Plasma Neurofilament Light (NfL) in Patients Affected by Niemann–Pick Type C Disease (NPCD)

(1) Background: Niemann–Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3β-5α-6β-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD.

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Cerebrospinal fluid neurofilament light chain is elevated in Niemann–Pick type C compared to psychiatric disorders and healthy controls and may be a marker of treatment response

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867419893431 ◽

2019 ◽

Vol 54 (6) ◽

pp. 648-649 ◽

Cited By ~ 1

Author(s):

Dhamidhu Eratne ◽

Samantha M Loi ◽

Qiao-Xin Li ◽

Shiji Varghese ◽

Amelia McGlade ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Psychiatric Disorders ◽

Treatment Response ◽

Light Chain ◽

Healthy Controls ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Type C ◽

Niemann Pick

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Role of Autophagy in Phosphatidyl- Glycerol Facilitated Cholesterol Clearance from the Endolysosomal System of Npc-1 Deficient Cells

Aresty Rutgers Undergraduate Research Journal ◽

10.14713/arestyrurj.v1i3.171 ◽

2021 ◽

Vol 1 (3) ◽

Author(s):

Tamara Allada ◽

Olga Ilnytska ◽

Judith Storch

Keyword(s):

Underlying Mechanism ◽

Lysosomal Storage ◽

Phosphatidyl Glycerol ◽

Treat Ment ◽

Lysobisphosphatidic Acid ◽

Autophagy Pathway ◽

Type C ◽

Niemann Pick ◽

Do So

Niemann Pick Type C (NPC) Disease is a rare lysosomal storage disorder in which one of the genes that codes for either the NPC-1 or NPC-2 pro-tein is mutated, causing cell lysosomes to accumu-late cholesterol and lipids. Previous studies discov-ered that a unique late endosomal/lysosomal phos-pholipid, lysobisphosphatidic acid (LPBA), is in-volved in cholesterol clearance from late endo-somes. It has also been shown that exogenous treat-ment of the NPC-1 deficient cells with LBPA’s precur-sor, phosphatidylglycerol (PG), leads to LBPA enrich-ment and subsequent endolysosomal cholesterol clearance. Autophagy is a mechanism of cellular clearance in the endolysomal system and we are in-terested to see if it is a partial route in cholesterol clearance during PG treatment of NPC-1 deficient cells. To do so, we silenced the gene that codes for an essential protein in the autophagy pathway, mak-ing the cells autophagy deficient. We then treated the cells with PG, measured the amount of choles-terol clearance in those cells, and compared it to cells with normal autophagy. We found significantly less cholesterol clearance by PG in cells with defec-tive autophagy, confirming that autophagy is in-volved as a partial route in cholesterol clearance dur-ing PG treatment, but not enough of a difference to conclude that it is a major underlying mechanism.

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Niemann-Pick Disease Type C with Isolated Splenomegaly: A Case Report in a Child

Journal of Pediatric Neurology ◽

10.1055/s-0040-1722209 ◽

2021 ◽

Author(s):

Bruna Ribeiro Torres ◽

Daniela Otoni Russo ◽

Vinícius Andrade Gomes Vuolo ◽

Tarcísio Silva Borborema ◽

André Vinícius Soares Barbosa ◽

...

Keyword(s):

Autosomal Recessive Inheritance ◽

Signs And Symptoms ◽

Disease Type ◽

Sphingolipid Metabolism ◽

Neurological Involvement ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Pick Disease

AbstractNiemann-Pick disease type C is an innate error of lysosomal storage metabolism with an autosomal recessive inheritance pattern. The disease causes intracellular cholesterol accumulation and changes in sphingolipid metabolism. If cholesterol accumulates, the signs and symptoms of visceral involvement predominate. Neurological involvement results from sphingolipid accumulation. A 7-year-old student was referred to a tertiary service for the investigation of asymptomatic splenomegaly. Following an extensive examination, he was diagnosed with Niemann-Pick disease type C. Interestingly, this case's only symptom was splenomegaly.

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Efficient Investigation and Differential Diagnosis of Childhood Onset Niemann-Pick Type C

European Neurological Review ◽

10.17925/enr.2012.07.03.153 ◽

2012 ◽

Vol 7 (3) ◽

pp. 153

Author(s):

Alasdair Parker ◽

Keyword(s):

