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)

Cytogenetic studies on a mentally retarded boy revealed an X-Y translocation, karyotype 46,X,t(X;Y)(p22;q11). Only 5 other such cases have been reported and these were all females. The unequivocal male phenotype suggested non-random inactivation of the normal maternally derived X chromosome, and that the non-inactivated X-Y translocation chromosome included the locus for male determination. Confirmation of this was provided by unassociated X and Y chromatin in interphase cells, as well as by reverse banding after BrdU incorporation and autoradiography of metaphase chromosomes. There was anomalous Xg blood group inheritance in the proband, indicating possible localisation of the Xg locus to the terminal portion of the X short arm. Linkage of Xg and a form of X-linked mental retardation is suggested. Close linkage of the Xg locus with the loci for alpha-galactosidase, phosphoglycerate kinase, G-6-PD, and MPS II was excluded.
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PMID:X-Y translocation in a retarded phenotypic male. Clinical, cytogenetic, biochemical, and serogenetic studies. 74 19

The fragile X syndrome is the most common cause of familial mental retardation. Genetic counseling and gene isolation are hampered by a lack of DNA markers close to the disease locus. Two somatic cell hybrids that each contain a human X chromosome with a breakpoint close to the fragile X locus have been characterized. A new DNA marker (DXS296) lies between the chromosome breakpoints and is the closest marker to the fragile X locus yet reported. The Hunter syndrome gene, which causes iduronate sulfatase deficiency, is located at the X chromosome breakpoint that is distal to this new marker, thus localizing the Hunter gene distal to the fragile X locus.
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PMID:A new DNA marker tightly linked to the fragile X locus (FRAXA). 257 53

X-linked mental retardation with fragile X or Martin-Bell Syndrome (MBS) is a frequent cause of mental retardation. So far segregation analysis of MBS in pedigrees ascertained by different, incomplete criteria has produced results, difficult to interpret, which suggest genetic complexity (Sherman et al. 1985). Biochemical and cell biological studies have failed to provide an assay for genetic heterogeneity in MBS and linkage analysis is the only available method. Such analysis, however, is complicated by the incomplete penetrance of the disease in males and the variable penetrance and expression of the defect in heterozygous females. We have used a new approach to test the heterogeneity of recombination between MBS and the coagulation factor IX gene or the anonymous probe 52A in a group of nine families who have sought genetic counselling at Guy's Hospital. We find that both our families alone and our families plus apparently complete samples of pedigrees reported in the literature, separate into two groups: one tightly and one loosely linked to factor IX. In the combined family sample these represent respectively 0.3 and 0.7 of the total and show recombination fractions of 0.0-0.15 and 0.25-0.5. Furthermore, the families with non-penetrant carrier males show tighter linkage to factor IX than the others, thus confirming the suggestion of a systematic difference among MBS families in the recombination between the disease and the factor IX locus. By contrast, no significant differences were found in the recombination between 52A and factor IX in the two groups of MBS families or in these families versus those with Hunter syndrome examined in our laboratory. The causes of the linkage heterogeneity we describe are not known. At least two alternatives can be considered: The existence of two MBS loci or differences in the recombination between a single MBS locus and the factor IX gene. The association between incomplete penetrance and tight linkage to factor IX as well as the discontinuous variation in recombination fraction we have observed seem to favour the former alternative.
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PMID:Genetic heterogeneity of X-linked mental retardation with fragile X. Association of tight linkage to factor IX and incomplete penetrance in males. 367 51

A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.
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PMID:Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. 772 66

Mucopolysaccharidosis type I (i.e., Hurler, Hurler-Scheie, and Scheie syndromes) and type II (i.e., Hunter syndrome) are lysosomal storage disorders resulting from alpha-L-iduronidase (IDUA) deficiency and iduronate-2-sulfatase (IDS) deficiency, respectively. The a priori probability that both disorders would occur in a single individual is approximately 1 in 5 billion. Nevertheless, such a proband was referred for whom clinical findings (i.e., a male with characteristic facies, dysostosis multiplex, and mental retardation) and biochemical tests indicated these concomitant diagnoses. In repeated studies, leukocyte 4 methylumbelliferyl-alpha-L-iduronidase activities in this kindred were as follows: <1.0 nmol/mg protein/h in the proband and proband's clinically normal sister; 45.3 in mother; and 45.7 in father (normal range 65.0-140). Leukocyte L-O-(alpha-iduronate-2-sulfate)-(1->4)-D-O-2,5-anhydro[1-3H]mannitol-6- sulfate activities were as follows: 0.0 U/mg protein/h in the proband; 5.7 in his sister; 4.9 in mother; and 15.0 in father (normal range 11.0-18.4). Multiple techniques, including automated sequencing of the entire IDS and IDUA coding regions, were employed to unravel the molecular genetic basis of these intriguing observations. The common IDS mutation R468W was identified in the proband, his mother, and his sister, thus explaining their biochemical phenotypes. Additionally, the proband, his sister, and his father were found to be heterozygous for a common IDUA mutation, W402X. Notably, a new IDUA mutation A300T was also identified in the proband, his sister, and his mother, accounting for reduced IDUA activity in these individuals; the asymptomatic sister, whose cells demonstrated normal glycosaminoglycan metabolism, is thus a compound heterozygote for W402X and the new allele. This A300T mutation is the first IDUA pseudodeficiency gene to be elucidated at the molecular level.
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PMID:Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency. 855 71

