The impact of biomarkers analysis in the diagnosis of Niemann-Pick C disease and acid sphingomyelinase deficiency

Deodato, Federica; Boenzi, Sara; Taurisano, Roberta; Semeraro, Michela; Sacchetti, Elisa; Carrozzo, Rosalba; Dionisi‐Vici, Carlo

doi:10.1016/j.cca.2018.08.039

Cited by 46 publications

(50 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results con rm previous studies demonstrating an increased cholestane burden with NPC disease progression [22]. However, unlike previous studies, the CT-ORZY-NPC-001 results reported here do not support a correlation between serum cholestane-triol levels and age of NPC disease onset (data on le) [22,41]. Together these data support the use of cholestane-triol as a biomarker of disease severity in the NPC population as a whole and may be useful in the follow-up of an individual patient to potentially monitor disease.…”

Section: Discussionsupporting

confidence: 69%

“…This study aimed to characterize novel NPC disease biomarkers in order to establish a set of biomarkers for NPC that are focused on interventions targeting the HSP system in NPC and the underlying cellular pathology of NPC, including altered NPC1/2 protein function and lipid metabolism. During the time of this study and its publication, it is worth noting that other biomarkers such as lyso-sphingomyelin-509 and bile acids have also shown potential as biomarkers of NPC disease [41,[48][49][50].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

Mengel¹,

Bembi²,

Toro

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundNiemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (ClinicalTrials.gov ID:NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians’ rating of four participants via video recordings, repeated after ≥3 weeks. Intraclass correlation coefficients (ICCs) were calculated.ResultsOf the 36 individuals with NPC (2–18 years) enrolled, 31 (86.1%) completed the 6–14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (±SD) increase in 5-domain NPCCSS scores of 1.4 (±2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (±SD) progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p<0.0001), HSP70 (p<0.0001) and skin unesterified cholesterol (p=0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p=0.008) and correlated with the 5-domain NPCCSS (Spearman’s correlation coefficient=0.265, p=0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC=0.995) and intra-rater reliability (ICC=0.937).ConclusionsProgression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.Trial Registration: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030; EudraCT 2014-005194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE. OR-REL-NPC-01: Unregistered.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

Mengel¹,

Bembi²,

Toro

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…He was confirmed genetically at 15 years and started miglustat therapy (200 mg, 3 times/day) a few months before biomarker analysis. A possible explanation is the negative correlation of lyso‐SM‐509 values with age, which is also evident in our adolescent patients. This may necessitate the determination of lower cutoff values for higher age groups.…”

Section: Clinical Biomarker and Mutational Spectrum Of Egyptian Niesupporting

confidence: 53%

Clinical, biomarker and genetic spectrum of Niemann‐Pick type C in Egypt: The detection of nine novel NPC1 mutations

et al. 2019

View full text Add to dashboard Cite

“…They are useful for a screening, but not very specific and can lead to false positive results. Currently, lyso-sphingomyelin-509 (LysoSM-509) is used for the primary diagnosis of Niemann-Pick disease type C [104]. Another biomarker is cholestane-3β,5α,6β-triol [105].…”

Section: Niemann-pick Disease Type Cmentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

View full text Add to dashboard Cite

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

show abstract

The impact of biomarkers analysis in the diagnosis of Niemann-Pick C disease and acid sphingomyelinase deficiency

Cited by 46 publications

References 21 publications

Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

Clinical Disease Progression and Biomarkers in Niemann–Pick Disease Type C: A Prospective Cohort Study

Clinical, biomarker and genetic spectrum of Niemann‐Pick type C in Egypt: The detection of nine novel NPC1 mutations

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Contact Info

Product

Resources

About