Clinical characteristics of female patients with Fabry disease and their correlation with biomarkers_West China Medical Journal

Authors：

DENG Xi ^1,2 , MI Fang ² , GAO Yinhua ² , ZHANG Yajuan ² , JIAN Lijun ² , MO Bangzhu ³ , TANG Yan ⁴ , WANG Junming ⁵ , WANG Zhaohui ⁶ , LU Yu ⁷ , YE Yuanxin ⁸ ,  ZHANG Ling ¹

1. Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Nephrology, West China Hospital Sichuan University Jintang Hospital / Jintang First People’s Hospital, Chengdu, Sichuan 610400, P. R. China;
3. Department of Laboratory Medicine, West China Hospital Sichuan University Jintang Hospital / Jintang First People’s Hospital, Chengdu, Sichuan 610400, P. R. China;
4. Department of Ultrasound Medicine, West China Hospital Sichuan University Jintang Hospital / Jintang First People’s Hospital, Chengdu, Sichuan 610400, P. R. China;
5. Department of Urology, West China Hospital Sichuan University Jintang Hospital / Jintang First People’s Hospital, Chengdu, Sichuan 610400, P. R. China;
6. Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China;
7. Rare Disease Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
8. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

ZHANG Ling, Email: zhangling_crrt@163.com

Keywords：

Fabry disease; female patients; clinical phenotype; genotype; biomarker

DOI：

10.7507/1002-0179.202605240

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Objective To analyze the clinical phenotypic characteristics and plasma biomarker levels in female patients with Fabry disease (FD), and to explore their correlation with disease severity. Methods Clinical data were cross-sectionally collected between March and December 2024 from female FD patients who had previously been diagnosed across China. GLA gene mutations, α-galactosidase A (α-Gal A) activity, and plasma globotriaosylsphingosine (Lyso-GL-3) levels were measured. Disease severity was assessed using the Mainz Severity Score Index (MSSI). Spearman partial correlation analysis (controlling for age) was performed to evaluate correlations. Results A total of 21 female patients with FD from six pedigrees were enrolled. The disease severity of female FD patients varied considerably, with MSSI scores ranging from 2 to 31 [median (lower quartile, upper quartile): 11 (7, 24)]. Even within the same pedigree, organ involvement such as hearing loss and proteinuria was observed to occur earlier in some younger female patients than in their older female patients. Regarding biomarkers,13 patients (61.9%) had normal α-Gal A activity. All the 21 female patients had elevated Lyso-GL-3 levels (median: 15.24 nmol/L). After controlling for age, Lyso-GL-3 was positively correlated with MSSI score (r_s=0.679, P=0.001) and left ventricular mass index (r_s=0.486, P=0.030), and negatively correlated with α-Gal A activity (r_s=?0.530, P=0.016). Estimated glomerular filtration rate showed no statistically significant correlation with any of the above parameters (P>0.05). Conclusions The disease severity of female patients with FD varies substantially. Significant phenotypic heterogeneity can also be observed among female heterozygotes with FD within the same pedigree. Plasma Lyso-GL-3 level is cross-sectionally correlated with disease severity and cardiac involvement, but its prognostic value requires validation in prospective studies.

Citation： DENG Xi, MI Fang, GAO Yinhua, ZHANG Yajuan, JIAN Lijun, MO Bangzhu, TANG Yan, WANG Junming, WANG Zhaohui, LU Yu, YE Yuanxin, ZHANG Ling. Clinical characteristics of female patients with Fabry disease and their correlation with biomarkers. West China Medical Journal, 2026, 41(7): 1107-1113. doi: 10.7507/1002-0179.202605240 Copy

