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Pain in Fabry disease: do experimental models reveal novel therapeutic targets?
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DOI：10.1016/j.bcp.2026.118323.png)
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Abstract
En 中文
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and progressive accumulation of globotriaosylceramide (Gb3). Although FD is a multisystemic disorder affecting the heart, kidneys, skin, and nervous system, pain is one of its earliest, most prevalent, and disabling manifestations. While several review articles have already addressed the clinical features and management of FD-associated pain, this review specifically focuses on the mechanisms underlying pain as revealed by experimental and preclinical models of the disease. By integrating findings from cellular and animal studies, we provide an updated overview of the molecular and neurobiological pathways implicated in FD-related pain, including dorsal root ganglia dysfunction, ion channel dysregulation, neuroimmune interactions, vascular abnormalities, and central sensitization processes. We further discuss how preclinical studies have identified novel therapeutic targets for pain, such as acid-sensing ion channels (ASIC), transient receptor potential (TRP) receptors, the prokineticin system, glial activation, and glutamatergic signaling, which may complement current disease-modifying therapies. By highlighting the translational relevance of these mechanistic insights, this review aims to bridge the gap between experimental research and the development of more effective pain-focused interventions. A better understanding of the pathophysiology of FD-associated pain may ultimately contribute to improving management strategies with a significant impact on the quality of life for affected individuals
Keywords:
Fabry disease
Neuropathic pain
Visceral pain
Chronic pain
Preclinical models
Neuroinflammation
Prokineticin system
Glial cells
α-Gal A
α-galactosidase A
AAV
adeno-associated viruses
ASIC
acid-sensing ion channels
CA9
carbonic anhydrase 9
CHO
chinese hamster ovary
CNS
central nervous system
DAMP
damage-associated molecular patterns
DJG
1-deoxy-galactonojirymicin,
DRG
dorsal root ganglia
EFNA5
ephrin-A5
EMA
European Medicines Agency
ERT
enzyme replacement therapy
FD
Fabry disease
FDA
Food and Drug dministration
Gb3
globotriaosylceramide
GCS
glucosylceramide synthase enzyme
GFAP
glial fibrillary acidic protein
GPM6A
glycoprotein M6A
HCN2
hyperpolarization-activated cyclic nucleotide-gated potassium and sodium channel 2
HEK
Human Embryonic Kidney
HIF
hypoxia-inducible factor
HSP
heat shock protein
Iba1
ionized calcium-binding adaptor molecule 1
IBS
irritable bowel syndrome
ICAM-1
intercellular adhesion molecule-1
IL
interleukin
iPSC
induced pluripotent stem cell
LAC
L-acetylcarnitine
LNP
lipid nanoparticle
LRG1
leucine-rich alpha-2-glycoprotein 1
Lyso-Gb3
globotriaosylsphingosine
mGluR2
type-2 metabotropic glutamate receptors
PBMCs
peripheral blood mononuclear cell
PKR
prokineticin receptor
PKS
prokineticin system
PNS
peripheral nervous system
PPARγ
peroxisome proliferator-activated receptor gamma
RNAi
RNA interference
SCFA
short chain fatty acid
SGC
satellite glial cell
shRNA
short hairpin RNA
SRT
substrate reduction therapy
TLR4
toll-like receptor 4
TNF-α
tumor necrosis factor alpha
TRP
transient receptor potential
TRPA
transient receptor potential ankyrin
TRPM
transient receptor potential melastatin
TRPV
transient receptor potential vanilloid
VCAM-1
vascular cell adhesion molecule-1
VEGF
vascular endothelial growth factor
XCI
X chromosome inactivation
Journal
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