Advancing diagnosis and treatment of Niemann-Pick C disease 
through biomarker discovery

Jiang, Xuntian; Ory, Daniel S.

doi:10.37349/ent.2021.00012

Cited by 13 publications

(10 citation statements)

References 85 publications

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“…13 Recent efforts have explored PPCS and TCG as more specific markers for NPC. 14 We report a case of an infant presenting with neurologic and hepatic failure leading to early death, along with foamy macrophages on liver biopsy and elevated plasma oxysterols suggestive of NPC. Cholestasis gene panel and sequencing of NPC1 and NPC2 were negative, and the child was diagnosed postmortem with ATP6AP1-CDG via exome sequencing.…”

Section: Introductionmentioning

confidence: 99%

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Elevated oxysterol and N‐palmitoyl‐O‐phosphocholineserine levels in congenital disorders of glycosylation

Dang

Chang

Jiang

et al. 2023

J of Inher Metab Disea

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Congenital disorders of glycosylation (CDG) and Niemann‐Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile‐onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N‐palmitoyl‐O‐phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1‐CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N‐(3β,5α,6β‐trihydroxy‐cholan‐24‐oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1‐, ALG1‐, ALG8‐, and PMM2‐CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

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Section: Introductionmentioning

confidence: 99%

“…Specifically, plasma oxysterol levels can be elevated in individuals with cholestatic liver disease 13 . Recent efforts have explored PPCS and TCG as more specific markers for NPC 14 …”

Section: Introductionmentioning

confidence: 99%

Elevated oxysterol and N‐palmitoyl‐O‐phosphocholineserine levels in congenital disorders of glycosylation

Dang

Chang

Jiang

et al. 2023

J of Inher Metab Disea

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“…Several biomarkers have been investigated to assess their ability to diagnose GM1 gangliosidosis and NPC, track disease progression and monitor therapeutic strategies [ 9 , 12 , 15 ]. In particular, cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG), and N-palmitoyl-O-phosphocholineserine (PPCS, initially referred to as lysoSM-509) have led to the development of blood-based diagnostics for NPC [ 16 ]. Substrate reduction therapy using Miglustat [N-Butyl-Deoxynojirimycin (NB-DNJ)], as a central nervous system modifier, has been approved for NPC in several countries [ 6 ] and has also been used in GM1 gangliosidosis [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Fluorescent In Situ Staining and Flow Cytometric Procedures as New Pre-Diagnostic Tests for Sialidosis, GM1 Gangliosidosis and Niemann–Pick Type C

et al. 2022

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Background: Early diagnosis is essential in the field of lysosomal storage disorders for the proper management of patients and for starting therapies before irreversible damage occurs, particularly in neurodegenerative conditions. Currently, specific biomarkers for the diagnosis of lysosomal storage disorders are lacking in routine laboratory practice, except for enzymatic tests, which are available only in specialized metabolic centers. Recently, we established a method for measuring and verifying changes in GM1 ganglioside levels in peripheral blood lymphocytes in patients with GM1 gangliosidosis. However, fresh blood is not always available, and using frozen/thawed lymphocytes can lead to inaccurate results. Methods: We used frozen/thawed fibroblasts obtained from stored biopsies to explore the feasibility of fluorescent imaging and flow-cytometric methods to track changes in storage materials in fibroblasts from patients with three lysosomal neurodegenerative conditions: GM1 gangliosidosis, Sialidosis, and Niemann–Pick type C. We used specific markers for each pathology. Results and Conclusions: We demonstrated that with our methods, it is possible to clearly distinguish the levels of accumulated metabolites in fibroblasts from affected and unaffected patients for all the three pathologies considered. Our methods proved to be rapid, sensitive, unbiased, and potentially applicable to other LSDs.

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“…The observation that all patients were diagnosed before neurological onset in the treated group (100%), compared to only 37.5% in the untreated group (p = 0.003) is likely a consequence of these combined factors. Of note, the strategy for laboratory testing had remained similar for both groups, since plasma biomarkers [3,32] were not routinely introduced in France before 2015.…”

Section: Discussionmentioning

confidence: 99%

Effects of miglustat therapy on neurological disorder and survival in early- infantile Niemann-Pick disease type C: a national French retrospective study

Freihuber

Dahmani-Rabehi

Brassier

et al. 2023

Preprint

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Background Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients. Method Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded. Results Ten patients were included in the treated group (year of birth: 2006–2012), and 16 patients in the untreated group [born 1987–2005 (n=15), 2012 (n=1)]. The median age at neurological onset was 9 months (5–18) in the treated group, and 12 months (3–18) in the untreated group (p=0.22). Miglustat therapy was started at a median age of 24.5 months (9–29) and median duration was 30 months (11–56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p=0.11). Conclusions Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C.

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Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

Cited by 13 publications

References 85 publications

Elevated oxysterol and N‐palmitoyl‐O‐phosphocholineserine levels in congenital disorders of glycosylation

Elevated oxysterol and N‐palmitoyl‐O‐phosphocholineserine levels in congenital disorders of glycosylation

Fluorescent In Situ Staining and Flow Cytometric Procedures as New Pre-Diagnostic Tests for Sialidosis, GM1 Gangliosidosis and Niemann–Pick Type C

Effects of miglustat therapy on neurological disorder and survival in early- infantile Niemann-Pick disease type C: a national French retrospective study

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