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)

Two children with mental retardation, choreoathetosis, dystonia, and muscle rigidity are reported. They had a history of severe hyperbilirubinemia after birth as a result of Rh isoimmunization. The history and clinical picture suggested the diagnosis of kernicterus. The magnetic resonance imaging examination showed a bilateral signal intensity increase in the globus pallidus on T2-weighted images. Additionally, our patients showed symmetric bilateral hyperintensity and volume loss in the hippocampus, which is known to be another characteristic area of bilirubin deposition in kernicterus.
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PMID:Bilateral mesial temporal sclerosis and kernicterus. 1509 Nov 33

Lesch-Nyhan syndrome (LNS) is a rare X-recessive disorder that leads to virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Partial HPRT deficiency results in uric acid overproduction with subsequent hyperuricemia, nephrolithiasis, renal failure and gouty arthritis. In contrast, at complete HPRT deficiency, besides overproduction of uric acid neurological problems appear including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The cause for the uric acid overproduction has been clarified, but the connection between the enzyme deficiency and the neurological manifestations in LNS remains unclear. A hypothesis, which explains this relation, is proposed in the paper. The hypothesis has several important points most substantial of which is the accelerated biosynthesis of semiessential amino acid histidine that against the background of accelerated purine de novo biosynthesis results in 5-aminoimidazole-4-carboxamideribotide (AICAR) and histamine accumulation. The histamine and AICAR were determined to be the compounds that cause the neurobehavioral symptoms of LNS for several reasons. First, in the basal ganglia a balance between the direct (activating) and the indirect (inhibiting) pathways arising on the basis of the antagonistic and reciprocal dopamine-adenosine interactions normally exists. This balance can tonically regulate smooth voluntary movements and the activity of the thalamus, which, in turn, processes the afferent sensorimotor signals from the whole body to the all areas of the cerebral cortex and is concerned to modulate mental development and bring sensory information into awareness. Second, histamine is known to induce a selective damage in dopaminergic neurons inhibiting the direct dopaminergic pathway, which could lead to muscular rigidity, and slowness in initiating movements as well as tremor that are characteristic of Parkinsonism in LNS. Third, AICAribosid (AICAR breakdown product) is a potent adenosine A2a receptor antagonist inhibiting the indirect dopamine-adenosinergic pathway and, therefore, could be responsible for the choreoathetosis, dystonia and ballismus found in LNS. The excitatory-inhibitory disbalance in the basal ganglia could result in inadequate modification of the thalamus activity with subsequent mental retardation and symptoms that include the patients not being aware for their own bodies that could give rise to self-mutilation. Finally, a possibility for the creation of a new animal model that could exactly match the human LNS is proposed in the paper.
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PMID:The biochemical basis of the neurobehavioral abnormalities in the Lesch-Nyhan syndrome: a hypothesis. 1519 65

Three families with X-linked mental retardation caused by a 24 base-pair duplication in ARX[428-451dup(24 bp)] are reported. The clinical features in these and six other published families are reviewed. In general, the clinical picture is variable. Mental retardation ranges from mild to severe. Infantile spasms (West syndrome) occurred in 12.5% and other less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. The focal dystonia, in association with mental retardation, may prove to be diagnostic of this mutation.
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PMID:Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. 1520 May 6

Lipoid proteinosis (LP) is an autosomal recessive disease that typically presents with papular, verrucous, poxlike, or acneiform scars and lesions and hoarseness. LP was recently mapped to the 1q21 locus and shown to result from mutations in the extracellular matrix protein 1 gene (ECM1). Epilepsy, mental retardation, and hippocampal calcifications can occur. The authors describe a patient with generalized dystonia caused by striatal calcifications.
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PMID:Generalized dystonia and striatal calcifications with lipoid proteinosis. 1559 73

Lesch-Nyhan disease (LND) is an inborn error of purine metabolism caused by defective activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT, EC 2.4.2.8), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classic phenotype occurs almost exclusively in males and is characterized by hyperuricemia, mental retardation, severe dystonia, and self-injurious behavior. Heterozygous carrier females are usually clinically normal. However, a small number of clinically affected females have been described. In all previous cases there was a mutation in one HPRT allele and non-random inactivation of the X chromosome carrying the normal HPRT gene. We have analyzed a female MZ twin pair discordant for Lesch-Nyhan disease. The mother and both twins are heterozygous carriers of a HPRT splicing mutation (IVS8 + 4A > G; c.609 + 4A > G) and all three express the mutant allele at similar frequencies in peripheral blood T cells. The mother and one sister are clinically normal. In the affected twin, the clinical phenotype is classical for Lesch-Nyhan disease, despite the fact that HPRT activity in the blood was also normal. X inactivation analysis showed a skewed pattern in the fibroblasts of the affected twin sister, with the X chromosome carrying the normal HPRT allele preferentially inactivated. As in many other reported cases of X-linked diseases, the discordant phenotype of the two monozygous twin sisters suggests that the process responsible for monozygotic twinning can trigger skewed X inactivation.
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PMID:Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. 1586 83

