Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two boys from separate families presented with hereditary multiple exostoses (EXT) and autism associated with mental retardation. Their fathers both expressed a clinical phenotype of hereditary multiple exostoses milder than those of the patients and without the associated mental disorder. The EXT1 and EXT2 genes from lymphocytes of the affected individuals were analyzed by using denaturing high-performance liquid chromatography and direct sequencing. A novel deletion mutation, 1742delTGT-G in exon 9 of EXT1, causing a frameshift was detected in one boy and his father. Another novel deletion mutation, 2093delTT in exon 11 of EXT1, causing transcription termination was detected in the other affected boy and his father. EXT1 is expressed in the brain, and both EXT1 and EXT2 proteins are associated with glycosyltransferase activities required for the biosynthesis of heparan sulfate, which also has activity in the brain. The coincidental association of mental disorders in the boys was not completely excluded. However, these results suggest the involvement of EXT1 in the development of mental disorders, including mental retardation and autism.
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PMID:Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1. 1203 95

A female Thai baby born to non-consanguineous parents, presented with primary hypomagnesemia at 10 weeks of age, and suffered recurrent convulsions that responded to magnesium supplementation. She was found to have hypomagnesemia (Mg 0.35-1.02 mEq/L) and a low urinary magnesium excretion of less than 10 mg per day, or urinary Mg/Cr that ranged from 0.005-0.01 mg/mg. Intermittent hypomagnesemia and one episode of hypocalcemia with occasional convulsions developed, due to irregular consumption of oral magnesium sulfate, which had a bitter taste, caused frequent loose stools and black staining of the teeth. Better compliance after switching from magnesium sulfate to magnesium oxide resulted in an increased level of serum magnesium and the gradual disappearance of the black staining of the teeth and frequent loose stools. The patient required an oral elemental magnesium dosage of 15-30 mg/kg/day to maintain the serum magnesium level at between 1.02-1.33 mEq/L and keep her free from convulsions. The follow-up period was 7 years during which the patient showed normal physical growth and a mild degree of mental retardation.
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PMID:Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature. 1254 21

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation/mental retardation syndrome with an estimated incidence among individuals of European ancestry of 1 in 20000 to 1 in 30000. It is caused by inactivity of the enzyme 7-dehydrosterol-delta(7)-reductase, which catalyses the terminal transformation in cholesterol synthesis. Patients show not only an increased level of 7-dehydrocholesterol in blood and tissues, but also increased 8-dehydrocholesterol because of the presence of an active delta(8)-delta(7) isomerase. A major consequence of these biochemical abnormalities is the alteration of normal embryonic and fetal somatic development causing postnatal abnormalities of growth, learning, language and behavior. While deficient cholesterol during early development is the primary cause of central nervous system (CNS) abnormalities and retardation, we questioned whether neurosteroids could also be involved since they can have a profound influence on behavioral characteristics. Disordered neurosteroidogenesis would be expected in SLOS and could be caused by a deficiency in classical neurosteroid synthesis secondary to cholesterol deficiency, or by synthesis from 7- and 8-dehydrocholesterol of novel neurosteroids with delta(7) or delta(8) unsaturation which may have altered activity compared with conventional neurosteroids. In particular we sought analogues of dehydroepiandrosterone sulfate, pregnenolone sulfate and the pregnanolone epimers. We targeted urine from post-pubertal females, as this type of sample would be most likely to yield identifiable amounts of the pregnanolone metabolites of progesterone. Analysis by GC/MS of urinary steroids excreted by post-pubertal females confirmed the presence of neurosteroid-like compounds in SLOS patient's urine. Even though the new neuroactive steroids identified were unlikely to have been formed in the brain, it is likely that mechanisms for their synthesis are operable in this organ.
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PMID:The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production. 1471 77

The Sanfilippo type A syndrome, one of the most frequent forms of mucopolysaccharidosis III, is characterized by severe mental retardation, progressive neurological degeneration, and mild somatic changes. It is due to a deficiency of heparan-N-sulfatase (sulfamidase) activity and consequent excretion of heparan sulfate in the urine. The disease is transmitted through an autosomal recessive mechanism, and more than 60 gene mutations have been identified. Up to now, only 10 cases of attenuated form of Sanfilippo type A syndrome have been described, and the specific mutation has been identified only in two of them. We report here on a female patient, 20 years old, with Sanfilippo type A syndrome presenting with a mild clinical phenotype characterized essentially by a moderate nonevolving mental retardation. The genetic analysis demonstrated that the patient is homozygous for mutation R206P; presence of polymorphism R456H was also found. This study places R206P as a mild mutation underlying Sanfilippo type A disease.
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PMID:An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene. 1563 19

Costello syndrome is a distinctive multiple congenital anomaly syndrome, characterized by loose soft skin with deep palmar and plantar creases, loose joints, distinctive coarse facial features, skeletal abnormalities, cardiac abnormalities (cardiovascular malformation (CVM), hypertrophic cardiomyopathy, tachycardia), predisposition to malignancy, developmental delays, and mental retardation. Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. Despite multiple clinical reports of cardiac abnormalities, there has been only one previously published report describing post-mortem findings in hearts from Costello syndrome patients. Here we provide a detailed description of the post-mortem findings of the hearts of three children with Costello syndrome. Routine histological examination and results of targeted histochemical and immunohistochemical studies revealed that in addition to cardiomyocyte hypertrophy, these hearts also demonstrated massive pericellular and intracellular accumulation of chondroitin sulfate-bearing proteoglycans and a marked reduction of elastic fibers. Normal stroma was replaced by multifocal collagenous fibrosis. Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. In contrast, deposition of chondroitin-4 sulfate was below the level detected in normal hearts. We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome.
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PMID:Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy. 1563 29

