In Brief | Rare Diseases | Fabry Disease
Exploring the Link Between Fabry Disease and Chronic Pain: Insights from the DOUFAB and DOUFABIS Studies
Time to read: 04:56
Time to listen: 09:39
Originally Published: August 2024
Sourced: Eur J. Pain
Type of article: In Brief
MedED Catalogue Reference: MIBRD001
Category: Rare Diseases
Cross Reference:Fabry Disease, Pain Management
Keywords: Fabry Disease, pain, genetic screening, pain management strategies
Routine screening for Fabry disease (FD) in chronic pain patients without relevant symptoms or family history is not warranted. However, pain specialists should remain vigilant for key FD symptoms, such as small fibre neuropathy, to ensure accurate differential diagnoses.
This article is a review of recent studies originally published in the Eur J Pain, Aug 2024. It has been reproduced here under Creative Commons Licence. This article does not represent the original research, nor is it intended to replace the original research. Access the full Disclaimer Information.
Fabry disease (FD) is a rare X-linked lysosomal disorder resulting from alpha-galactosidase deficiency due to pathogenic variants in the GLA gene.
The deficiency leads to globotriaosylceramide (Gb3) accumulation in lysosomes across multiple tissues, causing renal, cardiac, skin, and nervous system involvement.
The accumulation primarily damages small sensory fibres, starting in the distal extremities, resulting in neuropathic pain - known as acroparesthesias - which is often the earliest and most common symptom, reported by up to 80% of males and 65% of females with classic FD.
While FD is well-known for its association with renal failure, left ventricular hypertrophy, and early strokes, its prevalence in chronic pain conditions has not been extensively studied.
Study Purpose
The researchers of the studies under review aimed to estimate the prevalence of FD in a population of chronic pain patients.
Study Methodology
This review reported on the finginds of two studies – DOUFAB and DOUFABIS - conducted in France, which investigated the prevalence of Fabry disease (FD) in chronic pain patients.
Both studies were interventional studies with a single open arm for diagnostic purposes. Patients underwent clinical examination and completed a questionnaire covering the study's inclusion criteria.
The DOUFAB study (NCT01178164) was an exploratory, single-centre trial conducted from September 2010 to September 2012 at Bordeaux University Hospital. It's goal was to diagnose FD using alpha-galactosidase A activity testing in males and GLA gene analysis in females. The study included patients aged 6 to 65 with chronic pain of unknown origin, focusing on pain types such as acroparesthesia, pain crises, and neuropathic pain.
The follow-up DOUFABIS study (NCT02450604) expanded the research across 12 centres in France, including one in an overseas territory, from March 2015 to May 2020. This multicentric study aimed to confirm the findings of the earlier trial, involving a broader cohort of 1,000 patients with various types of undiagnosed chronic pain. The inclusion criteria were less restrictive to improve recruitment, evaluating pain typologies similar to those in DOUFAB. (See Figure 1)
The primary outcome measure of these studies was the diagnosis of FD in at least one patient suffering from chronic pain.
Findings
The DOUFAB study analysed 147 patients, including 112 females and 35 males, with a mean age of pain onset at 41.4 years. No male patients showed enzymatic deficiencies, and only two females carried benign GLA variants.
A 63-year-old woman was diagnosed with Fabry disease (FD) after presenting with paresthesia, burning limb pain, asthenia, and a 15-year history of abdominal pain. Examination revealed skin lesions suggestive of abdominal angiokeratomas.
Genetic sequencing of the patient's GLA identified a missense heterozygous pathogenic variant in exon 7: NM_000169.3: c.1087C > T, p.(Arg363Cys). Additional screening tests showed reduced alpha-galactosidase A activity and elevated urine Gb3 levels. Additional tests, including ophthalmological and cardiac tests, were normal.
The DOUFABIS study followed on from the DOUFAB study. Seven hundred seventy-three patients (746 usable cases: 100 males, 646 females, aged 6–80 years) across 12 pain centres were included in this study. The mean age of pain onset was 32 years, with a median of 33 years.