Motor and phonic tics are most frequently due to Tourette syndrome, but there are many other causes of tics. We analyzed data on 155 patients with tics and co-existent disorders (101M/54F; mean age 40.5 +/- 20.2 years). Fourteen (9.0%) patients had tics associated with an insult to the basal ganglia, such as head trauma (N = 4, 2.5%), stroke (N = 2, 1.2%), encephalitis (N = 3, 1.9%) and other causes. In addition, certain drugs, toxins, and post-infectious causes were associated with tics. Rarely, peripheral injury can cause movement disorders, including tics (N = 1, 0.6%). Pervasive developmental disorders, including Asperger's syndrome (N = 13, 8.3%), mental retardation (N = 4, 2.5%), autism (N = 3, 1.9%), and Savant's syndrome (N = 1, 0.6%), also may be associated with tics, as noted in 21 of the 155 patients (13.5%). Genetic and chromosomal disorders, such as Down's syndrome 5 (3.2%), neuroacanthocytosis (N = 2, 1.2%), and Huntington's disease (N = 1, 0.6%), were associated with tics in 16 patients (10.3%). We have also examined the co-existence of tics and other movement disorders such as dystonia (N = 31, 20.0%) and essential tremor (N = 17, 10.9%). Sixteen (10.3%) patients presented psychogenic tics, and one (0.6%) psychogenic tics and dystonia; conversely, Tourette syndrome preceded the onset of psychogenic dystonia (N = 1, 0.6%), and psychogenic tremor (N = 1, 0.6%) in two patients. Finally, 12 (7.7%) patients had tics in association with non-movement related neurological disorders, such as static encephalopathy (N = 2, 1.2%) and seizures (N = 3, 1.9%). To understand the physiopathology of tics and Tourette syndrome, it is important to recognize that these may be caused or associated with other disorders.
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PMID:Secondary tics and tourettism. 1596 46

Lesch-Nyhan disease (LND) is a rare disorder caused by a defect of an enzyme in the purine salvage pathway, hypoxanthine phosphoribosyl transferase (HPRT). It is still unknown how the metabolic defect translates into the complex neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in purine and pyrimidine nucleotide content in HPRT-deficient cells. We hypothesized that altered nucleotide concentrations in HPRT deficiency change G-protein-mediated signal transduction. Therefore, our original study aim was to examine the high-affinity GTPase activity of G-proteins in membranes from primary human skin and immortalized mouse skin fibroblasts, rat B103 neuroblastoma cells and mouse Neuro-2a neuroblastoma cells. Unexpectedly, in membranes from human fibroblasts, B103- and Neuro-2a cells, V(max) of low-affinity nucleoside 5'-triphosphatase (NTPase) activities was decreased up to 7-fold in HPRT deficiency. In contrast, in membranes from mouse fibroblasts, HPRT deficiency increased NTPase activity up to 4-fold. The various systems analyzed differed from each other in terms of K(m) values for NTPs, absolute V(max) values and K(i) values for nucleoside 5'-[beta,gamma-imido]triphosphates. Our data show that altered membrane NTPase activity is a biochemical hallmark of HPRT deficiency, but species and cell-type differences have to be considered. Thus, future studies on biochemical changes in LND should be conducted in parallel in several HPRT-deficient systems.
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PMID:Altered membrane NTPase activity in Lesch-Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT-deficient cell lines. 1593 74

Little information is available on the long-term course and adult outcome of patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. We describe the course of a 32-year-old woman with hypotonia, dystonia, choreoathetosis, mental retardation, behavioral disturbances, and incomplete puberty due to PTPS deficiency. From the age of 6 months she developed progressive hypotonia and choreoathtetoid movements despite good control of hyperphenylalaninemia. Tetrahydrobiopterin deficiency was diagnosed at age 3 years. She had a dramatic response to L-dopa, which persisted at a stable dose for 29 years. Reducing the L-dopa dose led to severe axial hypotonia and limb dystonia, and increasing it led to florid abnormal movements and behavioral disorders. This report illustrates the role of dopamine modulation in motor, psychiatric, and endocrine functions.
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PMID:Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. 1616 Nov 43

Defect of the purine salvage enzyme, hypoxanthine phosphoribosyl transferase (HPRT), results in Lesch-Nyhan disease (LND). It is unknown how the metabolic defect translates into the severe neuropsychiatric phenotype characterized by self-injurious behavior, dystonia and mental retardation. There are abnormalities in GTP, UTP and CTP concentrations in HPRT-deficient cells. Moreover, GTP, ITP, XTP, UTP and CTP differentially support Gs-protein-mediated adenylyl cyclase (AC) activation. Based on these findings we hypothesized that abnormal AC regulation may constitute the missing link between HPRT deficiency and the neuropsychiatric symptoms in LND. To test this hypothesis, we studied AC activity in membranes from primary human skin and immortalized mouse skin fibroblasts, mouse Neuro-2a neuroblastoma cells and rat B103 neuroblastoma cells. In B103 control membranes, GTP, ITP, XTP and UTP exhibited profound stimulatory effects on basal AC activity that approached the effects of hydrolysis-resistant nucleotide analogs. In HPRT- membranes, the stimulatory effects of GTP, ITP, XTP and UTP were strongly reduced. Similarly, in human and mouse skin fibroblast membranes we also observed a decrease in GTP-stimulated AC activity in HPRT-deficient cells compared with the respective controls. In mouse Neuro-2a neuroblastoma membranes, AC activity in the presence of GTP was below the detection limit of the assay. We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types.
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PMID:Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes. 1633 32

We report two brothers with an unknown form of early-onset familiar dystonia. Characteristic clinical features are (1) childhood-onset; (2) extrapyramidal motor symptoms; (3) dysarthria; and (4) mental retardation. Additional findings include loss of D(2)-receptors in both basal ganglia and hypoplasia of the cerebellar vermis with dilatation of the fourth ventricle and cisterna magna. There seems to be a progressive and non-progressive form of this clinical entity. Dystonic symptoms of the progressive form that occurred in one of the brothers were alleviated dramatically by bilateral internal globus pallidus (Gpi) stimulation, and the improvement has lasted now for 5 years.
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PMID:Two cases of autosomal recessive generalized dystonia in childhood: 5 year follow-up and bilateral globus pallidus stimulation results. 1643 72


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