Pathophysiology In GD, GBA1 mutations, Event / Observational markers, Types and Neuropathology

Pathophysiology In GD

• ↓ GBA → ↑ glucosylceramide accumulation in lysosome → ↑ glucosylceramide is deacylated by acid ceramidase to form glucosylsphingosine → glucosylsphingosine exits the lysosomal system → ① glucosylsphingosine triggers B cell proliferation (being a potent antigen for CD1d-restricted NKT cells) and metabolic inflammation, which underlie GD pathophysiology [10, 12]. ② glucosylsphingosine mediates osteoblastic dysfunction which results in osteopenia [11]. ③ glucosylsphingosine accumulates in tissues

GBA1 mutations figure labels: GBA1 mutations (title), R463C, L444P, R496H, N370S, D409H, R120W, R329C, R131C, G193E, G202R, Active site E235 and E340.

	GBA mutation	GBA protein trapped in ER (ER Retention)	glucosylceramide / glucosylsphingosine	Macrophage	a-syn	Clinical manifestation
event	GBA mutation		glucosylceramide, & glucosylsphingosine, in the lysosomes 축적	원래 macrophage 가 계속 dying RBC를 먹으니까, 특별히 Macrophage에 축적이 심해지고 커져서 'Gaucher cell'이 됨,	a-syn	Clinical manifestation
Observational markers		This is the marker of GD severity! ((Ron, 2005 #532)	↑ glucosylceramide (but plasma and erythrocyte, cellular origin is unclear), secondary increase in gangliosides (but cellular origin is unclear)	↑ markers of macrophage activation: angiotensin-converting enzyme, cathepsin S, chitotriosidase (produced by Gaucher cells and secreted into the circulation), and CCL18 (produced by Gaucher cells and secreted into the circulation), in the blood plasma; and TNFa in splenic Gaucher cells		Saccadic eye movement, EEG

Types and Neuropathology

• Good postmortem review on (Schneider, 2017 #1056)

