Fabry disease pain: patient and preclinical parallels

Abstract

Severe neuropathic pain is a hallmark of Fabry disease, a genetic disorder caused by a deficiency in lysosomal α-galactosidase A. Pain experienced by these patients significantly impacts their quality of life and ability to perform everyday tasks. Patients with Fabry disease suffer from peripheral neuropathy, sensory abnormalities, acute pain crises, and lifelong ongoing pain. Although treatment of pain through medication and enzyme replacement therapy exists, pain persists in many of these patients. Some has been learned in the past decades regarding clinical manifestations of pain in Fabry disease and the pathological effects of α-galactosidase A insufficiency in neurons. Still, it is unclear how pain and sensory abnormalities arise in patients with Fabry disease and how these can be targeted with therapeutics. Our knowledge is limited in part due to the lack of adequate preclinical models to study the disease. This review will detail the types of pain, sensory abnormalities, influence of demographics on pain, and current strategies to treat pain experienced by patients with Fabry disease. In addition, we discuss the current knowledge of Fabry pain pathogenesis and which aspects of the disease preclinical models accurately recapitulate. Understanding the commonalities and divergences between humans and preclinical models can be used to further interrogate mechanisms causing the pain and sensory abnormalities as well as advance development of the next generation of therapeutics to treat pain in patients with Fabry disease.

Figure 1.

Screening process for relevant articles included in this review.

Figure 2.

Human pain in Fabry disease. Patients with Fabry disease experience acute and chronic pain commonly in their hands, feet, and abdomen. Evoked pain is commonly experienced by patients, although pain can be spontaneous as well. Pain crises are intense pain episodes experienced by individuals with Fabry disease. Patients are often hyposensitive to thermal stimuli and hypersensitive to mechanical stimuli. The pathophysiology begins with dysfunction or absence of the lysosomal enzyme α-galactosidase A, which is essential for degrading the glycosphingolipid globotriaosylceramide (Gb3). Excess Gb3 is converted to globotriaosylsphingosine (lyso-Gb3). When Gb3 and lyso-Gb3 accumulate due to lack of enzyme, they builds up in the peripheral nervous system causing inclusion bodies and neuronal swelling, especially in the somata (dotted line indicates the zoomed-in image of spinal cord, DRG, and peripheral nerve). In addition, Gb3 and lyso-Gb3 build up in the blood and are transported into the DRG and nerve. Over time, many patients experience loss of small-diameter fibers from the skin and peripheral nerves. In addition, ion channels, including sodium, potassium, and transient receptor potential channels, in these nerves are dysfunctional. DRG, dorsal root ganglia.

Figure 3.

Research efforts: Publications and clinical trials for Fabry disease. (A) Cumulative summation of all PubMed articles (black) matching the search terms “Fabry” and “pain,” “nerve,” or “neuron” (not subject to screening in Fig. 1) and clinical trials listed on clinicaltrials.gov matching the “Condition or disease” “Fabry disease.” Data from the PubMed search were collected on May 29, 2020, and data from clinicaltrials.gov were collected on June 22, 2020. *Indicates that data collected for the year 2020 are only for the partial year. Currently there are 3 main therapies: Agalsidase alfa (Replagal), Agalsidase beta (Fabrazyme), and Migalastat (Galafold), approved by the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) to treat enzyme deficiency in patients with Fabry disease. (B) Clinical trials were stratified based on classification by the clinicaltrails.gov website. Interventional trials indicate patients were given one or more treatments, and observational trials indicate patients are assessed for biomedical or heath outcomes, but patients are not given a specific treatment. Expanded access indicates a clinical trial that may allow patients with serious disease complications to participate in the clinical trial, although they are not previously recruited (compassionate use).