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)

Purine nucleoside phosphorylase (PNP) deficiency is a rare inherited disease accounting for approximately 4% of patients with severe combined immunodeficiency. Thirty-three patients have been reported. PNP-deficient patients suffer from recurrent infections, usually beginning in the first year of life. Two thirds of patients have evidence of neurologic disorders. Findings range from spasticity to developmental delay, to mental retardation. One third of patients develop autoimmune disease. The most common manifestation of this is autoimmune hemolytic anemia. Idiopathic thrombocytopenic purpura and systemic lupus erythematosis have also been reported. Patients usually present with infections but approximately one fourth have come to medical care initially for neurological problems. In PNP deficiency, T- and B-cell immunity are affected. T-cell function may be profoundly deficient, may be normal at birth and then decrease with time, or may fluctuate repeatedly between low and normal. B-cell function can be normal but is deficient in approximately one third of patients. PNP protein is a trimer of approximately 90,000 daltons. It is found in most tissues of the body but is at highest levels in lymphoid tissues. This tissue distribution explains why the lymphoid system is predominantly affected in PNP deficiency. Many mechanisms have been proposed to explain the metabolic toxicity in PNP deficiency. The elevated dGTP found in PNP deficiency is thought to inhibit ribonucleotide reductase and, thus, impede cell division. Depressed GTP levels may correlate with neurologic dysfunction. The gene for PNP has been cloned; it is located on the long arm of chromosome 14. Studies of a mutant PNP gene isolated from one patient showed that a point mutation resulting in an amino acid substitution was responsible for PNP deficiency. PNP deficiency has a grave prognosis. No patient has reached the third decade of life. Twenty-nine of the 33 reported patients have died from their disease. Prenatal diagnosis is currently available. Many different therapies have been utilized for PNP deficiency including bone marrow transplantation, red cell transfusions, and supplementation of the diet with purines and pyrimidines. None of these therapies has been consistently successful. In light of the poor prognosis for PNP deficiency, bone marrow transplantation should be considered for all patients. In the future, improved forms of therapy such as gene therapy may become available.
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PMID:Purine nucleoside phosphorylase deficiency. 193 Oct 7

Several human inherited diseases have been localized to the Xq13.3 region of the human X chromosome (X-linked dystonia with Parkinsonism, sideroblastic anemia, SCID, Menkes disease and X-linked mental retardation loci). Genes involved in the phenotypes have been isolated for only two of them (Menkes and SCIDX). It was therefore interesting to isolate and characterize new genes from the region. In a previous work (12 and Consalez et al, in preparation) we isolated a gene (XNP), located 350 Kb proximal to PGK1, potentially coding for a nuclear protein. We describe here the cloning and characterization of the murine homologue. The pattern of expression of the gene in the newborn mouse (especially the expression in particular regions of the brain: optical lobe, frontal cortex, hippocampus and cerebellum), as well as the expression in human tissues, suggests that this gene might be involved in neuronal differentiation. Among the different morbid phenotypes assigned to the region, X-linked mental retardation would be the best candidate to be associated with this gene.
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PMID:Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3. 816 50

An association between personality disorder (PD) pathology, including symptoms of all PD types and Axis I disorders, and suicidal behaviour was studied in a series of 90 non-schizophrenic, non-bipolar in-patients of both sexes without mental retardation or organic brain syndrome. All of these patients, who scored positively on the SCID-II-PQ, were interviewed with the PDE and SCID-P, and with the Structured interview for the study of childhood trauma provided with supplementary items reflecting suicidal behaviour. Mood disorders were found to be significantly correlated with cluster C pathology (PD pathology always being expressed by dimensional PDE scores) and eating disorders were significantly correlated with cluster B pathology in women. Psychoactive substance use disorders were mainly correlated with cluster B pathology and anxiety disorders with cluster C pathology in both sexes. Suicidal behaviour was correlated with PD pathology of all clusters in women, but not in men. In women a strong correlation was found between suicidal behaviour and history of childhood trauma, especially sexual abuse. The results of this study indicate that there is some specificity with regard to the Axis I/Axis II association, more so in relation to PD clusters than in relation to the individual PD types. However, the relationships between PD pathology and Axis I disorders and suicidal behaviour are complex, and they differ between the sexes.
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PMID:Possible correlates of DSM-III-R personality disorders. 942 38

Leukocyte adhesion deficiency type 2 (LADII) is characterized by defective selectin ligand formation, recurrent infection, and mental retardation. This rare syndrome has only been described in 2 kindreds of Middle Eastern descent who have differentially responded to exogenous fucose treatment. The molecular defect was recently ascribed to single and distinct missense mutations in a putative Golgi guanosine diphosphate (GDP)-fucose transporter. Here, we describe a patient of Brazilian origin with features of LADII. Sequencing of the GDP-fucose transporter revealed a novel single nucleotide deletion producing a shift in the open-reading frame and severe truncation of the polypeptide. Overexpression of the mutant protein in the patient's fibroblasts did not rescue fucosylation, suggesting that the deletion ablated the activity of the transporter. Administration of oral L-fucose to the patient produced molecular and clinical responses, as measured by the appearance of selectin ligands, normalization of neutrophil counts, and prevention of infectious recurrence. The lower neutrophil counts paralleled improved neutrophil interactions with activated endothelium in cremasteric venules of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, fucose supplementation induced autoimmune neutropenia and the appearance of H antigen on erythrocytes, albeit without evidence of intravascular hemolysis. The robust response to fucose despite a severely truncated transporter suggests alternative means to transport GDP-fucose into the Golgi complex.
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PMID:Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. 1240 89

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease.
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PMID:Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications. 1718 67

Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme alpha-l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3-38-fold) in these organs. Neuropathological examination showed GM(3) ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.
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PMID:Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy. 1792 Apr 51

An 8-month-old boy was admitted to the hospital because of recurrent bronchopneumonia and gastrointestinal tract infections. On physical examination, he had hypotonia, mental retardation, microcephaly with flat facies, low nasal bridge, small nose, small ears. Laboratory evaluation revealed Down syndrome, lymphopenia, hypogammaglobulinemia, reduced proportions of the peripheral blood lymphocytes with an inverted CD4/CD8 ratio and markedly reduced mitogen response of the lymphocytes. We report here unique case of Down syndrome associated with severe combined immunodeficiency.
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PMID:Down syndrome associated with severe combined immunodeficiency: a case report. 1985 34

Children with congenital severe combined immunodeficiency disease (SCID) lack an immune system and require continuous reverse isolation to protect them from exogenously transmitted infection. In our setting, protected environments consist of laminar flow rooms in which everything is sterilized (food, clothing, toys and so on). Staff and family wear complete surgical garb, preventing skin contact, observation of mouth movement and olfaction of typical human odours. Case studies of language development in children reared from infancy in protected environments have cited instances of mental retardation or language delay with some improvements after intervention, although the degree of language exposure is not well documented . We report here the case of a male patient, successfully treated for SCID, who lived in reverse isolation from 9 months to 4 yr 4 months of age and who has demonstrated nearly complete recovery of language usage. Our study illustrates the resilience of human intellectual function following a condition of early severe deprivation.
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PMID:Language recovery following isolation for severe combined immunodeficiency disease. 2708 56

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.
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PMID:Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature. 3071 30