GM1 Gangliosidosis: Mechanisms and Management

Figures & data

Figure 1 Transmission Electron Microscopy (TEM) images of feline CNS tissue. Normal axon in cross-section surrounded by thick myelin sheath (A). Multiple axons in cross-section of GM1 white matter, surrounded by disjointed and unravelling myelin layers (B). Normal oligodendrocyte with round nuclear envelope and prominent cytocavitary network (C). GM1 oligodendrocyte with multiple swollen mitochondria (black arrows) and irregularly-shaped nuclear envelope (white arrow) (D). Scale bars are 1μm. Transmission electron micrographs in panels A, B, and D, reproduced with permission Gray-Edwards HL, Maguire AS, Salibi N, et al. 7T MRI predictsamelioration of neurodegeneration in the brain after AAV genetherapy. Mol Ther - Methods Clin Dev. 2020;17:258–270.¹⁴⁶ © 2019 Elsevier.

Table 1 Summary of GM1 Biomarkers Identified in the Serum, CSF, and by Brain MRS of Animal Models and Human Patients

Source	Biomarker	Change (±)	GM1 Subtype	Significance to Disease Progression
Serum^Citation17,Citation55,Citation135	AST	+	2	Liver damage
	Calcium	-	1, 2, 3	Global dysregulation of calcium homeostasis
	Creatinine	-	2	Low muscle mass; liver damage
	Albumin	-	1, 2	May indicate inflammation, malnutrition, or loss of protein due to an underlying condition
	IGFBP-2	+	1	Critical to CNS development; insulin sensitivity
	Osteopontin	+	1, 2	Inflammation; lipid metabolism
CSF^Citation17,Citation54,Citation147	AST	+	2	Liver Damage
	LDH	+	2	General tissue damage
	NSE	+	2	Neuronal injury
	MBP	+	2	Myelin loss/damage
	HB-EGF	+	1, 2	Neurogenesis; angiogenesis
	THP	+	1, 2	Renal protective; impaired protein catabolism
	AACT	+	1, 2	Protective role during inflammation
	HGF	+	1, 2	Inflammation; tissue regeneration
	SHBG	+	1, 2	Unknown
	ENA-78	+	1	Inflammation; neutrophil recruitment and activation
	MCP-1	+	1	Inflammation; infiltration of macrophages
	MIP-1a	+	1	Proinflammatory chemokine
	MIP-1b	+	1	Proinflammatory chemokine
	TNFR2	+	1	Cytokine receptor; mediates pro- and anti-inflammatory T-cell responses
	MIF	+	1, 2	Inflammation
	MMP-3	+	1, 2	Extracellular matrix turnover; inflammation
	GM1 ganglioside	+	2	Storage; impaired lysosomal catabolism; cell death
	GM3 ganglioside	+	2	Generalized lysosomal dysfunction; cell death
	Ceramide	+	2	Generalized lysosomal dysfunction; cell death
	Lactosyl ceramide	+	2	Generalized lysosomal dysfunction; cell death
	Sphingomyelin	+	2	Myelin loss/damage
	Sulfatide	+	2	Myelin loss/damage
	Galactosyl ceramide	+	2	Myelin loss/damage
	Glucosyl ceramide	+	2	Myelin loss/damage
	Sphingosine	+	2	Generalized lysosomal dysfunction; cell death
Brain MRS^Citation3,Citation20,Citation55,Citation148	Cho (GPC+PCh)	+	1, 2	Membrane turnover; myelin loss/damage
	NAA	-	1, 2	Neuronal damage
	Cr+PCr	+	2	Neuroprotective role; high-energy phosphate metabolism
	NAA+NAAG	-	2	Neuronal damage
	Ins	+	1	Gliosis

Notes: Refer to the text for definition of acronyms. For “Change”, “+” refers to an increase and ‘-‘ refers to a decrease. For GM1 subtype, 1 is infantile, 2 is late infantile/juvenile, and 3 is adult/chronic.

