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• W2318580025 abstract "Figure: NeuN-immunolabeled granule cells from wild-type, and untreated (no granule cell immunolabeling) and treated NP-C mice (GC, granule cells; BC, basket cells; P, Purkinje cells).Niemann–Pick type C disease (NP-C) is an autosomal recessive, lysosomal lipid storage disease characterized by defective trafficking of intracellular cholesterol and lysosomal accumulation of lipids. This is a fatal disease with a prevalence of 1 in 150,000. Affected children suffer from chronic neurological deterioration with neuronal accumulation of glycolipids, seizures, supranuclear ophthalmoplegia, and progressively decreasing motor and intellectual function. Death typically occurs during adolescence. No therapy has been shown to delay the onset of disease or slow its progression, however substantial progress has been made regarding the genetic etiology. NP-C is linked to the NPC1 and NPC2 loci, and approximately 95% of human NP-C is caused by mutations of the NPC1 gene. Dysfunction of the NPC1 gene product results in the accumulation of unesterified cholesterol and glycosphingolipids. The naturally occurring BALB/c NP-C mouse contains a retroposon inserted in the NPC1 gene, recapitulating the phenotype of NP-C seen in humans. Neuronal accumulation of cholesterol and gangliosides, cerebellar degeneration, Purkinje cell degeneration, irregular dendritic trees, decreased numbers of dendritic spines and progressive loss of glia, neurons and myelin, occur in a predictable fashion. Using this excellent animal model of NP-C, Griffin and colleagues from the University of California at San Francisco have identified a treatment that may be applicable to humans (Nature Medicine 10:704–711, 2004). They based their approach on the observation that NP-C mice are hypoandrogenic and have underdeveloped reproductive organs consistent with a disorder of steroid biosynthesis from cholesterol. In addition to the classic steroidogenic tissues (adrenal gland, gonad and placenta), the brain also produces steroids (“neurosteroids”) de novo from cholesterol. Griffin and colleagues hypothesized that a similar disordered steroidogenesis would be seen in the brains of NP-C mice. In a series of elegant experiments the authors demonstrated that the brains of NP-C mice contain substantially less neurosteroid than wild-type brain, and that an age-related decrease in the ability to synthesize 5-dihydroprogesterone and allopregnanolone occurs. Immuno-histochemical assessment confirmed a decrease in expression of 5-reductase and 3-hydroxysteroid dehydrogenase, especially in the cerebellum. Impressively, neonatal administration of allopregnanolone delayed the onset of neurological symptoms, increased Purkinje and granule cell survival, reduced cortical GM2 and GM3 ganglioside accumulation and doubled the lifespan of NP-C mice. Earlier administration increased the treatment efficacy. The work by Griffin and colleagues confirms that decreased production of allopregnanolone contributes to the pathology of NP- C in the mouse model. Although translating these observations into a viable clinical treatment protocol will require documenting similar defects in human patients, the possible impact of this work could be profound. Any improvement in survival or delay of symptom onset in patients with NP-C would be a historic step forward in effectively treating this fatal disease. JAMES S. WALDRON, M.D. ANDREW T. PARSA, M.D., PH.D. TRANSLATIONAL RESEARCH" @default.
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• W2318580025 date "2004-09-01" @default.
• W2318580025 modified "2023-09-27" @default.
• W2318580025 title "Hope For Niemann- Pick Type C Disease" @default.
• W2318580025 doi "https://doi.org/10.1227/01.neu.0000309674.94569.14" @default.
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