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27/03/2025

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Fabry Disease: Five Key Signs Clinicians Should Be Aware Of 

And how our understanding of Fabry symptoms in females has evolved 

Author: Dr James O’Donovan  

Fabry disease is a complex, multisystem disorder that was once thought to primarily affect men. However, we now understand that it can have significant clinical consequences in both genders - with unique challenges often seen in female patients^1,2. Up to 70% of women with Fabry develop manifestations that can be as severe as those observed in men³.  

I have partnered with Amicus Therapeutics to raise awareness about this disease and the symptoms to be cognisant of. In this post, I outline five important potential signs and symptoms of Fabry disease that fellow clinicians should be aware of.  

1. Neuropathic Pain and Heat Intolerance 

What to look for:

• Sharp, burning pains in the hands and feet. 
• Increased frequency of “pain crises,” especially during illness, stress, or exposure to hot temperatures. 
• Hypohidrosis or anhidrosis (reduced or absent sweating). 

Why it matters: 

Many people with Fabry disease experience neuropathic pain, with studies showing that up to 80% of men with the classic form and about 65% of women report these painful episodes⁴. In fact, from as early as four years old, girls with Fabry can develop severe, chronic neuropathic pain described as burning or tingling, with episodes intensifying during fever or hot weather⁵. Although previously underestimated, this pain can severely affect quality of life⁶. Inquiring specifically about pain and its triggers can be an important first step in uncovering an atypical presentation, especially in a female patient.  

2. Gastrointestinal Disturbances 

What to look for:

• Persistent or intermittent abdominal cramping, diarrhoea, constipation, or bloating. 
• Ongoing symptoms mimicking irritable bowel syndrome (IBS), often with no obvious dietary cause.  

Why it matters:

For many people with Fabry disease, digestive issues are a common concern. The most frequent symptom is diarrhoea - characterized by frequent, loose bowel movements paired with cramping abdominal pain. Many patients also notice that these issues tend to worsen after meals, leading to an urgent need to go to the toilet and uncomfortable gas⁷. In fact, more than half of patients with Fabry may experience GI issues, with diarrhoea and abdominal pain being the most common. These symptoms often begin early and can be dismissed as functional or related to diet. If GI disturbances are chronic, cyclical, and resistant to standard treatments, consider the possibility of Fabry - particularly if other hallmark signs align. 

3. Renal and Cardiac Red Flags 

What to look for in renal health: 

• Proteinuria and/or microscopic haematuria during routine urinalysis. 
• Gradual reduction in estimated glomerular filtration rate (eGFR). 

What to look for in cardiac health: 

• Left ventricular hypertrophy (LVH) and arrhythmias at a younger-than-expected age. 
• Mitral valve prolapse or thickened valves. 
• Palpitations, fainting, or exercise intolerance.  

Why it matters:

While kidney problems are typically seen earlier in men with Fabry disease, some women also develop renal insufficiency - typically in a milder form and at a later stage⁸. Chronic kidney disease (CKD) is a major feature of Fabry and, although it appears in only about 0.01% of patients on dialysis according to European and US registries,^9,10 screening studies indicate the true prevalence could be potentially up to 100 times higher. Before modern treatments were available, renal failure often led to death by the early 50s. Recognizing these patterns is essential for early diagnosis and timely intervention, with the goal of improving patient outcomes. 

 Similarly, cardiac manifestations, especially in female patients, are frequently overlooked until they’ve progressed to serious heart disease, including hypertrophic cardiomyopathy and arrhythmias. This can escalate the risk of heart failure, stroke, and early mortality if unrecognized. 

4. Cerebrovascular Symptoms and Stroke Risk 

What to look for:

• Transient ischemic attacks (TIAs) or unexplained stroke at a younger age 
• Vertigo, tinnitus, or hearing loss 
• White matter lesions on brain MRI 

Why it matters:

Stroke is a significant and often early complication in patients with Fabry disease, and it warrants careful attention from clinicians. In one study, strokes occurred in approximately 7% of males and 4% of females, with the first stroke happening at a median age of 39 years in men and 45.7 years in women¹¹. Notably, the majority of patients experienced a stroke without having had previous renal or cardiac events, and for many, stroke was the initial manifestation of Fabry disease - occurring even before a formal diagnosis was made. 

