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

Continuing progress has been made in the exploration of the biochemical causes of mental illness. Recent research has indicated that selected abnormalities of specific isoenzymes play an important role in the pathogenesis of heritable metabolic disorders such as phenylketonuria and Niemann-Pick disease. The roles of "animal lectins" and glycosidic enzymes in brain development and synaptogenesis appear to have received important substantiation within the past year. In additions, it has been shown that the blood-brain barrier can be temporarily altered so that exogenous enzymes can enter the central nervous system, and imperative consideration for enzyme replacement therapy in mental disorders. Less satisfactory progress has been made concerining potential anabolic disorders of lipids affecting the nervous system. Finally, novel experimental directions concerning energy metabolism by the brain offer considerable hope for the elucidation of some of the causes of mental retardation.
 ...
PMID:Inherited metabolic diseases and pathogenesis of mental retardation. 10 26

Clinical, biochemical, and electron microscopic studies are presented in two brothers with Niemann-Pick disease. The clinical features include hepatosplenomegaly and mental retardation without any other neurological signs. Roentgenograms of the chest showed bilateral diffuse reticular infiltration. The amounts of sphingomyelin and cholesterol in liver were increased, and sphingomyelinase activities in both liver and skin fibroblasts were markedly reduced in Case 1. Numerous foam cells and myelin figures were observed in the liver, kidneys, bone marrow, and lymph nodes on electron microscopical examination. These cases were regarded as a variant of Niemann-Pick disease from our investigations as they have mental retardation as an exceptional symptom when they are diagnosed as type B.
 ...
PMID:Chronic Niemann-Pick disease with sphingomyelinase deficiency in two brothers with mental retardation. 20 52

A simple one-vial-method was developed for the quantitative determination of sphingomyelinase activity in human leukocytes and urine, using [14C-methyl] sphingomyelin. The measured activities of healthy control persons show a higher scatter in (n=50) urine (1.2 +/- 0.5 nmol/h . ml urine) than in (n=9) leukocytes (2.15 +/- 0.35 nmol/h . mg protein). Long term tests showed that the enzyme activities in urine can best be correlated to the 24-h-creatinine excretion. A distinct loss of enzyme activity was found in dialyzed urine starting at about the third day; this did not occur in undialyzed urine. The method also shows good reproducibility in micro-tests. It is therefore suitable for screening tests (urine of persons suffering from Niemann Pick disease) and for the prenatal diagnosis of sphingomyelinosis. For one out of two children with symptoms of sphingomyelinosis (hepatosplenomegaly, mental retardation, and neurological deterioration) the diagnosis was confirmed by morphological examination of tissues obtained by biopsy. In both cases leukocytes and urine revealed normal sphingomyelinase activity. These biochemical results in conjunction with the clinical and morphological picture were indicative of type C Niemann-Pick disease.
 ...
PMID:An improved and simple micro-method of sphingomyelinase assay in leukocytes and urine. 21 Nov 76

What is the connection among the following three medical conditions: Niemann-Pick type C disease (a cause of mental retardation and early death), systemic lipidosis (in which an obscure side effect of numerous drugs transforms lysosomes into lamellar bodies), and holoprosencephaly (a catastrophe in embryonic development)? Recent evidence suggests that the pathogenesis in each use involves impaired sensing of cellular cholesterol.
 ...
PMID:Four cholesterol-sensing proteins. 972 33

We report the association of Beckwith-Wiedemann syndrome (BWS) and a residual acid sphingomyelinase (ASM) activity of about 35% in a 23 months old Hungarian boy. Besides the classical triad of exomphalos, macroglossia and gigantism some other BWS-related features: polyhydramnios (known from the praenatal history), hemihypertrophy, craniofacial dysmorphy, a mild mental retardation, bilaterally undescended testes, cardiac anomalies and a terminally developed, fatal embryonal rhabdomyosarcoma were present in the patient. The decreased activity of the ASM was measured in the patient s skin fibroblasts. This result, with hepatomegaly, mental retardation, feeding problems, a failure to thrive and muscle-hypotony, partially resembled the ASM-deficient forms of Niemann-Pick disease (NPD). Morphological analysis of the bone-marrow cells gave normal results. There was no chromosomal alteration found by conventional karyotyping of the patient s lymphocytes.BWS-associated genes as well as the human ASM gene (SMPD1) are all located at 11p15. DNA-studies by region specific markers as well as mutational analysis for the most common NPD-mutations are planned in the future. This is the first report on the simultaneous occurrence of BWS and ASM-deficiency.
 ...
PMID:Acid sphingomyelinase deficiency in Beckwith Wiedemann syndrome. 1117 64