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2.	Dobyns WB. The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked[J]. Acta Paediatr Suppl, 2006, 95(451): 11-15.
3.	Sens F, Guittard L, Knebelmann B, et al. Prevalence of Fabry disease in patients on dialysis in France[J]. Int J Mol Sci, 2024, 25(18): 10104.
4.	Simonetta I, Tuttolomondo A, Daidone M, et al. Treatment of Anderson-Fabry disease[J]. Curr Pharm Des, 2020, 26(40): 5089-5099.
5.	Whybra C, Kampmann C, Krummenauer F, et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy[J]. Clin Genet, 2004, 65(4): 299-307.
6.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-423.
7.	王秋菊, 沈亦平, 鄔玲仟, 等. 遺傳變異分類標準與指南[J]. 中國科學: 生命科學, 2017, 47(6): 668-688.
8.	Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[J]. J Am Soc Echocardiogr, 2015, 28(1): 1-39.e14.
9.	Inker LA, Eneanya NM, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race[J]. N Engl J Med, 2021, 385(19): 1737-1749.
10.	Lenders M, Hennermann JB, Kurschat C, et al. Multicenter female Fabry study (MFFS) - clinical survey on current treatment of females with Fabry disease[J]. Orphanet J Rare Dis, 2016, 11(1): 88.
11.	Beck M, Ramaswami U, Hernberg-St?hl E, et al. Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry[J]. Orphanet J Rare Dis, 2022, 17(1): 238.
12.	Barba-Romero Má, Pintos-Morell G. Gender differences in the application of Spanish criteria for initiation of enzyme replacement therapy for Fabry disease in the Fabry Outcome Survey[J]. Int J Mol Sci, 2016, 17(12): 1965.
13.	Sánchez R, Ripoll-Vera T, López-Mendoza M, et al. The Spanish Fabry women study: a retrospective observational study describing the phenotype of females with GLA variants[J]. Orphanet J Rare Dis, 2023, 18(1): 8.
14.	鄧曦, 陳曉玲, 米芳, 等. 家族性法布雷病三例[J]. 華西醫學, 2022, 37(7): 1118-1120.
15.	Duineveld MD, Kers J, Vleming LJ. Case report of progressive renal dysfunction as a consequence of amiodarone-induced phospholipidosis[J]. Eur Heart J Case Rep, 2023, 7(9): ytad457.
16.	Menke AF, Heitplatz B, Van Marck V, et al. Hydroxychloroquine-induced renal phospholipidosis: case report and review of differential diagnoses[J]. Case Rep Nephrol Dial, 2024, 14(1): 20-29.
17.	Anker P, Fés?s L, Kiss N, et al. A cross-sectional study of the dermatological manifestations of patients with Fabry disease and the assessment of angiokeratomas with multimodal imaging[J]. Diagnostics (Basel), 2023, 13(14): 2368.
18.	Zhao F, Yuan S, Kaittanis C, et al. Volumetric MRI of dorsal root ganglia as a biomarker for disease progression and response to AAV treatment in a mouse model of Fabry disease[J]. PLoS One, 2025, 20(10): e0334840.
19.	Rajan JN, Ireland K, Johnson R, et al. Review of mechanisms, pharmacological management, psychosocial implications, and holistic treatment of pain in Fabry disease[J]. J Clin Med, 2021, 10(18): 4168.
20.	Burand AJ, Stucky CL. Fabry disease pain: patient and preclinical parallels[J]. Pain, 2021, 162(5): 1305-1321.
21.	Caputo F, Lungaro L, Galdi A, et al. Gastrointestinal involvement in Anderson-Fabry disease: a narrative review[J]. Int J Environ Res Public Health, 2021, 18(6): 3320.
22.	Gragnaniello V, Cazzorla C, Gueraldi D, et al. The hidden burden: gastrointestinal involvement in lysosomal storage disorders[J]. Metabolites, 2025, 15(6): 361.
23.	Ouyang Y, Chen B, Pan X, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease[J]. Exp Ther Med, 2018, 15(4): 3733-3342.
24.	Brand E, Linhart A, Deegan P, et al. Clinical management of female patients with Fabry disease based on expert consensus[J]. Orphanet J Rare Dis, 2025, 20(1): 7.
25.	Beir?o I, Cabrita A, Torres M, et al. Biomarkers and imaging findings of Anderson-Fabry disease–what we know now[J]. Diseases, 2017, 5(2): 15.
26.	Duro G, Anania M, Zizzo C, et al. Diagnosis of Fabry disease using alpha-galactosidase A activity or lysoGb3 in blood fails to identify up to two thirds of female patients[J]. Int J Mol Sci, 2024, 25(10): 5158.
27.	Hossain MA, Yanagisawa H, Miyajima T, et al. Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene[J]. Mol Genet Metab Rep, 2019, 20: 100497.
28.	Tuttolomondo A, Chimenti C, Cianci V, et al. Females with Fabry disease: an expert opinion on diagnosis, clinical management, current challenges and unmet needs[J]. Front Cardiovasc Med, 2025, 12: 1536114.
29.	Najafian B, Svarstad E, Bostad L, et al. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease[J]. Kidney Int, 2010, 79(6): 663-670.
30.	Di Risi T, Vinciguerra R, Cuomo M, et al. DNA methylation impact on Fabry disease[J]. Clin Epigenetics, 2021, 13(1): 24.
31.	?eboun M, Sikora J, Magner M, et al. Pitfalls of X-chromosome inactivation testing in females with Fabry disease[J]. Am J Med Genet A, 2022, 188(7): 1979-1989.
32.	Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease[J]. Clin Genet, 2016, 89(1): 44-54.