5. Eye Changes 

What to look for:

• Cornea verticillata (whorl-like corneal opacities visible on slit-lamp exam) 
• Characteristic lenticular lesions or angiokeratomas (small, dark red to blue-black papules) 
• Tortuous vessels 
• Unexplained bleeds in the eye 
• Fabry Cataracts  

Why it matters:

Although these ocular findings do not typically impair vision, they are a telltale sign of Fabry disease when present.¹² A slit-lamp exam by an ophthalmologist or optometrist can confirm corneal verticillata, which can appear in up to 70–80% of those with Fabry - men and women alike. When combined with other systemic signs, these findings can help clinch the diagnosis early.

Understanding the Shift: “Carriers” Versus “Patients” 

Previously described as “carriers,” female patients with Fabry frequently develop organ damage and experience significant morbidity. The degree to which symptoms manifest can vary widely - some women have severe disease on par with classic males, whereas others have milder or later-onset complications.  

Clinical takeaway: If a woman has a confirmed family history of Fabry or presents with suggestive signs—such as neuropathic pain, cardiac anomalies, or unexplained GI problems—genetic counseling and enzyme or genetic testing are recommended.

5 Key Takeaways for Clinicians 

1. Be Aware of Non-Classical Signs: Fabry is not limited to the classic male presentation; up to 70% of women have disease manifestations. 
2. Probe for Neuropathic Pain: Chronic pain in the hands and feet, worse with heat or fever, could be Fabry. 
3. Investigate Unusual Cardiac or Renal Findings: LVH, arrhythmias, proteinuria, or reduced GFR at an early age warrant further screening. 
4. Include Fabry in Young Stroke Workups: TIAs or strokes in young women should prompt consideration of metabolic causes. 
5. Use Targeted Testing & Specialist Referral: If clinical suspicion arises, refer to the local genetics service.  

References

1. Deegan, P.B., et al., Fabry disease in females: clinical characteristics and effects of enzyme replacement therapy, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, and G. Sunder-Plassmann, Editors. 2006, Oxford PharmaGenesis opyright © 2006, Oxford PharmaGenesis™. Oxford. 
2. Deegan, P.B., et al., Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet, 2006. 43(4): p. 347-52. 
3. Wang, R.Y., et al., Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genetics in Medicine, 2007. 9(1): p. 34-45. 
4. Stepien, K.M., et al., Management of pain in Fabry disease in the UK clinical setting: consensus findings from an expert Delphi panel. Orphanet Journal of Rare Diseases, 2023. 18(1): p. 203. 
5. Politei, J.M., et al., Pain in Fabry Disease: Practical Recommendations for Diagnosis and Treatment. CNS Neurosci Ther, 2016. 22(7): p. 568-76. 
6. Morand, O., et al., Symptoms and Quality of Life in Patients with Fabry Disease: Results from an International Patient Survey. Adv Ther, 2019. 36(10): p. 2866-2880. 
7. Zar-Kessler, C., et al., Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis. Therap Adv Gastroenterol, 2016. 9(4): p. 626-34. 
8. Torra, R., Renal manifestations in Fabry disease and therapeutic options: New strategies to prevent cardiovascular risk in chronic kidney disease. Kidney International, 2008. 74: p. S29-S32. 
9. Thadhani, R., et al., Patients with Fabry disease on dialysis in the United States. Kidney Int, 2002. 61(1): p. 249-55. 
10. Tsakiris, D., et al., Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant, 1996. 11 Suppl 7: p. 4-20.
11. Sims, K., et al., Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke, 2009. 40(3): p. 788-94. 
12.  Idrus, E.A. and E. Iskandar, Cornea verticillata in Fabry disease. QJM: An International Journal of Medicine, 2024. 117(6): p. 452-453. 

NP-NN-UK-00090622
July 2022