Niemann-Pick disease (NPD) represents a type of lysosomal storage diseases in which sphingomyelin accumulates in the histocytes and reticuloendothelial cells of the spleen, liver, lymph nodes, bone marrow and central nervous system. We report a child with massive hepatosplenomegaly, lymphadenopathy, mental retardation and widespread papulonodular lesions. His clinical features conform to the type A subgroup of NPD.
 ...
PMID:Type A Niemann-Pick disease. 1120 22

In 471 adult mentally retarded adult patients (mean age 46 years; 92.6% males) living in an institution for the mentally retarded, a clinical examination, cytogenetic and molecular studies were done. 306 patients were screened for metabolic disorders. In 7 additional patients a metabolic disorder (phenylketonuria (n = 5), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and mucopolysaccharidosis type VII (Sly syndrome) (n = 1)) was diagnosed in the past. The abnormal metabolic findings in this group of 313 patients were classified in three categories and the clinical findings are reported: 1. metabolic disorders as the cause of mental retardation (MR), 2. metabolic disorders not explaining the MR, and 3. metabolic abnormalities of unknown significance. The first two groups included 16 patients, i.e. 26.2% of the group of monogenic disorders and 3.4% of the total population: phenylketonuria (PKU) (n = 5), S-sulfocysteinuria (n = 3), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and Gm1-gangliosidosis type 3 (n = 1) (first group), and mucopolysaccharidosis type VII (Sly syndrome) (n = 1), Niemann-Pick syndrome, type B (n = 1), cystinuria (n = 1) and hyperprolinemia type 1 (n = 3) (second group). The third group included patients with citrullinemia (n = 2), methionine sulphoxide reductase deficiency (n = 1), ornithinemia (n = 1), glycinuria (n = 20), neuraminaciduria (n = 8), uraciluria (n = 6) and diabetes mellitus (n = 2). Screening for Congenital Disorders of Glycosylation (CDG) in 144 patients and for Smith-Lemli-Opitz syndrome (SLO) in a selected group of 6 patients was normal. Of the total group of 306 patients screened for inborn errors of metabolism, only 5 (1.6%) were found with a true metabolic disorder. These 5 patients presented clinical symptoms, neurodegenerative or behavioural problems, indicating further metabolic screening. The present study illustrates that a selected group of patients with mental retardation of unknown origin are candidates for metabolic screening, especially if aberrant behaviour, neurodegenerative problems or dysmorphic features are present.
 ...
PMID:Metabolic studies in older mentally retarded patients: significance of metabolic testing and correlation with the clinical phenotype. 1133 72

The RSH/Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/mental retardation syndrome caused by an inborn error of cholesterol synthesis. Mutations in the 3beta-hydroxysteroid Delta(7)-reductase gene result in impaired enzymatic reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. Cells obtain cholesterol by either de novo synthesis or from exogenous sources by the binding and uptake of low density lipoprotein (LDL) particles. Because de novo synthesis of cholesterol is impaired in SLOS, current investigational therapy for SLOS consists of dietary cholesterol supplementation. However, the potential effects of elevated intracellular levels of 7-DHC on intracellular LDL metabolism have not been described. We now report that in addition to the primary defect in de novo cholesterol synthesis, SLOS fibroblasts have a secondary defect of LDL cholesterol metabolism. Staining of fibroblasts with filipin, a fluorescent polyene antibiotic which binds unesterified sterols, shows that SLOS fibroblasts accumulate unesterified sterols. Further studies show that this increased filipin staining was due to an abnormal accumulation of LDL derived cholesterol rather than due to storage of endogenously synthesized 7-dehydrocholesterol (7-DHC). We have also found that SLOS fibroblasts failed to degrade LDL at a normal rate, and examination of SLOS fibroblasts by electron microscopy demonstrated the formation of lysosomal inclusions similar to that seen in Niemann-Pick type C (NPC) cells. We propose that 7-DHC may directly or indirectly inhibit the function of the NPC protein through its sterol-sensing domain (SSD), and that 7-DHC may perturb the function of other SSD containing proteins in SLOS.
 ...
PMID:Cholesterol storage defect in RSH/Smith-Lemli-Opitz syndrome fibroblasts. 1205 64

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.
 ...
PMID:Synaptic vesicle docking: sphingosine regulates syntaxin1 interaction with Munc18. 1939 May 77

DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.
 ...
PMID:Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene. 3284 22


1