1. 中國法布雷病專家協作組. 中國法布雷病診療專家共識(2021 年版)[J]. 中華內科雜志, 2021, 60(4): 321-330.
2. Dobyns WB. The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked[J]. Acta Paediatr Suppl, 2006, 95(451): 11-15.
3. Sens F, Guittard L, Knebelmann B, et al. Prevalence of Fabry disease in patients on dialysis in France[J]. Int J Mol Sci, 2024, 25(18): 10104.
4. Simonetta I, Tuttolomondo A, Daidone M, et al. Treatment of Anderson-Fabry disease[J]. Curr Pharm Des, 2020, 26(40): 5089-5099.
5. Whybra C, Kampmann C, Krummenauer F, et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy[J]. Clin Genet, 2004, 65(4): 299-307.
6. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-423.
7. 王秋菊, 沈亦平, 鄔玲仟, 等. 遺傳變異分類標準與指南[J]. 中國科學: 生命科學, 2017, 47(6): 668-688.
8. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[J]. J Am Soc Echocardiogr, 2015, 28(1): 1-39.e14.
9. Inker LA, Eneanya NM, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race[J]. N Engl J Med, 2021, 385(19): 1737-1749.
10. Lenders M, Hennermann JB, Kurschat C, et al. Multicenter female Fabry study (MFFS) - clinical survey on current treatment of females with Fabry disease[J]. Orphanet J Rare Dis, 2016, 11(1): 88.
11. Beck M, Ramaswami U, Hernberg-St?hl E, et al. Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry[J]. Orphanet J Rare Dis, 2022, 17(1): 238.
12. Barba-Romero Má, Pintos-Morell G. Gender differences in the application of Spanish criteria for initiation of enzyme replacement therapy for Fabry disease in the Fabry Outcome Survey[J]. Int J Mol Sci, 2016, 17(12): 1965.
13. Sánchez R, Ripoll-Vera T, López-Mendoza M, et al. The Spanish Fabry women study: a retrospective observational study describing the phenotype of females with GLA variants[J]. Orphanet J Rare Dis, 2023, 18(1): 8.
14. 鄧曦, 陳曉玲, 米芳, 等. 家族性法布雷病三例[J]. 華西醫學, 2022, 37(7): 1118-1120.
15. Duineveld MD, Kers J, Vleming LJ. Case report of progressive renal dysfunction as a consequence of amiodarone-induced phospholipidosis[J]. Eur Heart J Case Rep, 2023, 7(9): ytad457.
16. Menke AF, Heitplatz B, Van Marck V, et al. Hydroxychloroquine-induced renal phospholipidosis: case report and review of differential diagnoses[J]. Case Rep Nephrol Dial, 2024, 14(1): 20-29.
17. Anker P, Fés?s L, Kiss N, et al. A cross-sectional study of the dermatological manifestations of patients with Fabry disease and the assessment of angiokeratomas with multimodal imaging[J]. Diagnostics (Basel), 2023, 13(14): 2368.
18. Zhao F, Yuan S, Kaittanis C, et al. Volumetric MRI of dorsal root ganglia as a biomarker for disease progression and response to AAV treatment in a mouse model of Fabry disease[J]. PLoS One, 2025, 20(10): e0334840.
19. Rajan JN, Ireland K, Johnson R, et al. Review of mechanisms, pharmacological management, psychosocial implications, and holistic treatment of pain in Fabry disease[J]. J Clin Med, 2021, 10(18): 4168.
20. Burand AJ, Stucky CL. Fabry disease pain: patient and preclinical parallels[J]. Pain, 2021, 162(5): 1305-1321.
21. Caputo F, Lungaro L, Galdi A, et al. Gastrointestinal involvement in Anderson-Fabry disease: a narrative review[J]. Int J Environ Res Public Health, 2021, 18(6): 3320.
22. Gragnaniello V, Cazzorla C, Gueraldi D, et al. The hidden burden: gastrointestinal involvement in lysosomal storage disorders[J]. Metabolites, 2025, 15(6): 361.
23. Ouyang Y, Chen B, Pan X, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease[J]. Exp Ther Med, 2018, 15(4): 3733-3342.
24. Brand E, Linhart A, Deegan P, et al. Clinical management of female patients with Fabry disease based on expert consensus[J]. Orphanet J Rare Dis, 2025, 20(1): 7.
25. Beir?o I, Cabrita A, Torres M, et al. Biomarkers and imaging findings of Anderson-Fabry disease–what we know now[J]. Diseases, 2017, 5(2): 15.
26. Duro G, Anania M, Zizzo C, et al. Diagnosis of Fabry disease using alpha-galactosidase A activity or lysoGb3 in blood fails to identify up to two thirds of female patients[J]. Int J Mol Sci, 2024, 25(10): 5158.
27. Hossain MA, Yanagisawa H, Miyajima T, et al. Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene[J]. Mol Genet Metab Rep, 2019, 20: 100497.
28. Tuttolomondo A, Chimenti C, Cianci V, et al. Females with Fabry disease: an expert opinion on diagnosis, clinical management, current challenges and unmet needs[J]. Front Cardiovasc Med, 2025, 12: 1536114.
29. Najafian B, Svarstad E, Bostad L, et al. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease[J]. Kidney Int, 2010, 79(6): 663-670.
30. Di Risi T, Vinciguerra R, Cuomo M, et al. DNA methylation impact on Fabry disease[J]. Clin Epigenetics, 2021, 13(1): 24.
31. ?eboun M, Sikora J, Magner M, et al. Pitfalls of X-chromosome inactivation testing in females with Fabry disease[J]. Am J Med Genet A, 2022, 188(7): 1979-1989.
32. Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease[J]. Clin Genet, 2016, 89(1): 44-54.

West China Medical Journal

Clinical characteristics of female patients with Fabry disease and their correlation with biomarkers

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