Several lines of evidence suggest that loss of estrogen after menopause may play a role in the cognitive declines associated with Alzheimer's disease (AD). Women with Down syndrome (DS) experience early onset of both menopause and AD. This timing provides a model to examine the influence of endogenous estrogen deficiency on risk of AD. We hypothesized that low serum levels of bioavailable estradiol (E2) would be associated with increased risk of AD. One hundred and nineteen postmenopausal women with DS, 42-59 years of age, were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Women with DS who developed AD had lower levels of bioavailable E2, lower levels of total estradiol, higher levels of sex-hormone binding globulin, and lower levels of dehydroepiandrosterone sulfate at baseline than women who remained dementia free over the course of follow-up. Women who had low levels of bioavailable E2 at baseline were four times as likely to develop AD (HR=4.1, 95% CI: 1.2-13.9) and developed AD, on average, 3 years earlier, than those with high levels of bioavailable E2, after adjustment for age, level of mental retardation, ethnicity, body mass index, history of hypothyroidism or depression and the presence of the apolipoprotein varepsilon4 allele. Our findings support the hypothesis that reductions in estrogen following menopause can contribute to the cascade of pathological processes leading to AD.
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PMID:Bioavailable estradiol and age at onset of Alzheimer's disease in postmenopausal women with Down syndrome. 1692 67

Sanfilippo type B is an autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by deficiency of N-acetyl-alpha-D-glucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulfate. It is characterized by neurologic degeneration, behavioral problems, and mental decline. Somatic features are relatively mild and patients with this disorder can reach late adulthood. It is the most common subtype of MPS in the Netherlands and probably underdiagnosed in adult persons with mental retardation (MR). In order to increase knowledge on the adult phenotype and natural history in Sanfilippo type B, we present the clinical data of 20 patients with this disorder. Sixteen of them were followed for one to three decades. Six died between 28 and 69 years of age, mainly from pneumonia and cachexia; the surviving patients were 18-63 years old. Apart from the youngest, they had lost mobility at 36-68 years. Most had developed physical problems, in particular in the 4th-6th decade of life: cardiac disease (cardiomyopathy, atrial fibrillations), arthritis, skin blistering, swallowing difficulties requiring feeding by a gastrostomy tube, and seizures. The course of the disease was dominated in most of them by challenging behavioral problems with restlessness, extreme screaming and hitting, difficult to prevent or to treat pharmaceutically. Even in absence of knowledge of the history of an elderly patient with MR, the presence of behavioral problems should prompt metabolic investigation for MPS.
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PMID:Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems? 1764 47

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 VII (MPS VII; Sly syndrome) is an autosomal recessive disorder caused by a deficiency of beta-glucuronidase (GUS, EC 3.2.1.31; GUSB). GUS is required to degrade glycosaminoglycans (GAGs), including heparan sulfate (HS), dermatan sulfate (DS), and chondroitin-4,6-sulfate (CS). Accumulation of undegraded GAGs in lysosomes of affected tissues leads to mental retardation, short stature, hepatosplenomegaly, bone dysplasia, and hydrops fetalis. We summarize information on the 49 unique, disease-causing mutations determined so far in the GUS gene, including nine novel mutations (eight missense and one splice-site). This heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII. One pseudodeficiency allele, one polymorphism causing an amino acid change, and one silent variant in the coding region are also described. Among the 103 analyzed mutant alleles, missense mutations accounted for 78.6%; nonsense mutations, 12.6%; deletions, 5.8%; and splice-site mutations, 2.9%. Transitional mutations at CpG dinucleotides made up 40.8% of all the described mutations. The five most frequent mutations (accounting for 44/103 alleles) were exonic point mutations, p.L176F, p.R357X, p.P408S, p.P415L, and p.A619 V. Genotype/phenotype correlation was attempted by correlating the effects of certain missense mutations or enzyme activity and stability within phenotypes. These were in turn correlated with the location of the mutation in the tertiary structure of GUS. A total of seven murine, one feline, and one canine model of MPS VII have been characterized for phenotype and genotype.
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PMID:Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). 1922 84

Mucopolysaccharidoses are autosomal and recessive lysosomal storage disorders caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycan catabolism. The Sanfilippo type A disease (MPS III A) results from sulfamidase deficiency, which leads to accumulation of heparan sulfate, whereas Sly disease (MPS VII) results from beta-glucuronidase deficiency, leading to accumulation of heparan, dermatan, and chondroitin sulfates. These syndromes are characterized by severe central nervous system degeneration, resulting in progressive mental retardation, and fatality occurs in severely affected children. To date, no effective treatment is available except for bone marrow transplantation in specific cases. Recently, the use of genistein, an isoflavone that inhibits glycosaminoglycans synthesis, has been tested as substrate reduction therapy for neuronopathic forms of these diseases.We tested five natural analogs to genistein in human fibroblasts from both Sanfilippo A and Sly patients. Four molecules were as efficient as genistein in decreasing glycosaminoglycan accumulation. Moreover, a combination of several isoflavones was more efficient than one single isoflavone, suggesting a synergistic effect. These preliminary data may offer new perspectives for treating Sly and Sanfilippo A diseases and could be relevant to other neurological forms of mucopolysaccharidoses.
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PMID:Storage correction in cells of patients suffering from mucopolysaccharidoses types IIIA and VII after treatment with genistein and other isoflavones. 2008 60


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