20240722_184247

		Anniversary year of this Agreement, → They mentionned that they have always found a compromise with all groups for the type and timing of some of the possible results.
		[publication] The Parties are committed to the principle of rapid release of research results to the scientific community and to disseminating all results as widely as possible.... In the event that no scientific publication arises from the Research Project, Recipient also agrees that written report progress of the Research Project will be published in the C-BIG public dataset.

Niemann-Pick disease

	Type A	Type B	Type C
Cause	caused by mutations in the sphingomyelin phosphodiesterase-1 gene (SMPD1),		two genotypes related to (Loss-of-function) mutations in the NPC1 gene (95%) (NPD-C1; chromosome 18q11-q12, MIM 257220) or mutations in the NPC2 gene (also called the HE1 gene) on chromosome 14q24.3 (NPD-C2; MIM 607625).
MIM			257220
Inheritance			Autosomal recessive
Onset	Severe, EO	Less severe, later-onset	Variable, onset in middle to late childhood after normal early development.
Life expectancy			Niemann-Pick type C is always fatal. However, life expectancy depends on when symptoms begin. If symptoms appear in infancy, your child isn't likely to live past the age of 5. If symptoms appear after 5 years of age, your child is likely to live until about 20 years of age.
Cause of death			Dysphagia has been identified as a major risk factor for mortality in patients with NP-C [46]. In fact, impaired swallowing is associated with aspiration pneumonia, the most common cause of death in neurodegenerative disease including NP-C [45,46,80]
Systemic Sx	Hepatosplenomegaly, neurologic dysfunction		Systemic involvement of liver, spleen or lung, is present in ≥85 percent of patients, and precedes the development of neurologic symptoms [28]. → Jaundice, recurrent pneumonia (js there are not much systemic symptoms!)
Neurologic Sx		Most patients have no neurologic abnormalities. However, in those who survive earlychildhood, prolonged NCV and varying degrees of CNS, ie cbll signs, nystagmus, EPS, MR), psychiatric disorders, and peripheral neuropathy [1,2,19-22]. I	NP-C symptoms-vs-age timeline schematic (Systemic involvement vs. Neurological involvement; age 0-50 years). Tracks: Visceral, Hypotonia, Cognitive impairment, Cataplexy, Hearing loss, Seizures, Ataxia, Dystonia, Dysarthria, Dysphagia, Behavioural problems, Bipolarity, Atypic Dementia, Cerebellar ataxia, Psychosis, Pediatric Spasmonotic, Vertical supranuclear ophthalmoplegia, Premature cognitive decline. have cerebellar involvement characterized by clumsiness and gait problems progressing to frank ataxia and slow cognitive deterioration [26,29]. Vertical supranuclear ophthalmoplegia is another early manifestation (see "Supranuclear disorders ofgaze in children"). Progressive dystonia, dysarthria, and dysphagia are common, eventually impairing oral feeding, and approximately one-third of patients develop seizures The clinical features most strongly associated with NPD-C were vertical supranuclear gaze palsy, gelastic cataplexy, premature cognitive decline
prevalence			1:100,000 in Europe [28]. 1:120,000 (J Rare Disease, 2010), 1:100,000 to 150,000 (NDDMF)
Imaging			2-panel bar chart 'Cerebellar volume - white matter (TCWM), grey matter (TCGM) and total (TCV)' comparing NPC vs CTL groups (Fig. 3, 2013 MolGenMetabo). - Volumetric changes on brain MRI in patients with NPC include GM reductions involving the thalamus, hippocampus, striatum, cerebellum, and insular cortex, as well as WM reductions involving the corpus callosum - widespread reductions in fractional anisotropy of WM tracts [41-43] show early changes prior to MRI findings, but data are limited. Reported findings include decreased n-acetyl aspartate/creatine ratios in the frontal and parietal cortex, centrum semiovale and caudate nucleus with increased choline/creatinine ratios in the frontal cortex and centrum semiovale [44]. Review in Benussi 2018.
MOA			NPC1 encodes a large membrane glycoprotein primarily located to late endosomes; this protein plays a role in the intracellular trafficking, levels, and distribution of LDL-cholesterol [53-56]. Disruption of this trafficking leads to lysosomal lipid (cholesterol & glycolipid) accumulation and neuronal degeneration [57]. NPC2 encodes a small soluble lysosomal protein previously known as cholesterol-binding protein [46].