Figure 2 An example of data collected from Magnetic Resonance Spectroscopy (MRS) and MRI of normal and GM1 cats. Cerebellar voxel defined in the cat for measurement of ¹H MRS (open white square) (A). Example ¹H spectrum with metabolites labeled and data output for the respective metabolites (B). Transverse T2w images of the cerebral cortex and cerebellum in normal and GM1 cats at 2 and 8 months of age. The isointensity of gray and white matter is prominent at 8 months for both the cerebral cortex and cerebellum of GM1 cats compared to normal controls. In GM1 cats, atrophy is mild and unilateral ventriculomegaly is apparent in the provided example (also occurs in normal controls) (C).

Figure 3 Management of GM1 Gangliosidosis. Clockwise, beginning on the left: Pharmacological chaperones for enzyme enhancement and small molecules for substrate reduction therapy (1–7), stem cell transplantation, gene therapy, and enzyme replacement (RCSB PDB ID: 3THC).¹²

Table 2 Pharmacological Chaperone Influence on Mutant β-Gal Activity

Pharmacological Chaperones – GM1 [Molecular Structures in Figure 2]	Mutation (Fold Enhancement of β-gal Activity) in Each GM1 Subtype
	Type 1	Type 2	Type 3
Iminosugar derivatives
Miglustat (NB-DNJ) [3]	-	-	-
DGJ^Citation50		R201C (5.8)	R201H (1.8) R457Q (5.3)
NB-DGJ^Citation50 [4]		R201C (5)	R201H (2.8) R457Q (6.1)
NN-DGJ^Citation90 [5]	R351X (-) R148S/D332N (4)	R201H/IVS14-2A>G (7.8)	G438E (-) R201H/W509C (13.8)
DLHex-DGJ^Citation165 [7]	I181K (2.1) C230R (9) Y270D (1.7) A301V (1.3) Y333H (1.8) P549L (1.4) R208C (2.5)	R201C (9.4)	G438E (2.3) R201H (11.1)
6S-NBI-DGJ^Citation172,Citation175	R59H (-) G190D (2)	R201C (3)	I51T (2.5) G438E (2.5) R457Q (2) R201H/G481X (3)
4-epi-isofagomine derivatives^Citation92,Citation176 [1]
(5ar)-5a-C-pentyl-4-epi-isofagomine^Citation92	R59H (1.4/1.1)^a	R201C (5.4/15)^a	I51T (1.6)
	R208C/IVS10+1G>A (4.4)	S191N/R351X (11)	G438E (2)
	Q255H/K578R (20)	R201H/c.247dup1 (3.5)	R442Q/W92X (1.5)
	H281Y (35)	R201H/G76E (6.7)	R457Q (7.3)
	P549L (-) R351X (-)	R201H/H281Y (4.7)
Sugars
Galactose^Citation93 [2]			R442Q (2.5)
Valienamine derivatives
NOEV^Citation50,Citation88 [6]	G190D (6)	R201C (5.1)	R201H (4.5) R457Q (2.4) I51T (-) R201H/G481X (3.5)
6-deoxy-NOEV·HCl^Citation180		R201C (5.2)
N-octyl-(+)-conduramine F-4·HCl^Citation180		R201C (5.4)
N-2-ethylbutyl-(+)-conduramine F-4·HCl^Citation180		R201C (7.4)
N-cylcohexylmethyl-(+)-conduramine F-4·HCl^Citation180		R201C (8.5)

Notes: Type 1, 2, and 3 refers to infantile, late infantile/juvenile, and adult/chronic, respectively. Mutations in β-gal protein were assigned given literature precedent, but may be found in heterozygous allelic combinations of all subtypes. 6S-NBI-DGJ and NBT-DGJ were reported as very weak inhibitors of β-gal, but low micromolar inhibitors of β-glucocerebrosidase or α-gal, respectively, and were not included. [1–7] correspond to molecular structures in Figure 3. Fold-change is variable and dependent on concentration of chaperone, frequency of dose, and experimental system. PC treatment of patient fibroblasts, murine fibroblasts, feline fibroblasts, transiently transfected β-gal-deficient fibroblasts, and transiently transfected β-gal-deficient COS7 cells is represented. ^aMaximal fold enhancement of β-gal activity from two different homozygous patient lines.

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