Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 32-year-old male was admitted to our hospital complaining of dementia, gait disturbance and blindness. These symptoms developed at the early two decade and were progressive. On admission, his clinical features included dementia (IQ = 69), spasticity, accentuated deep tendon reflexes, ataxia and hypesthesias in his distal limbs. Brain CT scans showed diffuse cerebral atrophy. On light microscopy, many abnormal lipopigments resembling ceroid and lipofuscin were found in Schwann cells of sural nerve and histiocytes of colon. Ultrastructurally, these materials showed lamellar structure like Zebra bodies. Nine lysosomal enzymes, serum very long-chain fatty acids, serum amino acids and urinary oligosaccharides were all normal. Neuronal ceroid lipofuscinosis (NCL) of adult type was diagnosed on the basis of clinical features, radiological and pathological findings, and biochemical studies. Many previous studies suggested that NCL was a disorder with lysosomal dysfunction. We examined lysosomal protein degradation, using 125I-low density lipoprotein (LDL) in cultured fibroblasts from this patient. The degradation of LDL was normal, compared to control subjects. The activities of cathepsin and lysosomal glycosidases, were also normal. The amount of urinary dolichol has been reported to be elevated in the patients with infantile and late infantile types of NCL. However, no elevation was found in the urine of our patient.
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PMID:[Adult-onset neuronal ceroid lipofuscinosis--a case report with biological study]. 129 Nov 75

Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase and neuraminidase, caused by a defect of another lysosomal protein, the protective protein. Three subtypes are recognized: the early infantile form, the late infantile form and the juvenile/adult form. We saw a patient with galactosialidosis of the juvenile/adult form, a 51-year-old Japanese man with angiokeratomas on both elbows and knees, myoclonus, ataxia, mental retardation and macular cherry-red spots. An electron-microscopic study of a skin biopsy showed membrane-limited vacuoles in the cytoplasm of the endothelial cells, pericytes and fibroblasts. Assays of enzymatic activity in cultured fibroblasts showed a marked decrease in both beta-galactosidase and neuraminidase (sialidase). The substance contained in the cytoplasmic vacuoles appears to be glycoproteins with sialic acid, which is a terminal glycosyl residue, because the cytoplasm of the endothelial cells of the vessels and pericytes are stained by the Limax flavus agglutinin, a lectin that binds specifically with sialic acid. This technology may be useful for easy investigation of the distribution of the accumulation of such substances in the central nervous system.
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PMID:A case of galactosialidosis. 1293 52

Gaucher disease is caused by defective acid beta-glucosidase (GCase) function. Saposin C is a lysosomal protein needed for optimal GCase activity. To test the in vivo effects of saposin C on GCase, saposin C deficient mice (C-/-) were backcrossed to point mutated GCase (V394L/V394L) mice. The resultant mice (4L;C*) began to exhibit CNS abnormalities approximately 30 days: first as hindlimb paresis, then progressive tremor and ataxia. Death occurred approximately 48 days due to neurological deficits. Axonal degeneration was evident in brain stem, spinal cord and white matter of cerebellum accompanied by increasing infiltration of the brain stem, cortex and thalamus by CD68 positive microglial cells and activation of astrocytes. Electron microscopy showed inclusion bodies in neuronal processes and degenerating cells. Accumulation of p62 and Lamp2 were prominent in the brain suggesting the impairment of autophagosome/lysosome function. This phenotype was different from either V394L/V394L or C-/- alone. Relative to V394L/V394L mice, 4L;C* mice had diminished GCase protein and activity. Marked increases (20- to 30-fold) of glucosylsphingosine (GS) and moderate elevation (1.5- to 3-fold) of glucosylceramide (GC) were in 4L;C* brains. Visceral tissues had increases of GS and GC, but no storage cells were found. Neuronal cells in thick hippocampal slices from 4L;C* mice had significantly attenuated long-term potentiation, presumably resulting from substrate accumulation. The 4L;C* mouse mimics the CNS phenotype and biochemistry of some type 3 (neuronopathic) variants of Gaucher disease and is a unique model suitable for testing pharmacological chaperone and substrate reduction therapies, and investigating the mechanisms of neuronopathic Gaucher disease.
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PMID:Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. 2004 48

Niemann-Pick Type C (NP-C) is an inherited neurovisceral lysosomal storage disease characterized by a defect in the trafficking of endocytosed cholesterol. In 95% of patients the gene encoding NPC1 is affected. The correlation of the genetic background in NP-C with the clinical phenotype such as, severity and onset of liver dysfunction, ataxia, dystonia and vertical gaze palsy, has not been elucidated at the molecular level. We have designed strategies to investigate the effect of different mutations in the NPC1 gene at the protein and cellular levels. The NPC1 mutants were expressed in mammalian cells and their structural features, maturation pathways and subcellular localization elucidated. Interestingly, three classes of NPC1 mutants could be identified and further characterized. The first group comprised mutants in which the NPC1 protein revealed virtually similar structural features to the wild type species. It was trafficked to the lysosomes and colocalized with the lysosomal protein marker Lamp2. The second class of NPC1 mutants was only partially trafficked to the lysosomes, but predominantly localized to the endoplasmic reticulum (ER). In the third group with the most severe phenotype, NPC1 mutants were entirely retained in the ER, colocalizing with the ER-protein marker calnexin. In conclusion, this study relates NPC1 mutations to the trafficking behavior of the NPC1 mutants along the secretory pathway. The findings are essential for a comprehensive understanding of the pathogenesis of NP-C and propose a mutation-based personalized therapeutical approach.
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PMID:Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes that Vary in their Intracellular Processing, Trafficking and Localization. 3092 29