Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann–Pick type C disease

Pérez-Poyato, María S.; Gordo, M Mar O'Callaghan; Marfá, Mercedes Pineda

doi:10.1016/j.gene.2012.06.054

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…Miglustat has been shown to be an effective therapy for NPC and a new drug, 2-hydroxypropyl-beta-cyclodextrin (Cyclodextrin), is being tested [9], with promising results. Earlier treatment seems to be associated with a better prognosis for the disease outcome [10], making prompt and accurate diagnosis extremely important.…”

Section: Introductionmentioning

confidence: 99%

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Ribas

Souza

Mari

et al. 2016

Clinica Chimica Acta

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Background: Niemann-Pick type C (NPC) is a treatable genetic disorder, mainly characterized by neurological dysfunction and liver damage. Its diagnosis is based on an invasive test which requires a skin biopsy to demonstrate the cholesterol accumulation in culture fibroblasts of affected patients. In the last years, new biomarkers have been investigated aiming to facilitate the diagnosis and screening of NPC; two of these possible candidates are the oxysterol cholestane-3β,5α,6β-triol (triol), a product of non-enzymatic oxidation of cholesterol, and the enzyme chitotriosidase (CT), a fully active chitinase (EC-3.2.1.14) synthesized by activated macrophages. Methods: In this work, we investigated the potential use of the combined analysis of triol levels and CT activity for diagnosis, screening and monitoring of NPC in Brazilian patients, correlating with the results of Filipin staining and genetic analysis. We studied 122 untreated individuals with clinical suspicion of NPC who were separated in two groups according their concentrations of triol (higher or lower than the cutoff value of 100 ng/mL). We also analyzed blood samples from 5 patients with previous diagnosis of NPC who were under treatment with miglustat. Results:The results of this work demonstrated that patients with higher concentrations of triol (group A) also presented a high activity of CT and most of them had also a positive Filipin test. Two patients of this group presented an inconclusive Filipin test, being one eventually diagnosed as NPC by molecular investigation and the other eventually diagnosed as Niemann-Pick type A or B (NPA/B) by the low acid sphingomyelinase activity presented. Three patients with high triol concentrations who had a negative result in the Filipin test presented low activities of acid sphingomyelinase, being diagnosed as NPA/B. On the other hand, triol concentrations were normal in NPC patients treated with miglustat, although CT activity in these individuals remained abnormal. In the patients with triol lower than 100 ng/mL (group B), most presented a normal activity of CT. No patient of this group had a positive Filipin test and the few patients with inconclusive Filipin test did not present pathogenic mutations in the NPC1 or NPC2 genes. Conclusions: In conclusion, our data demonstrated that the combined analysis of triol and CT is quite sensitive and specific for the identification of NPC patients. Although the number of analysis in NPC patients treated with miglustat was small, the data indicate that the measurement of triol could also be potentially useful for treatment monitoring.

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Section: Introductionmentioning

confidence: 99%

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Ribas

Souza

Mari

et al. 2016

Clinica Chimica Acta

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“…Generally, there was a long lag time between the initial onset of neurological manifestations and definite diagnosis [10]. Miglustat has been shown to be an effective therapy for NP-C [11] and a new drug, 2-hydroxypropyl-beta-cyclodextrin (Cyclodextrin), is being tested in a clinical trial for this disease. Earlier treatment with Miglustat has been shown to be associated with a better prognosis [12].…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients

Zhang

Wang

Lin

et al. 2014

Orphanet J Rare Dis

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BackgroundIt has been reported that oxidation product of cholesterol, 7-ketocholesterol, increases in plasma of patients with NP-C. Previously, we established a rapid test to determine the plasma 7-ketocholesterol level and found it elevated significantly in patients with acid sphingomyelinase deficient NPD and NP-C disease.MethodsIndividuals randomly referred to our outpatient clinics in the past two years for hepatosplenomegaly or isolated splenomegaly, who have been excluded as acid sphingomyelinase deficient NPD or Gaucher disease, and individuals with newborn cholestasis, psychomotor regression/retardation, were screened for plasma 7-ketocholesterol level. Individuals with high 7-ketocholesterol level were then analyzed for NPC1 and NPC2 gene mutation to confirm the accuracy of NP-C diagnosis.ResultsBy screening the plasma 7-ketocholesterol of suspect individuals, 12 out of 302 (4%) had shown remarkable high levels compared with reference. All these twelve individuals were subsequently confirmed to be NP-C by DNA analysis of NPC1 and NPC2 genes, with the early infantile form (n = 7), the late infantile form (n = 1), the juvenile form (n = 1) and the adult form (n = 1). Furthermore, two NP-C patients without observable neuropsychiatric disability were picked up through this procedure. Only one patient had NP-C due to NPC2 gene mutations, with the rest due to NPC1 gene mutations. We found that in NP-C patients AST was usually mildly elevated and ALT was in a normal range when jaundice was not present. In total, 22 mutant alleles were identified in the NPC1 gene, including six novel small deletions/insertions, e.g., c.416_417insC, c.1030delT, c.1800delC, c.2230_2231delGT, c.2302_2303insG, and c.2795dupA; seven novel exonic point mutations, c.1502A>T (p.D501V), c.1553G>A (p.R518Q), c.1832A>G (p.D611G), c.2054T>C (p.I685T), c.2128C>T(p.Q710X), c.2177G>C (p.R726T), c.2366G>A (p.R789H), and one novel intronic mutation c.2912-3C>G. Small deletions/insertions constituted nearly half of the mutant alleles (10/22, 45%), indicating a unique mutation spectrum in this cohort of Chinese NP-C patients.ConclusionOur data confirm in a clinical setting that screening plasma 7-ketocholesterol is an efficient and practical diagnostic tool to identify NP-C patients from suspect individuals. Patients without neuropsychological involvement could also be identified by this method therefore allowing an opportunity for earlier treatment.

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“…In our patients, a clear beneficial response was observed in one case. We should note that disability scores at diagnosis were already high in cases which did not show observed beneficial response, which could have contributed to our results, as miglustat is less likely to provide substantial therapeutic benefits if severe neurological impairment is already present at diagnosis 4,6,[12][13][14] . In these cases, decisions to start treatment should be on a case-by-case basis 4,6,12 .…”

Section: Discussionmentioning

confidence: 84%

“…We should note that disability scores at diagnosis were already high in cases which did not show observed beneficial response, which could have contributed to our results, as miglustat is less likely to provide substantial therapeutic benefits if severe neurological impairment is already present at diagnosis 4,6,[12][13][14] . In these cases, decisions to start treatment should be on a case-by-case basis 4,6,12 . Comparisons between disability scores at diagnosis and treatment response in our study agree with the classical clinical opinion that treatment response is better in patients with mild neurological disability 4,6,13 .…”

Section: Discussionmentioning

confidence: 84%

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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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Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann–Pick type C disease

Cited by 11 publications

References 26 publications

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients

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

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