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)

Homogenates of cultured skin fibroblasts from a non-ambulatory, 20-year-old male with cherry-red spots, corneal clouding, seizures, mental retardation, dysostosis multiplex, dwarfism, coarse facies and loss of vision, originally described by Goldberg et al. (1971), have diminished neuraminidase activity and an excess of neuraminic acid-rich compounds. Specifically, these cells have 2-17% normal neuraminidase when measured with 2-(3' methoxyphenyl)-N-acetyl-alpha-neuraminic acid, N-acetyl-neuramin-lactose and fetuin. Activities of 12 other lysosomal enzymes were either at or above the range of normal control fibroblasts. Total neuraminic acid concentration was 44.3 nmol/mg protein versus an average control value of 14.2. It is concluded that the Goldberg syndrome should be considered, along with mucolipidosis I and the cherry-red spot -- myoclonus syndrome, as resulting from a primary neuraminidase deficiency.
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PMID:Neuraminidase deficiency in the original patient with the Goldberg syndrome. 51 4

Electrophysiological investigation was performed in 3 patients with beta-galactosidase and sialidase deficiencies (sialidosis type 2) in order to elucidate the underlying mechanism of intention myoclonus. It is a rare neuronal storage disease that begins in childhood with mental retardation, skeletal abnormalities, progressive myoclonus and cherry-red spots in the macula. Electrophysiological studies showed paroxysmal activities in the EEG, consistent temporal relationship between the EEG spikes and myoclonic jerks demonstrated by jerk-locked averaging, high amplitude somatosensory evoked potentials with altered wave form, and enhanced long-loop reflexes. These results suggest that there is a hyperexcitability of the cerebral cortex, which results in induction of intention myoclonus. The intention myoclonus in sialidosis type 2 is consistent with 'cortical reflex' myoclonus described in progressive myoclonic epilepsy due to various etiologies.
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PMID:Electrophysiological studies of myoclonus in sialidosis type 2. 257 48

There is a deficiency of human alpha-N-acetylneuraminidase in several inherited diseases. In patients with mucolipidosis I (refs 1,2) and in adults with a variant form with out bony abnormalities and mental retardation, both also classified as sialidoses, it is the only deficient enzyme. In mucolipidosis II ('I-cell' disease) neuraminidase is one of many deficient lysosomal hydrolases and a third manifestation combines deficiency of neuraminidase and beta-galactosidase. We have investigated the genetic background of these various neuraminindase deficiencies by somatic cell hybridization and co-cultivation. The principal conclusions from work on mutant fibroblasts, reported here, are that at least three gene mutations are involved and that the combined beta-galactosidase/neuraminidase deficiency is likely to be due to defective post-translational modification of these enzymes.
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PMID:Genetic heterogeneity in human neuraminidase deficiency. 677 59

A further patient with a presumed primary deficiency of sialidase N-acetylneuraminic acid hydrolase EC 3.2.1.18) is described. Clinically the patient falls into the sialidosis type 2 category of the recent classification of Lowden & O'Brien (1979), i.e. he manifests coarse facies, mental retardation and skeletal changes of dysostosis multiplex as well as myoclonus and a cherry-red spot at the macula. Sialidase activity in fibroblasts was 4% of control values using a methylumbelliferone substrate. The father of the patient was found to have 50% activity. Abnormal amounts of sialyloligosaccharides were found in the urine. The electrophoretic mobility of known glycosylated enzymes and proteins was found to be altered (more anodal than usual), but could be corrected by incubation of the cell extracts with bacterial neuraminidase. The relationship of the present patient to the Lowden & O'Brien classification is discussed.
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PMID:Sialidosis type 2 (acid neuraminidase deficiency): clinical and biochemical features of a further case. 677 97

Glycoprotein consist of oligosaccharides chains covalently attached to the polypeptide backbone. They are synthesized by two pathways; sugar nucleotide pathway and dolichol pathway. The degradation of glycoproteins occurs predominantly in the lysosomes through the ordered actions of lysosomal proteases, glycosidases, and aspartylglucosaminidase. Genetic deficiencies of these enzymes cause progressive accumulation of partially degraded oligosaccharides and glycopeptides, resulting in specific lysosomal storage diseases. Clinically, the diseases are characterized by the various degree of mental retardation, coarse facies, dysostosis multiplex, and visceromegaly. Although the urinary screening test for storage compounds is highly supportive, the definitive diagnosis of the disease is based on the measurement of lysosomal enzyme activity. This paper presents the review of clinical and biochemical features of this group of diseases including alpha-mannosidosis, beta-mannosidosis, fucosidosis, sialidosis, and aspartylglucosaminuria. Recent advances in molecular genetics in fucosidosis and aspartylglucosaminuria are also reviewed.
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PMID:[Disorders of glycoprotein degradation]. 857 45