Genetic Testing ◽

Age Of Onset ◽

Unmet Need ◽

Lysosomal Storage ◽

Cultured Skin ◽

Specificity And Sensitivity ◽

Niemann Pick Disease ◽

History Of ◽

Type C ◽

Niemann Pick

Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is rare with a broad phenotypic spectrum and variable age of onset. This complicates diagnosis, which is often delayed by several years after presentation of the first symptoms. It is a treatable condition if detected early, therefore reliable means of diagnosis are essential. Clinical diagnosis of NPC involves identifying characteristic neurological features, taking a detailed history of the patient’s details, and must be confirmed by biochemical and/or genetic testing. The key laboratory diagnostic test for NPC is filipin staining of cultured skin fibroblasts, which shows free cholesterol accumulation in lysosomes resulting from impaired intracellular cholesterol transport. Genetic testing for mutations in theNPC1andNPC2genes is also important for confirmation of the diagnosis. However, there is an unmet need for cheaper diagnostic tests with greater specificity and sensitivity

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Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

European Journal of Immunology ◽

10.1002/eji.201141821 ◽

2012 ◽

Vol 42 (7) ◽

pp. 1886-1892 ◽

Cited By ~ 12

Author(s):

Anneliese O. Speak ◽

Nicholas Platt ◽

Mariolina Salio ◽

Danielle te Vruchte ◽

David A. Smith ◽

...

Keyword(s):

T Cells ◽

Natural Killer T Cells ◽

Disease Type ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Killer T Cells ◽

Invariant Natural Killer ◽

Pick Disease

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Elevated Neurofilament Light Chain in Cerebrospinal Fluid and Plasma Reflect Inflammatory MRI Activity in Neurosarcoidosis

Brain Sciences ◽

10.3390/brainsci11020238 ◽

2021 ◽

Vol 11 (2) ◽

pp. 238

Author(s):

Keld-Erik Byg ◽

Helle H. Nielsen ◽

Tobias Sejbaek ◽

Jonna Skov Madsen ◽

Dorte Aalund Olsen ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Light Chain ◽

Plasma Levels ◽

Healthy Controls ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Potential Biomarker ◽

Fluid Levels

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.

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Uncovering the role of lysosomal Ca2+ signalling in two neurodegenerative lysosomal disorders, Niemann-Pick disease type C and mucolipidosis type IV

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2013.12.158 ◽

2014 ◽

Vol 111 (2) ◽

pp. S70

Author(s):

Emyr Lloyd-Evans ◽

Helen Waller-Evans ◽

Ksenia Peterneva ◽

Laura Francis ◽

Mathew Walker

Keyword(s):

Disease Type ◽

Mucolipidosis Type Iv ◽

Type Iv ◽

Lysosomal Disorders ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Mucolipidosis Type ◽

Pick Disease

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Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

Cell Death and Disease ◽

10.1038/s41419-020-03262-7 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Seung-Eun Lee ◽

Nari Shin ◽

Myung Geun Kook ◽

Dasom Kong ◽

Nam Gyo Kim ◽

...

Keyword(s):

Stem Cells ◽

Lysosomal Storage Disorder ◽

Disease Type ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Storage Disorder ◽

Niemann Pick ◽

Pick Disease

AbstractRecent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.

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cAMP-mediated regulation of cholesterol accumulation in cystic fibrosis and Niemann-Pick type C cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90402.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. L809-L819 ◽

Cited By ~ 29

Author(s):

Mary E. Manson ◽

Deborah A. Corey ◽

Nicole M. White ◽

Thomas J. Kelley

Keyword(s):

Cystic Fibrosis ◽

Cellular Response ◽

Cholesterol Accumulation ◽

Camp Pathway ◽

Model Cell ◽

Type C ◽

Niemann Pick ◽

Primary Tissue ◽

Independent Model

The goal of this study was to identify a mechanism regulating cholesterol accumulation in cystic fibrosis (CF) cells. Both CFTR activation and expression are regulated by the cAMP pathway, and it is hypothesized that a feedback response involving this pathway may be involved in the phenotype of cholesterol accumulation. To examine the role of the cAMP pathway in cholesterol accumulation, we treated two CF model cell lines with the Rp diastereomer of adenosine 3′,5′-cyclic monophosphorothioate ( Rp-cAMPS) and visualized by filipin staining. Rp-cAMPS treatment eliminated cholesterol accumulation in CF cells, whereas 8-bromo-cAMP treatment led to cholesterol accumulation in wild-type cells. To confirm these findings in an independent model system, we also examined the role of cAMP in modulating cholesterol accumulation in Niemann-Pick type C (NPC) fibroblasts. Expression of the protein related to NPC, NPC1, is also directly regulated by cAMP; therefore, it is postulated that NPC cells exhibit the same cAMP-mediated control of cholesterol accumulation. Cholesterol accumulation in NPC cells also was reduced by the presence of Rp-cAMPS. Expression of β-arrestin-2 (βarr2), a marker of cellular response to cAMP signaling, was significantly elevated in CF model cells, Cftr−/− MNE, primary tissue obtained by nasal scrapes from CF subjects, and in NPC fibroblasts compared with respective controls.

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