Logo American Journal of Case Reports

Call: 1.631.629.4328
Mon-Fri 10 am - 2 pm EST

Contact Us

Logo American Journal of Case Reports Logo American Journal of Case Reports Logo American Journal of Case Reports

17 March 2025: Articles  Poland

Enzyme Replacement and Immunosuppression in Heart Transplant Recipients with Fabry Cardiomyopathy: A 7-Year Case Study

Challenging differential diagnosis, Unusual or unexpected effect of treatment, Rare disease

Katarzyna Muras-Szwedziak ORCID logo1ABCDEF, Maciej Wójcik ORCID logo2ABCDEF, Olga Wojtyczka ORCID logo2ABCDEF*, Krzysztof Kaczmarek ORCID logo3ABCDEF

DOI: 10.12659/AJCR.945873

Am J Case Rep 2025; 26:e945873

0 Comments

Abstract

0:00

BACKGROUND: Fabry disease (FD) is a rare storage disorder caused by the absence or deficiency of alpha-galactosidase A, which leads to accumulation of glycosphingolipids in tissues, chronic inflammation, fibrosis, and multiple-organ dysfunction. There are only a few cases of orthotopic heart transplantation (OHT) in patients with FD in the literature. This report shows the manifestation of FD, its course in OHT recipient and outcome of 4-year enzyme replacement therapy (ERT) combined with post-transplant immunosuppression.

CASE REPORT: A 54-year-old female patient had cardiomegaly revealed by a chest X-ray. Subsequent diagnostics included transthoracic echocardiography (TTE), which showed left ventricular hypertrophy. Despite typical therapeutic management, she had progression of heart failure (HF) symptoms. After 6 years, cardiac magnetic resonance imaging (MRI) showed myocardial fibrosis. This finding and TTE analysis led to suspicion of storage disease with cardiac involvement. Further biochemical and genetic diagnostics showed low activity of alpha-galactosidase A and detected mutations of the GLA gene. Five years after the first cardiac symptoms, Fabry cardiomyopathy was diagnosed. Due to HF progression, she underwent OHT with subsequent standard immunosuppressive treatment. As soon as ERT was available in Poland, it was included to the treatment. Currently, there is no evidence of cardiac involvement of FD or graft rejection.

CONCLUSIONS: Severe HF not responding to medical therapy in patients with FD can be successfully treated with cardiac transplantation. The risk of disease recurrence in the graft appears to be low. The anti-inflammatory action of post-transplant immunosuppression may play a role in that phenomenon, but further research is needed to confirm this hypothesis.

Keywords: enzyme replacement therapy, Immunosuppression Therapy, inflammation, Lysosomal Storage Diseases, Rare Diseases, Transplantation

Introduction

Fabry disease (FD) is a rare genetic storage disorder leading to the abnormal accumulation of glycosphingolipids in numerous organs [1]. It results from mutations in the X-linked GLA gene, causing a deficiency or absence of alpha-galactosidase A (α-Gal A) [1]. The clinical presentation of FD can vary between patients. There are 2 main types of FD [2]. The early-onset type, also referred to as “classic”, involves many organs, while the late-onset type affects only 1 organ, usually the heart, kidneys, or central or peripheral nervous systems [3]. Thus, common symptoms of the disease include burning pain in the extremities, hearing loss, gastrointestinal manifestations, anhidrosis or hypohidrosis, angiokeratoma, renal and cardiac failure [4], and severe neurological complications such as ischemic stroke [5,6].

Usually, male patients are more likely to present cardiovascular symptoms of the disease at a younger age compared to females [7]. However, women can present with a wide range of symptoms, from single-organ involvement to an almost “classic” type of the disease [5,6]. Differences in severity and organ involvement between male and female patients are mainly caused by inactivation of the GLA wild allele on the X chromosome, as there is a correlation between the level of inactivation and disease severity [8–12].

