Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) For patients with type 1 Gaucher's disease the standard treatment is imiglucerase enzyme replacement therapy, provided in fortnightly intravenous infusions. (2) Miglustat inhibits the synthesis of glucosyl-ceramide, the cerebroside that accumulates in Gaucher's disease. Miglustat is now licensed for oral therapy in patients with mild to moderate type 1 Gaucher's disease and who cannot take imiglucerase, regardless of the reason. (3) The evaluation data we managed to gather (see literature search) includes data from three trials involving a total of 82 patients. One of these trials compared miglustat with ongoing imiglucerase therapy. Miglustat slightly reduced the size of the liver and spleen, and slightly increased the haemoglobin level and platelet count after 18 months. The impact of these effects is unknown, especially on bone disorders. In patients with previous response to imiglucerase, miglustat has not been found to maintain clinical effects in the longer term. (4) Miglustat has many adverse effects, some of which occur very frequently, such as diarrhea (86%), weight loss (64%), peripheral neuropathies (19%), tremor (29%), and cognitive disorders. Animal studies suggest a risk of reproductive toxicity. (5) In practice, miglustat therapy offers minimal benefits for the few patients who cannot use imiglucerase. The potential advantages of miglustat therapy relative to purely symptomatic treatment must be carefully weighed in individual patients.
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PMID:Miglustat: new drug. In type 1 Gaucher's disease : a slight benefit after imiglucerase therapy. 1628 70

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