correction			(Cao, 2015 #1726) in vitro: In NPC1-/- CELLS: i) TRPML1 activator (ML-SA1) → ↓ lipofuscin (fig6e) ii) mucolipin-1 (ML1) protein overexpression → ↓ lipofuscin (figIe) Miglustat (see section Tx below) Cyclodextrin (whller 2019): cyclodextrin is endocytosed (Chen et al. 2010; Rosenbaum et al. 2010) → they sequester excess cholesterol in the LEL (late endosome) and return it to circulation - cholesterol is thus exocytosed,(Chen et al. 2010) reduced at the lysosome (Rosenbaum et al. 2010) and increased at the ER; (Abi-Mosleh et al. 2009) → cholesterol synthesis is reduced (Liu et al. 2009).
PATHOLOGY			Progressive Purkinje cell death is the hallmark [wheeler 2019] Various lipids accumulate in NPCD including di- and tri-acylglycerols (Tharkeshwar et al. 2017), phosphoethanolamine (Tharkeshwar et al. 2017), sphingosine (Te Vruchte et al. 2004), sphingomyelin (Vanier 1983; Harzer et al. 2003; Tharkeshwar et al. 2017), GlcCer (Harzer et al. 2003) and gangliosides (Te Vruchte et al. 2004; Zhou et al. 2011). [zervas 2001] in the NPC cortex pyramidal neurons: ↑GM2 & ↑GM3 in soma, ↑unesterified cholesterol (filipin staining), meganeurites
Dx			The diagnosis of NPD-C is suspected on the basis of the clinical features and biomarker screening for oxysterols; it is confirmed when genetic testing identifies both disease causingalleles in NPC1 or NPC2.A Suspicion Index tool (figure 1) may be useful as a screening tool for NPD-C [65]. A risk prediction score of ≥70 indicates a strong suspicion for NPD-C. The index was derived by a retrospective review that compared the clinical features of patients with NPD-C confirmed by filipin staining (n = 71), noncasesexcluded from the diagnosis of NPD-C by negative filipin staining (n = 64), and control patients whohad at least one characteristic symptom of NPD-C (n = 81). Individual signs and symptoms were analyzed by logistic regression to develop prediction scores for NPD-C. The accumulation of unesterified cholesterol in the LE/L (late endosomal/lysosomal) compartment can be visualized by fluorescence microscopy after staining with filipin. The "filipin test," performed on cultured fibroblasts, is the historical gold standard method to establish the diagnosis in patients
Tx			Miglustat: good review in Pineda 2018, Miglustat, which reversibly inhibits glycosphingolipid synthesis, (approved in EU in 2009), was shown to decrease lipid storage, improve endosomal uptake, and normalize lipid trafficking in B lymphocytes [74]. However, it is unclear if miglustat reduces disease progression in NPD-C, and data are limited and conflicting: Js: detailed clinical trial data of miglustat in NPD-C is seen in UpToDate
Pipeline			Company/ Drug name NIH/Vorinostat Orphazyme/ Arimoclomol Vtesse/VTS-270/ Cyclodextrin Official Trial Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1 NCT02124083 A Prospective Non-therapeutic Study in Patients Diagnosed With Niemann-Pick Disease Type C in Order to Characterise the Individual Patient Disease Profile and Historic Sign-symptomatology Progression Pattern NCT02435030 A Phase 2b/3 Prospective, Randomized, Double-Blind, Sham-Controlled 3-Part Trial of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in Subjects With Neurologic Manifestations of Niemann-Pick Type C1 (NPC1) Disease NCT02534844 Purpose Study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective is to determine the safety and tolerability of Vorinostat in NPC1 disease. This is a prospective non-therapeutic observational study in NP-C patients. The aim is to characterize the individual patient disease progression profile through the historical and 6 months prospective evaluation of clinical, imaging, biological(biomarkers) and quality of life data. Patients will be offered enrollment into a Phase II/III study on arimoclomol at the end of the study. This study evaluates the efficacy and safety of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in patients with neurologic manifestations of Niemann-Pick Type C1 (NPC1) Disease. Approximately two-thirds of patients will receive the study drug, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), while the remaining study participants will receive a sham control. Current Phase 1/2 2/3 2/3 Estimated Enrollment: 15 46 51 Study Start Date April 2015 September 2015 September 2015 Estimated Primary Completion Date June 2017 March 2016 (Observational Phase), March 2017 Interventional phase December 2016