Sialidase (neuraminidase, EC 3.2.1.18) catalyses the hydrolysis of terminal sialic acid residues of glyconjugates. Sialidase has been well studied in viruses and bacteria where it destroys the sialic acid-containing receptors at the surface of host cells, and mobilizes bacterial nutrients. In mammals, three types of sialidases, lysosomal, plasma membrane and cytosolic, have been described. For lysosomal sialidase in humans, the primary genetic deficiency results in an autosomal recessive disease, sialidosis, associated with tissue accumulation and urinary excretion of sialylated oligosaccharides and glycolipids. Sialidosis includes two main clinical variants: late-onset, sialidosis type I, characterized by bilateral macular cherry-red spots and myoclonus, and infantile-onset, sialidosis type II, characterized by skeletal dysplasia, mental retardation and hepatosplenomegaly. We report the identification of human lysosomal sialidase cDNA, its cloning, sequencing and expression. Examination of six sialidosis patients revealed three mutations, one frameshift insertion and two missense. We mapped the lysosomal sialidase gene to human chromosome 6 (6p21.3), which is consistent with the previous chromosomal assignment of this gene in proximity to the HLA locus.
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PMID:Cloning, expression and chromosomal mapping of human lysosomal sialidase and characterization of mutations in sialidosis. 905 50

Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the hydrolysis of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype, dysostosis multiplex, mental retardation and hepatosplenomegaly (sialidosis type II). We have analyzed the genomic DNA from nine sialidosis patients of multiple ethnic origin in order to find mutations responsible for the enzyme deficiency. The activity of the identified variants was studied by transgenic expression. One patient had a frameshift mutation (G623delG deletion), which introduced a stop codon, truncating 113 amino acids. All others had missense mutations: G679G-->A (Gly227Arg), C893C-->T (Ala298Val), G203G-->T (Gly68Val), A544A-->G (Ser182Gly) C808C-->T (Leu270Phe) and G982G-->A (Gly328Ser). We have modeled the three-dimensional structure of sialidase based on the atomic coordinates of the homologous bacterial sialidases, located the positions of mutations and estimated their potential effect. This analysis showed that five mutations are clustered in one region on the surface of the sialidase molecule. These mutations dramatically reduce the enzyme activity and cause a rapid intralysosomal degradation of the expressed protein. We hypothesize that this region may be involved in the interface of sialidase binding with lysosomal cathepsin A and/or beta-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.
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PMID:Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex. 1076 32

Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the catabolism of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots, and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype, dysostosis multiplex, mental retardation, and hepatosplenomegaly (sialidosis type II). We analyzed the effect of the missense mutations G68V, S182G, G227R, F260Y, L270F, A298V, G328S, and L363P, which are identified in the sialidosis type I and sialidosis type II patients, on the activity, stability, and intracellular distribution of sialidase. We found that three mutations, F260Y, L270F, and A298V, which are clustered in the same region on the surface of the sialidase molecule, dramatically reduced the enzyme activity and caused a rapid intralysosomal degradation of the expressed protein. We suggested that this region might be involved in sialidase binding with lysosomal cathepsin A and/or beta-galactosidase in the multienzyme lysosomal complex required for the expression of sialidase activity. Transgenic expression of mutants followed by density gradient centrifugation of cellular extracts confirmed this hypothesis and showed that sialidase deficiency in some sialidosis patients results from disruption of the lysosomal multienzyme complex.
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PMID:Mutations in sialidosis impair sialidase binding to the lysosomal multienzyme complex. 1127 74

The deficiency of the lysosomal neuraminidase (NEU1; sialidase) causes the storage disorder sialidosis with symptoms ranging from eye abnormalities and neurological disturbances to skeletal malformations, mental retardation and early death. Sialidosis patients encompassing a wide spectrum of clinical symptoms were screened for mutations in neu1. We identified the same homozygous interstitial deletion (11 kb) in two patients causing the fusion of exon 10 of CTL4 (New Gene 22; NG22) with the 3'-UTR of neu1. In one patient we found the resulting CTL4/Neu1 fusion transcript, in the other we detected an alternatively spliced CTL4 transcript (retention of intron 9).
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PMID:Identification of a CTL4/Neu1 fusion transcript in a sialidosis patient. 1206 18

Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme.
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PMID:Molecular pathology of NEU1 gene in sialidosis. 1451 45


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