elevated TSH levels in a mentally retarded boy. 1993 87

Thyroid hormones are known to be essential for growth, development and metabolism. Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia. Here we describe in detail the clinical and biochemical features in a boy affected by AHDS with severe neurological abnormalities and a novel de novo SLC16A2 gene insertion, 1343-1344insGCCC, resulting in a truncated protein lacking the last four transmembrane domains (TMDs) as well as the carboxyl cytoplasmic end. He presents mental retardation, axial hypotonia, hypertonia of arms and legs, paroxysmal dyskinesias, seizures. The endocrine phenotype showed low serum total and free thyroxine (T4), very elevated total and free triiodothyronine (T3) and normal thyrotropin (TSH) with blunted response to thyrotropin-releasing hormone (TRH). The latter finding was unexpected and suggested that the lack of functional MCT8 was counterbalanced at the thyrotrope cell level by high serum T3 concentration and/or by increased intrapituitary type 2 deiodinase (D2) activity. Our case constitutes a relevant contribution to better characterize this disorder and to elucidate the functional consequences of SLC16A2 gene mutations.
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PMID:Allan-Herndon-Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH. 2071 92

Background: The thyroid hormones (THs) triiodothyronine (T3) and thyroxine (T4) are crucial regulators of brain development and function. Cell-specific transporter proteins facilitate TH uptake and efflux across the cell membrane, and insufficient TH transport causes hypothyroidism and mental retardation. Mutations in the TH transporters monocarboxylate transporter 8 (MCT8, SLC16A2) and the organic anion-transporting polypeptide 1C1 (OATP1C1, SLCO1C1) are associated with the psychomotor retardation Allan-Herndon-Dudley syndrome and juvenile neurodegeneration, respectively. Methods: To understand the mechanisms and test potential treatments for the recently discovered OATP1C1 deficiency, we established an oatp1c1 mutant (oatp1c1-/-) zebrafish. Results: oatp1c1 is expressed in endothelial cells, neurons, and astrocytes in zebrafish. The activity of the hypothalamic-pituitary-thyroid axis and behavioral locomotor activity increased in oatp1c1-/- larvae. Neuropathological analysis revealed structural alteration in radial glial cells and shorter neuronal axons in oatp1c1-/- larvae and adults. Notably, oatp1c1-/- and oatp1c1-/-Xmct8-/- adults exhibit an enlarged thyroid gland (goiter). Pharmacological assays showed that TH analogs, but not THs, can reduce the size and improve the color of the thyroid gland in adult mutant zebrafish. Conclusion: These results establish a vertebrate model for OATP1C1 deficiency that demonstrates endocrinological, neurological, and behavioral alterations mimicking findings observed in an OATP1C1-deficient patient. Further, the curative effect of TH analogs in the oatp1c1-/- zebrafish model may provide a lead toward a treatment modality in human patients.
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PMID:Neural Alterations and Hyperactivity of the Hypothalamic-Pituitary-Thyroid Axis in Oatp1c1 Deficiency. 3179 46