Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update

Patterson, Marc C.; Hendriksz, Christian J.; Walterfang, Mark; Sedel, Frédéric; Vanier, Marie T.; Wijburg, Frits A.

doi:10.1016/j.ymgme.2012.03.012

Cited by 407 publications

(740 citation statements)

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“…Available screening methods are limited to filipin staining of unesterified cholesterol in cultured fibroblasts, measurement of chitotriosidase activity, and genetic analysis of the NPC1 and NPC2 genes. Filipin staining of fibroblasts is currently the most specific diagnostic method for NPC (Wraith et al 2009;Patterson et al 2012), showing the classical storage pattern, characterized by massive accumulation of unesterified cholesterol in 85% of NPC patients. However, 15% of patients present the so-called variant biochemical phenotype, characterized by mild to moderate intracellular cholesterol accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…However, 15% of patients present the so-called variant biochemical phenotype, characterized by mild to moderate intracellular cholesterol accumulation. In these cases the diagnosis of NPC might still be uncertain (Vanier et al 1991;Wraith et al 2009;Patterson et al 2012). Since filipin staining requires living cells, a skin biopsy is needed, and the procedure is time-consuming.…”

Section: Discussionmentioning

confidence: 99%

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Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

et al. 2015

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Introduction: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1.Methods: Plasma cholestane-3b,5a,6b-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining.Results: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3b,5a,6b-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3b,5a,6b-triol concentration markedly above the reference range was found.Conclusions: Measurement of plasma cholestane3b,5a,6b-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

et al. 2015

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“…Molecular analyses typically show NPC1 (in 95% of cases) or NPC2 (in around 4% of cases) gene mutations [1][2][3][4]6,7 . Nevertheless, vertical supranuclear gaze palsy, cataplexia, high chitotriosidase serum…”

Section: Introductionmentioning

confidence: 99%

“…Conclusão: Embora coloração de filipina seja utilizada para confirmar o diagnóstico, o histiócito azul-marinho no aspirado de medula óssea frequentemente auxilia a confirmar o diagnóstico de NP-C. A mutação p.P1007A está correlacionada com o padrão " variante" na coloração de filipina. A resposta ao tratamento com miglustate parece estar correlacionada com a idade e escore de desabilidade no momento do diagnóstico.Palavras-chave: doença de Niemann-Pick tipo C, medula óssea, coloração de filipina, gene NPC1, miglustate.Niemann-Pick disease type C (NP-C) is a rare inherited disease, caused by mutations in either the NPC1 or the NPC2 gene, which leads to impaired intracellular lipid trafficking and the accumulation of cholesterol and glycosphingolipids in the brain and other tissues [1][2][3][4][5][6] . The clinical signs and symptoms of NP-C can develop at any age, and significant phenotypic heterogeneity is frequently observed in NP-C 1,2,4-7 .…”

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“…Niemann-Pick disease type C (NP-C) is a rare inherited disease, caused by mutations in either the NPC1 or the NPC2 gene, which leads to impaired intracellular lipid trafficking and the accumulation of cholesterol and glycosphingolipids in the brain and other tissues [1][2][3][4][5][6] . The clinical signs and symptoms of NP-C can develop at any age, and significant phenotypic heterogeneity is frequently observed in NP-C 1,2,4-7 .…”

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Niemann-Pick disease type C: a case series of Brazilian patients

Lorenzoni

Cardoso

Crippa

et al. 2014

Arq. Neuro-Psiquiatr.

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The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method: Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result: The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the "classical" pattern in two patients and a "variant" pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion: Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the "variant" pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.Keywords: Niemann-Pick disease type C, bone marrow, filipin stain, NPC1gene, miglustat.RESUMO O objetivo desse estudo foi analisar uma série de casos de pacientes brasileiros com doença de Niemann-Pick tipo C (NP-C). Método: Correlação entre manifestações clínicas, alterações laboratoriais, estudo molecular e resposta ao tratamento foram realizadas. Resultado: A amostra consiste de 5 pacientes com idade entre 8 e 26 anos. Paralisia do olhar vertical supranuclear, ataxia cerebelar, demência, distonia e disartria estavam presentes em todos os casos. Coloração de filipina na cultura de fibroblastos mostrou padrão "clássico" em dois pacientes e padrão "variante" em três casos. O estudo molecular encontrou mutações no gene NPC1 em todos os alelos. O tratamento com miglustate foi realizado em 4 pacientes. Conclusão: Embora coloração de filipina seja utilizada para confirmar o diagnóstico, o histiócito azul-marinho no aspirado de medula óssea frequentemente auxilia a confirmar o diagnóstico de NP-C. A mutação p.P1007A está correlacionada com o padrão " variante" na coloração de filipina. A resposta ao tratamento com miglustate parece estar correlacionada com a idade e escore de desabilidade no momento do diagnóstico.Palavras-chave: doença de Niemann-Pick tipo C, medula óssea, coloração de filipina, gene NPC1, miglustate.Niemann-Pick disease type C (NP-C) is a rare inherited disease, caused by mutations in either the NPC1 or the NPC2 gene, which leads to impaired intracellular lipid trafficking and the accumulation of cholesterol and glycosphingolipids in the brain and other tissues [1][2][3][4][5][6] . The clinical signs and symptoms of NP-C can develop at any age, and significant phenotypic heterogeneity is frequently observed in NP-C 1,2,4-7 . Vertical supranuclear gaze palsy, cerebellar ataxia, dystonia, dementia, epilepsy and visceral manifestations are the most common symptoms of NP-C 1,2,4-7 .NP-C patients often show sea-blue histiocytes or foamy cells in bone marrow analyses and intracellular lipid accumulation with filipin stain...

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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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Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update

Cited by 407 publications

References 145 publications

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

Niemann-Pick disease type C: a case series of Brazilian patients

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

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