Neuropathy and Fabry disease: pathogenesis and enzyme replacement therapy

Area of Science:

• Neurology
• Genetics
• Metabolic Disorders

Background:

• Fabry disease is a genetic disorder caused by alpha-galactosidase A deficiency.
• This deficiency leads to the accumulation of alpha-D-galactosyl moieties, primarily globotriosylceramide (Gb3).
• Gb3 accumulation affects both the central and peripheral nervous systems, including Schwann cells, dorsal root ganglia, and neurons.

Purpose of the Study:

• To investigate the neurological manifestations of Fabry disease.
• To understand the impact of Gb3 accumulation on the peripheral nervous system.
• To evaluate the efficacy of enzyme replacement therapy (ERT) on neurological and autonomic dysfunction in Fabry disease.

Main Methods:

• Review of neurological manifestations in Fabry disease.
• Analysis of Gb3 deposition in nervous system tissues.
• Assessment of peripheral nervous system function, including sensory and autonomic function.
• Evaluation of ERT effects on neuropathic pain, sensory thresholds, and autonomic functions like sweating.

Main Results:

• Neurological involvement includes peripheral and central nervous system damage due to alpha-galactosidase A deficiency and Gb3 accumulation.
• Peripheral nervous system involvement primarily affects small Adelta and C fibers, contributing to autonomic dysfunction and neuropathic pain.
• ERT shows partial improvement in neuropathic pain, sensory detection thresholds (cold/warm), sweating, and heat tolerance.
• Despite improvements, ERT does not fully normalize peripheral nervous system function.

Conclusions:

• Neurological complications in Fabry disease are significant and linked to Gb3 accumulation.
• ERT provides symptomatic relief and partial functional recovery for peripheral nerve deficits.
• Further research and therapeutic strategies are needed to fully restore peripheral nervous system function in Fabry disease.