Isolated acroparesthesia was reported as the initial pain in 15% of patients and as the current pain in 7%. No enzymatic deficiencies were identified in the male cohort. In the female cohort, six benign/likely benign variants (Class 1 and 2) were found in 14 patients, including three missense and three synonymous variants.
One variant of uncertain significance (VUS, Class 3), NM_000169.3: c.311G>A, p.(Gly104Asp), was detected in a 58-year-old woman with a 10-year history of chronic pain and acroparesthesia. A biochemical assessment conducted on the patient revealed no enzymatic deficiency or plasma lysoGb3 accumulation. A family segregation study showed her sons were hemizygous for the VUS but had normal enzyme activity, suggesting the VUS was likely benign and ruling out Fabry disease.
Below is a schematic representation of the process and main results of the DOUFAB and DOUFABIS projects.
Figure 1: Process and Main Results of DOUFAB and DOUFABIS Projects
Click to enlarge view
Source: Angelini, C., Bar, C., Baudier, M. P. et al(2024). Prevalence of Fabry disease in patients with chronic pain: Lessons from the DOUFAB and DOUFABIS studies. European Journal of Pain, 29(1), e4708. https://doi.org/10.1002/ejp.4708
Discussion
A systematic search for Fabry disease (FD) among nearly 1,000 patients with chronic pain identified only one case, suggesting a prevalence of approximately 1 in 1,000 in this population.
This rate is notably lower than prevalence estimates in other groups, such as patients with renal failure (0.1%–0.3%), stroke (0.1%–4%), or left ventricular hypertrophy (around 1%).
The study highlighted significant diagnostic challenges, including that the measurement of alpha-galactosidase A activity, a common diagnostic tool, fails to identify FD in nearly one-third of affected women. Furthermore, previous studies may have overestimated FD prevalence due to misinterpretation of benign variants or variants of uncertain significance (VUS), such as c.311G>A, p.(Gly104Asp). The researchers in this study encountered one such case, emphasising the importance of cautious interpretation of genetic variants.
Considering the high frequency of chronic pain in the general population of Western countries, the researchers estimated that a diagnosis of FD could be expected in approximately 1 in 19,000 individuals screened. On this basis, they noted that their study's outcome may not be reflected in the general population, underscoring the need for further research in broader chronic pain populations to validate these findings.
Conclusion
In conclusion, a systematic search for Fabry disease (FD) in 893 chronic pain patients identified only one case, suggesting FD prevalence is not higher in this population.
Routine screening for FD in chronic pain patients without other relevant symptoms or family history appears unwarranted.
However, pain specialists should remain aware of FD's key features, such as small fibre neuropathy-related pain (burning, tingling, prickling), to include FD in differential diagnoses. Early recognition can reduce diagnostic delays and enable timely access to specific treatments, which are particularly effective in alleviating pain, especially in women.
Importance of this study for South Africa
Fabry disease is a rare condition, with an incidence of approximately 1 in 40,000 in males and an estimated 1 in 20,000 in females.
However, experts agree that FD is likely under-recognised in South Africa, with misdiagnoses being common and limited awareness among both healthcare practitioners and the public.1
In patients with a family history and classic disease presentation, testing for FD is more likely to occur earlier, though this depends on the clinician's knowledge and awareness.
Pain, the most frequently reported symptom of FD, can be a key early indicator, and physicians should keep this in mind when presented with patients with chronic, unremitting pain, particularly female patients.
Access the original study
Angelini, C., Bar, C., Baudier, M. P. et al(2024). Prevalence of Fabry disease in patients with chronic pain: Lessons from the DOUFAB and DOUFABIS studies. European Journal of Pain, 29(1), e4708. https://doi.org/10.1002/ejp.4708
Additional References
1. Edu, E., Okesanya, O. J., & Lucero-Prisno, D. E. (2024). Burden of rare diseases in Africa: Recommendations for improving access to medications and healthcare. Journal of Medicine, Surgery, and Public Health, 2, 100032. https://doi.org/10.1016/j.glmedi.2023.100032
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