GD 1 Summary tail, GD 3 Summary, GlcCer / GlcSph (detail), Narita 2016 patient table

GD 1 Summary (continued)

GD 1 Summary / Chitotriosidase ERT cell carry-over: the normal levels at 5 years of treatment.

SRT response (Smid 2016 #529)

(Smid, 2016 #529) ERT response를 보면, GlcCer: 약 6개월까지 내려가서 residual 40%만들고는 plateau, GlcSph는 1년까지 내려가서 residual 75%만들고 plateau, GlcCer와 GlcSph 둘다 acute response 로서는 비슷한 속도로 떨어지는 것 같음.

Smid 2016 6-panel SRT plot legend: Eliglustat, ERT, Miglustat. Panels g, h, i show GlcSph (y-axes pmol/mL, pmol/mL, %); panels j, k, l show GlcCer (y-axes nmol/mL, nmol/mL, %); x-axes weeks / year / year.

	GlcCer plasma	GlcSph plasma	Chitotriosidase plasma	Spleen volume	Liver volume	Hemoglobin (g/L)	Platelet	Bone	Serum CCL18	GauSSI
SRT response	Brazil (2010 Muller)				2016 Murugesan	2016 Murugesan	2016 Murugesan	2015 Marcos	2016 Murugesan	2016 Murugesan
					2017 El-Beshlawy
	13.5의 반 정도? (table 1에 61.4) 2016 Murugesan

2019 Lukina (Eliglustat)

2019 Lukina에 잘 나옴. Most parameters including GlcCer & GlcSph reaches plateau by 4 years. GlcCer is normalized but GlcSph ends up still very high (47.6 ng/ml vs <5 in normal

Biomarker	Normal Range	Baseline	Year 8	Percent Reduction
Glucosylceramide (GL-1) (μg/mL) (n=18)	<2.0 to 6.6	12.15	2.70	-80%
Plasma glucosylsphingosine (Lyso-GL-1) (ng/mL) (n=16)	<5	624	47.6	-92%
Chitotriosidase (nmol/hr/mL) (n=17)	<15 to 181	6084	902	-81%
CCL18 (ng/mL) (n=18)	17 to 246	3560	442	-87%

Lukina chart x-axis annotations: (n=24-25), (n=20-21), (n=15-19), (n=17-19), (n=17-18), (n=16-18), (n=17-18), (n=16-18), (n=16-18) for years 0 through 8.

GD 3 Summary

	GlcCer plasma	GlcSph	Chitotriosidase plasma	Spleen volume	Liver volume	Hemoglobin (g/L)	Platelet	Bone	Serum CCL18 (ng/ml) (pulmonary and activation-regulated chemokines)	CNS	CNS
Pathophysiology		2016Smid) neurotoxic and directly implicate in GD pathology
Incidence
Method				imaging	imaging			Bone Marrow Burden Score (BMB)		mSST (used in Venglustat's LEAP trial)
SRT response		-2019 Charkhand,(CSF)		34.6→ 15 following 3-4y ERT	Normalized following 3-4y ERT regardless of splenectomy status					(
		-2011 Dekker (plasma)		4 ERT→ Gradually decreasing (11.9 at y 5) 2017 El-Beshlawy

GlcCer and GlcSph (detail)

	GBA protein	GBA activity	GlcCer	GlcSph
GlcCer			More abundant	(Hannun, 1987 #558) in vitro (and in human platelets) GlcSph inhibits Protein Kinase C (table1에서 IC50이 85uM 이나 되는데도 potent inhibitor라고 하네? ) (Schueler, 2003 #555) Neurotoxic in neuronal cell line. on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 M glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and -galactosidase were reduced in a dose-dependent manner. Acetylcholine in cells exposed to glucosylsphingosine also declined. Cells switched to glucosylsphingosine-free medium partially recovered. Js: 시작용량인 1 u M 에서부터 cell death 보임. (2016 Smid) Toxic and directly implicate in GD pathology (hemolysis ↓ PKC등)
GD (Venglu GD Leap)			CSF GL-1 in GD (2020world): 7.1±2.8 ng/mL (range 4.4-11.1 ng/ml); 즉 normal과 비슷 healthy range 4.5-5.9 ug/mL) ng/mL의 typo?	Csf Lyso-GL-1 In GD = 39.3±22.9 pg/mL (range 20.1-67.6; ), , not detectable in healthy subjects.(LLOQ <5.0 pg/mL) Sato: LLOQ in CSF of GD patients was 10 pg/mL by our method (The same LLOQ as Dr. Narita's paper
norte ain in 2/3	Choi에 있을 것		1985 Nilsson) Type 1에서 수배 증가 (cerebral cortex에서 7배증가, cerebellum에서 2배), type 2와 3은 수십배 증가 (둘 사이 우열은 어려움)	(1985 Nilsson),, type 1 에서는 no change/약간 증가, (2002 Orvisky) type 3 에서 증가 (23.25 ng/ml), type 2 에서 훨씬 증가(142 ng/ml), HC (<1 ng/ml) 즉 GlcSph가 neurologic manifestation 결정하는구나! (Narita, 2014 #562): ↑ 80 fold (83.95 vs 2.9 pg/ml, ,): Type 2 (237.45 pg/ml,) 에서 type 3 (74.75 pg/ml) 보다 더 심함. age, neurocognitive status와 no correlation. ↓ by ambroxol
n GD or 3	(Schiffmann, 1997 #1304)		GD2) ↑ (4.6 배) (Gornati, 2002 #1184) Case report Type 2) ↑ (몇 배인지 ND) (Gornati, 2002 #1184) Inherit Metab Dis. 2002 Feb;25(1):47-55., case report

Narita 2016 #560 (with no normal controls)

Patient	1	2	3	4	5
GD type	3	3	3	2	3
Genotype	N188S/G193W	N188S/?	N188S/?	F213I/D...?	D409H/IVS10-1
Age (y)	28	20	15	3	25

Uncertain Spans

location	transcription	uncertainty
GD 1 Summary tail cell	the normal levels at 5 years of treatment.	reads as written from a clipped cell at the top of frame; full row context is in 20240722_182224.
Smid 2016 plot label	panel-letter-only labels g, h, i, j, k, l	the panels are labelled with lowercase letters only; figure caption is not visible on this capture.
GD 3 Summary / SRT response / liver	4 ERT→ Gradually decreasing (11.9 at y 5)	reads as written; the leading 4 may be a footnote/citation marker.
GlcCer detail / norte row label	norte ain in 2/3	the leftmost row label is partly clipped and reads as fragmentary norte / ain in 2/3; preserved verbatim.
Narita 2016 table / Patient 4 genotype	F213I/D...?	the second allele is partly clipped at the right edge of the cell.