Review: Multidisciplinary Care Is Crucial to Fabry Disease Management

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Pain is a hallmark of many Fabry disease cases, and improvements in management could dramatically improve quality of life for patients.

A review published in the Journal of Clinical Medicine explored the mechanisms behind pain in Fabry disease and its pharmacological management, psychosocial implications, and treatment. The article also highlighted the importance of interdisciplinary rehabilitation for pain reduction and better patient quality of life.

The most common manifestation of Fabry disease—a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene—is neuropathic pain that often develops during childhood and can be debilitating.

“Pain has a significant impact on both male and female patients and leads to a significant reduction in quality of life compared to the general population,” the authors wrote. “This appears to coincide with depression, anxiety and chronic fatigue in a significant percentage of people living with Fabry disease.”

Up to 62-80% of male and 30-65.3% of female Fabry patients experience neuropathic pain, with a mean onset of 14.8 years and 19.8 years, respectively, based on long-term observational studies. This can include episodes of burning, sharp, stabbing, and shooting pains in the limbs that worsens as patients exercise or experience ambient temperature changes. Gastrointestinal pain is also common, both chronically and intermittently after eating.


The GLA mutation that causes Fabry encodes the lysosomal hydrolase α-galactosidase A (α-Gal A) and results in toxic accumulation of glycosphingolipids. These include globortriaosylceramide (Gb3 or GL3), and lyso-Gb3, the deacylated form of Gb3.

The pain patients experience is dependent on the amount of residual enzymatic activity. In the classical phenotype, which has no residual enzymatic activity, pain is a hallmark of the disease.

Enzyme replacement therapy (ERT) is a recent development in Fabry treatment that has become part of the standard of care and changed the course of disease by preventing major organ complications and reducing pain. However, many patients do not see complete responses due to irreversible nerve damage.

Another therapy option, migalastat, is a daily oral pharmacological chaperon therapy. Migalastat stabilizes amenable mutant forms of α-Gal A in the endoplasmic reticulum to facilitate passage to the lysosomes and enzymatic breakdown of Gb-3.

An ongoing phase 3 study of the iminosugar lucerastat has a primary end point of neuropathic pain. Other trials are investigating gene therapy as a potential treatment method. But there is a lack of therapies to effectively manage pain, while authors noted that a holistic approach is key to pain management.

“A multidisciplinary approach is important when forming an analgesic care plan involving not just metabolic and pain specialists, but also specialist pharmacists, pain psychologists and physiotherapists in the service,” they wrote.

Psychosocial support is another important aspect of Fabry management given the most severe symptoms often appear in males in their youth—a crucial time for psychosocial development.

“A multimodal pharmacological approach using a combination of neuropathic agents such as the gabapentinoids and duloxetine may facilitate a reduction in neuropathic pain whilst achieving an opioid-sparing effect. In turn, a reduction in neuropathic pain may also facilitate greater engagement with interdisciplinary rehabilitation to achieve a better quality of life,” researchers concluded.


Rajan JN, Ireland K, Johnson R, and Stepien K. Review of mechanisms, pharmacological management, psychosocial implications, and holistic treatment of pain in Fabry disease. J Clin Med. Published online September 15, 2021. doi:10.3390/jcm10184168