Hunter syndrome, or mucopolysaccharidosis type II, is an X-linked recessive disorder resulting from iduronate sulfatase deficiency. Typical manifestations include short stature, mental retardation, hydrocephalus, macroglossia and cardiac valvulopathy. We describe a 21-year-old patient who presented with acute ischemic stroke and evidence of cerebral embolization. The echocardiogram demonstrated thickened mitral and aortic valves as potential sources of emboli. We conclude that ischemic stroke secondary to cardioembolization is a potential complication of Hunter syndrome.
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PMID:Cerebral infarction in Hunter syndrome. 1705 60

Chromosomal microarray analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test for the detection of well-characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7-9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6-year-old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X-inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X-inactivation and iduronate 2-sulfatase (IDS) enzyme activity were therefore examined. X-inactivation was found to be random in the child's peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.
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PMID:Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation. 1750 8

Hunter disease (mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disease caused by deficiency of iduronate-2-sulfatase. Accumulation of chondroitin sulfate B and heparan sulfate in various tissues is the biochemical consequence of MPS II. Children with Hunter disease are normal at birth, and symptoms occur between 2 and 10 years of age. Typical symptoms include coarse facies with enlarged tongue and prominent forehead as well as a short, stocky built stature with short neck. The cardiovascular, respiratory and gastrointestinal systems may be affected, and oral, dermatological and psychiatric as well as neurological complications are described. Life expectancy is markedly reduced and may be limited to 12 years for severely affected patients. The most common causes of death are airway obstruction and cardiac failure. The most severe symptoms may result from neurological symptoms or complications including hydrocephalus, spinal cord compression, cervical myelopathy, optic nerve compression, and hearing impairment. Patients may also develop carpal tunnel syndrome, sleep apnoea, seizures or mental retardation. This review describes characteristic neurological manifestations in MPS II and its underlying pathophysiology. In addition, an appraisal is given whether or not enzyme replacement therapy may be able to improve in particular the neurological symptoms of Hunter disease.
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PMID:Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed. 1861 89

Mucopolysaccharidosis (MPS) type II (Hunter syndrome, OMIM 309900) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). Major clinical manifestations include joint contractures, obstructive and restrictive airway disease, cardiac disease, skeletal deformities and often mental retardation. As with all the MPS disorders, mucopolysaccharidosis type II is a clinically heterogeneous disease in terms of the extent and rate of progression of organ impairment in affected individuals. Common causes of death, which usually occurs within the second decade of life, are obstructive airway disease and cardiac failure due to valvular dysfunction, pulmonary hypertension and myocardial disease. Patients with the more attenuated (so-called adult) form usually have a normal intelligence, but often have many complaints such as progressive loss of vision due to retinal dysfunction, spastic paresis due to myelon compression at the cranio-cerevical region, severe hip disease and cardiac complications. Clinical investigations that have been performed in the last years in a great number of patients have shown that many of these complications are still underdiagnosed and untreated. Until recently, no specific treatment was available for the affected patients; management mainly consisted of supportive care and treatment of complications. Enzyme replacement therapy with recombinant iduronate-2-sulphatase (idursulfase), however, has now been introduced. And it could be demonstrated that weekly intravenous infusions of idursulfase is able to improve many of the symptoms and signs of Hunter syndrome. This review will present the efficacy and safety data of the enzyme preparation and discuss benefits and limitations of this new therapeutic option.
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PMID:Mucopolysaccharidosis Type II (Hunter Syndrome): clinical picture and treatment. 2123 46

The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral. In this overview, the clinical features of the MPS disorders and a brief review of treatment options will be presented in order to aid the rheumatologist in recognizing the features of these rare genetic disorders.
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PMID:Overview of the mucopolysaccharidoses. 2221 Jun 69


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