outcome measure			Niemann Pick Type C Severity Scale (NPC-SS): THE HIGHer IS THE WORSE Original is 17-domain, abbreviated version of the 17-domain NPCCSS was developed comprising five domains (the 5-domain NPCCSS) selected by individuals with NPC,their caregivers and NPC experts as the most clinicallyrelevant domains [18]. These five domains are ambulation, cognition, fine motor skills, speech and swallowing(Fig. 1).
animal model			BALB/cNctr-Npc1m1N/-J (NPC1 KO mice, NPC1NIH): The mouse model of Niemann pick C1 disease, Begin to lose weight and to show tremor and ataxic gait at about 7 weeks of age. Weight loss continues and tremor and ataxia become more severe until death at about 12 to 14 weeks of age. The liver and spleen are also enlarged and Purkinje cells in the cerebellum are severely depleted. Neuroaxonal distrophy, liver and spleen histology (HE stain), 2002 Hum Mol Genet
biomarker-established			The accumulation of unesterified cholesterol in the LE/L (late endosomal/lysosomal) compartment can be visualized by fluorescence microscopy after staining with filipin. The "filipin test," performed on cultured fibroblasts, is the historical gold standard method to establish the diagnosis in patients (Since filipin is highly fluorescent and binds specifically to cholesterol, it has found widespread use as a histochemical stain for cholesterol.) . .Typical pattern in the filipin staining was observed in 80 to 85% of cases with NPC33,41-43, and a positive staining occurred in 80 to 100% of cells33. - ↑ oxidated cholesterol derivatives (oxysterol) in the serum - moa: ↑ unesterified cholesterol in the late endosome eg cholestane-3β,5α,6β-triol (cholestanetriol triol),have been demonstrated to aid diagnosis of NPC and cholestane-triol levels correlate with NPC diseaseseverity and age of NPC disease onset [22]. Review in (Elmonem, 2020 #1715)
biomarker-new			(Bradbury, 2016 #1725) Brain: 2nd: In both the murine and feline models of NPC1 disease, ↓ calbindin in Purkinje cells (Davidson et al., 2009; Vite et al., 2015). CSF: (fig2) in NPC1 patients (20 untreated and 16 miglustat-treat patients): ↑ (~8x) calbindin (MOA: degenerating neurons, predominately Purkinje cells in the cerebellum, leak calbindin into the CSF),, slowly decreases with age (근데 이게 보호적이니까, 어쨌건 우리는 약으로 낮춰야 함) but no correlation with 'NPC1 Neurological Severity Score' In cat model of NPC1 (fig1): CSF ↑ calbindin (normalized by cyclodextrin) Cf) Calcium-binding protein calbindin D-28K (calbindin) is pre sent at high levels in the cerebellum, where it is predominantly localized in dendrites, soma, and axons of Purkinje cells. [↓ 24(S)-HC so far this is only plasma] (Tortelli, 2014 #1729) (Porter, 2010 #1730) cholestane-3b,5a,6b-triol ('triol'), a cholesterol oxidation product that is elevated 10-fold in the plasma of NPC1 subjects 24(S)-hydroxycholesterol (24(S)-HC), an enzymatically generated oxygenated cholesterol that is reduced in the plasma of NPC1subjects (36).- a sterol that is synthesized exclusively in neurons in the CNS and exported to the plasma, studied in clinical trial ((Maarup, 2015 #1728, plasma only )). 이것들을 animal model 에서도 확인함.

Uncertain Spans

• “EPS, MR), psychiatric disorders” — the closing parenthesis MR) has no matching opening parenthesis on the photo; transcribed as printed.
• “(figIe)” — Cao 2015 #1726 bullet uses both figIe and fig6e for two consecutive points; the lowercase l vs uppercase I is ambiguous in the photo.
• “(whller 2019)” — likely “Wheeler 2019” but the original prints two consecutive l characters; transcribed as visible.
• “EPS, MR” — MR is followed only by ); could be MRI truncated.
• “Pediatric Spasmonotic” — schematic label appears to read Pediatric Spasmonotic; uncertain whether the term is Spastic or some related word, transcribed as visible.