Background & Aims

Fabry disease (FD) is an X-chromosomally linked lysosomal storage disorder. Variants in the ?- galactosidase A gene (GLA), which encodes the enzyme ?-galactosidase A, lead to an accumulation of glycosphingolipids in various cell types. Patients suffer from a multisystemic disease manifestation including cardiomyopathy, nephropathy, and neuropathy [1]. Quantitative sensory testing (QST) and skin punch biopsy show evidence for small nerve fiber affection in FD neuropathy [2]. Due to the small number of included patients and the short follow-up period in previous literature, the correlation between small fiber function and covariates such as genetics, disease severity, and treatment remains unclear. To address these questions, we investigated small fiber function of FD patients at baseline and long-term follow-up.

Methods

2005-2022, we recruited FD patients carrying a pathogenic GLA variant via our Fabry Center. All patients underwent neurological and internal medicine examinations and were assessed with QST at the right dorsal foot applying the standardized QST protocol of the German Research Network Neuropathic Pain. Data were compared with our healthy control group consisting of 225 subjects. Patients received a skin punch biopsy at the distal leg and at the back for skin innervation. Nephropathy was evaluated by the glomerular filtration rate (GFR) and the urine albumin:creatinine ratio. Patients were seen at baseline and data collection went on for a total of 16 years with a median of 2 annual follow-up investigations. QST data were analyzed with one-way ANOVA and results are given as mean z-score and ± standard error of the mean.

Results

The baseline cohort consisted of 136 men (median age 42.5, range 18-73 years) and 176 women (median age 47, range 18-77 years). Neurological examination was mostly normal (249/311 patients, 80%). QST z-scores results revealed elevated cold detection (?1.72 ± 1.42, p < 0.001) and temperature change thresholds (?1.13 ± 1.17, p < 0.001) in FD men at baseline. In contrast, women with FD had normal QST profiles at baseline. Furthermore, we categorized the baseline cohort into three groups using the Kidney Disease: Improving Global Outcomes albuminuria categories (<30 mg/d, 30-300 mg/d, and >300 mg/d). Men with severe albuminuria > 300 mg/d had higher cold detection thresholds (-2.36 ± 1.13, p < 0.001) than men with no to mild albuminuria < 30 mg/d (-1.23 ± 1.34). Moreover, a positive correlation between GFR and distal intraepidermal nerve fiber density (IENFD) was found in men with FD (Spearman’s ? = 0.427; p < 0.001).

Conclusions

The key results indicate that functional small fiber impairment in FD is influenced by gender and is associated with impaired kidney function. We invested the largest FD cohort so far and results at baseline revealed impaired temperature perception, mainly in male patients, especially those with an elevated albuminuria. This finding aligns with small fiber morphology, as distal IENFD was reduced in patients with lower GFR, also indicating reduced renal function. Statistical analysis of patient subgroups with ? 3 follow-ups is ongoing. Results will allow us to draw conclusions about the long-term trajectory of dysfunction of small fibers in FD patients. By considering important covariates such as genetic variants, disease severity and treatment, risk factors and regeneration scenarios or spared groups can be identified.

References

[1] Zarate YA, Hopkin RJ (2008). Fabry’s disease. Lancet 372:1427 – 1435

[2] El-Abassi R, Singhal D., England JD (2014). Fabry’s disease. Journal of the Neurological Sciences 344 (2014) 5–19

Presenting Author

Aljosha Lang

Poster Authors

Aljosha Lang

University of Würzburg

Lead Author

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Barbara Broll

Department of Neurology, University Hospital Würzburg, Würzburg, Germany

Lead Author

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Lau Kolja

Dr.

Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany

Lead Author

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Claudia Prof. Dr. Sommer

University Hospital Würzburg

Lead Author

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Wanner Christoph

Prof. Dr.

Department of Clinical Studies and Epidemiology, University Hospital Würzburg, Würzburg, Germany

Lead Author

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Malzahn Uwe

Dr.

Clinical Trial Center Würzburg, University Hospital Würzburg, Würzburg, Germany

Lead Author

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Nurcan Üçeyler

MD

Department of Neurology, University of Würzburg, Germany

Lead Author

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Topics

  • Specific Pain Conditions/Pain in Specific Populations: Burn Pain