Niemann-Pick disease type C: Diagnosis and outcome in children, with particular reference to liver disease

Kelly, Déirdre; Portmann, Bernard; Mowat, Alex P.; Sherlock, Sheila; Lake, B. D.

doi:10.1016/s0022-3476(05)81695-6

Cited by 166 publications

(135 citation statements)

References 12 publications

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“…The prevalence of NP-C in the general population has been estimated at 1/150,000 live births (Patterson, et al, 2001). This estimate may be low, as about 50% of NP-C cases may present with neonatal liver disease (Kelly, et al, 1993,Vanier, et al, 1988. Thus, the true prevalence of NP-C is likely to be greater than 1/150.000.…”

Section: Niemann Pick Type C Diseasementioning

confidence: 98%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Section: Niemann Pick Type C Diseasementioning

confidence: 98%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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“…Niemann‐Pick C (NPC) is a severe autosomal recessive lipid storage disorder that can give rise to liver disease during infancy 1, 2 and produce neurological dysfunction starting in childhood/early adult life. To date, mutations in two genes have been identified: NPC1 (OMIM 607623), in ~ 95% of NPC patients, and NPC2 (OMIM 601015) in 5% 3, 4.…”

mentioning

confidence: 99%

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Mazzacuva¹,

Mills²,

Mills³

et al. 2016

FEBS Letters

107

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This article describes a rapid UPLC‐MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann‐Pick C (NPC). Two new compounds, NPCBA1 (3β‐hydroxy,7β‐N‐acetylglucosaminyl‐5‐cholenoic acid) and NPCBA2 (probably 3β,5α,6β‐trihydroxycholanoyl‐glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40‐ and 10‐fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker.

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“…The majority of patients with NPC die as a consequence of their neurological disease; however, approximately 45%-65% of patients with NPC also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. [2][3][4] Ten percent of these patients die from liver failure before they reach 6 months of age. 3 NPC disease is the second most common cause of neonatal cholestasis.…”

mentioning

confidence: 99%

“…[2][3][4] Ten percent of these patients die from liver failure before they reach 6 months of age. 3 NPC disease is the second most common cause of neonatal cholestasis. 5 Multiple cases have reported patients suffering from liver failure.…”

mentioning

confidence: 99%

In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

et al. 2008

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Niemann-Pick type C (NPC) is a fatal autosomal recessive lipidosis that is characterized by lysosomal storage of cholesterol and glycosphingolipids. Patients exhibit prolonged neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration that generally result in death by the teen years. Most clinical cases are caused by mutations in the NPC1 gene. Current mouse models of NPC are not well suited for studying the liver disease due to the rapidly progressing neurological disease. To facilitate study of NPC-associated liver dysfunction, we have developed a novel mouse model using antisense oligonucleotides to ablate NPC1 expression primarily in the liver. Here, we show that the NPC1 knockdown leads to a liver disease phenotype similar to that of patients with NPC and the NPC nih mouse model. Key features include hepatomegaly, lipid storage, elevated serum liver enzymes, and increased apoptosis. Conclusion: This novel NPC1 antisense mouse model will allow delineation of the mechanism by which NPC1 dysfunction leads to liver cell death. (HEPATOLOGY 2008;47:1504-1512

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Niemann-Pick disease type C: Diagnosis and outcome in children, with particular reference to liver disease

Cited by 166 publications

References 12 publications

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

In vivoantisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease

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