	Incidence Inherit Metab Dis (2008) 31:738-744		Genotype	neuropathology	Course		Tx
Type 1	~94%	non-neuronopathic form of GD	N370S/N370S is the most common in type 1 (아래 incidence 표 보면 거의 Type 1의 70-80%이상이 N370이네)	(Wong, 2004 #175)Postmortem] astroglios without significant neuronal loss, most type 1 GD had at least one allele with N370S, that was hitherto considered a "neuroprotective" allele.	Death age: 64.5 y (2012 Stirnemann)	hepatosplenomegaly, bone infarction, and anaemia with a wide range of symptom severity, may have subtle slow saccades in some patients 22, 34-36	Thrombocytopenia frequently normalizes within 1 to 2 years of ERT in patients with an intact spleen and moderate baseline thrombocytopenia. Persistent thrombocytopenia in GD patients treated with ERT for over 4 years relates to refractory splenomegaly.
Type 1 + PD				[2004Wong,Postmortem] astroglios without significant neuronal loss + LB (hippocampal CA2-4 neurons.)
Type 2	~1%		L444P is most common in type 2,	In all GD types: (Wong, 2004 #175) (Arévalo, 2022 #2476) of lysosome dysfunction in nGD. In physiological conditions, lysosomes are distributed throughout the cytosol in wild-type neurons (left in green). In nGD, lysosomes are increased in number and size with a perinuclear localization of LIMP2+ lysosomal compartments accompanied by elevated intraluminal pH and decreased lysosomal enzyme activity, along with the accumulation of GluCer and secondary substrates such as glucosylsphingosine (GluSph) and cholesterol (right in light blue). The Altered lysosome distribution with preferentially perinuclear distribution is an early characteristic of nGD (Awad et al., 2015, 2017; Zigdon et al., 2017). The cause of altered lysosome distribution is unclear.	usually die within days to years after birth Death age: 1y (2012 Stirnemann)	the most severe type
Type 3	5%	Chronic neuronopathic n.	(Schwartz, 2018 #547) L444P/L444P (69.6%), L444P/other (21.7%)		variable longevity and a slower progressive course Onset: 1.4 y Dx: 10m-2 y (2016 Nalysnyk) 90% 가 (진단직후) ERT함 (Velaglucerase alfa, imiglucerase 둘다 비슷하게 많이 씀) 26.9% splenectomy GOS entry: 17.1 y (entry시 46.2%가 18이상임, 즉 반 정도가 18세 이상 산다고 볼 수 있겠군) Death age: 8.4y (2012 Stirnemann, 근데 이거 아닐 것 같음) 사인: neurologic Cx (2012 Stirnemann)	CNS symptom: half experience onset before 2 years of age [10]. Universal clinical findings include eye movement disorder, either presenting as oculomotor apraxia in younger children or as horizontal supranuclear gaze palsy and slowed saccades.	Tx guideline: ERT should be commenced at a starting dose of 60 U/kg every other week as soon as possible after diagnosis in children with GD3, or at 30 to 60 U/kg every other week in adults [14,20]. Available Tx: Velaglucerase alfa was approved in Japan in 2014 for GD, including GD3, while imiglucerase is indicated in Europe for patients with GD3 who exhibit clinically significant nonneurological disease manifestations [21]. however, there are no approved GD-specific treatments for GD3 in the US
	perivascular Gaucher cells (Fig. 6B and 7B (globus pallidus) ) and nonspeciWc white matter gliosis (not shown) were seen in all 14 patients. Non-speciWc grey matter and perivascular gliosis was present in 12 of 14 patients (all except Patients 11 and 12). Laminar		perinuclear localization of LIMP2+ lysosomal compartments accompanied by elevated intraluminal pH and decreased lysosomal enzyme activity, along with the accumulation of GluCer and secondary substrates such as glucosylsphingosine (GluSph) and cholesterol (right in light blue). The Altered lysosome distribution with preferentially perinuclear distribution is an early characteristic of nGD (Awad et al., 2015, 2017; Zigdon et al., 2017). The cause of altered lysosome distribution is unclear.	(Wong, 2004 #175), n=3, Postmortem] -Neuronal loss (Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b) predominated in both type 2 and type 3 No wong 2004, n=4, patients with progressive myoclonic encephalopathy,, -astrogliosis는 1 case에서만 (hippocampus), patients with type 2 and 3 GD had more prominent gliosis and larger and more frequent collections of perivascular Gaucher cells than type 1 patients. - ↑ GBA expression (Büttner-Ennever, 2008 #798) one case report: neuronal loss 없이 brainstem midline에 gliosis만으로 horizontal saccade이상 초래.
			(Perucca, 2018 #919): VARIABLE!	Brain MRI) findings are usually normal or non-specific Enhanced signal in dentate nuclei and thalamus (혹시 intramyelinic edema) (2nd) DTI: WM abnormlity (Hill, 1996 #921) CT or MRI in 13 patients , 이중 4명에서만 mild cerebral atrophy		(Schwartz, 2018 #547)[Brazil, 2018, mean 17.1y] Hematologic: Hb, Platelet 는 (약 때문에) 정상, no cases of severe hepatomegaly or splenomegaly Bone problem (40%): avascular necrosis, bone marrow infiltration, lytic lesions, bone pain, osteopenia, acute bone crises, and fractures Splenectomy 26.9% Pulmonary problem (50%) CNS 28%): Eye movement disorders (14%) > sz (7%), peripheral neuropathy (7%) (Abdelwahab, 2017 #548)=Egyptian study,(n=78) mean age 7.9 y] Supranuclear

Uncertain Spans

location	transcription	uncertainty
Types table / 6th row	(Abdelwahab, 2017 #548)=Egyptian study,(n=78) mean age 7.9 y] Supranuclear	trailing word Supranuclear is clipped at the photo edge.
Statusbar continuation	(50%), bulbar symptoms (55.9%),, seizures (29.4%), convergent strabismus (29.4%),, abnormal gait (20.6%) and neck retroflexion	visible only in the statusbar crop; full sentence is clipped at the bottom edge.