Characteristic features of Fabry cardiomyopathy may be observed even in the most common of cardiologic diagnostic tests. For instance, while performing an ECG, we may observe a short P wave resulting in the shortening of the PQ interval, as well as QT and QRS prolongation, atrioventricular and bundle branch blocks, bradycardia, atrial fibrillation, and signs of left ventricular hypertrophy (LVH) [13]. Echocardiography may reveal features of LVH, various disorders in the posterior basal wall (hyperdensity, thinning, akinesia), abnormal contraction of segments affected by fibrosis, normal systolic function combined with diastolic dysfunction, and disorders and thickening of the aortic and mitral valves [14]. Features of FD in cardiac MRI are similar to those present in echocardiography. Additionally, late gadolinium enhancement of the mid-myocardial layer of fibrosis-affected segments and a decrease in T1 of non-affected segments may be visible [14,15].

The aim of this case study is to present the long medical history of a female patient with FD who underwent a heart transplant due to the progression of Fabry cardiomyopathy and thereafter had a favorable course of the disease on ERT and immunosuppressive therapy.

To the best of our knowledge, there are very few documented cases of heart transplantation in patients with FD worldwide, with only 1 presenting a woman (Table 1).

Case Report

The chest X-ray of a 38-year-old woman, conducted as part of a routine check due to shortness of breath, uncovered an enlarged cardiac silhouette. Further diagnostics included transthoracic echocardiography (TTE), which showed concentric left ventricular hypertrophy (LVH) with a maximum diastolic intraventricular septum thickness of 13 mm and posterior wall thickness of 12 mm. Electrocardiography (ECG) disclosed a normal sinuous rhythm at 72 bpm with features of left ventricular hypertrophy. A treadmill exercise test, 24-hour Holter monitoring (24hHM), and dobutamine stress echocardiography, performed due to chest pain at rest, did not reveal additional abnormalities. Eventually, hypertrophic cardiomyopathy was diagnosed and typical therapy with beta-blockers was initiated.

TTE performed during a routine cardiac evaluation after 6 years suggested a storage disorder as the underlying cause of LVH. ECG revealed bradycardia and deep inverted T waves in V4-V6 leads, and 24-hour Holter monitoring revealed episodes of nonsustained ventricular tachycardia. Therefore, diagnostics were extended with cardiac magnetic resonance imaging (cMRI). T1 mapping confirmed LVH and revealed subendocardial late gadolinium enhancement in inferolateral segments of LV (Figure 1). A high level of lyso-Gb3 (Figure 2) and positive genetic testing confirmed the diagnosis of FD. Heterozygous mis-sense mutations (c.138C>F [p.His46Gln], c.153G>T [p.Met51Ile], c.167G>T [p.Cys56Phe]) were identified.

The patient was the first one diagnosed with FD in her family. Further genetic screening revealed that her mother, brother, 2 sisters, son, and niece also had FD.

At the time of diagnosis, enzyme replacement therapy (ERT) was not available in Poland, so the patient received standard conservative treatment with beta-blockers and was scheduled for regular check-up visits. Despite the therapy, over the following 2 years the heart failure symptoms aggravated to the point of resting dyspnea, and the patient was placed on the waiting list for a cardiac transplant. Orthotopic heart transplantation (OHT) was performed in June 2016. During the early postoperative period, there were no signs of cardiac complications or transplant rejection. Nevertheless, there was a temporary, moderate deterioration in renal function (creatinine 78.0 μmol/L a year before OHT vs 146 μmol/L 3 months after OHT), most probably related to transient ischemia during the surgery and the high doses of immunosuppressive agents administered afterwards. Renal parameters normalized and remained within nearly normal ranges (from 92.5 μmol/L to 107.3 μmol/L 6 years after OHT). Additionally, an ultrasonography performed soon after OHT disclosed a thrombus in the right internal jugular vein, without any severe clinical implications or further consequences. Further recovery after OHT went uneventfully, and improvement in clinical symptoms and biochemical parameters (NT-proBNP, hsTnT, CK-MB mass) was observed (Figure 2). Until late 2019, when ERT became reimbursable in Poland, the patient was treated solely according to standard post-transplant care.

In early 2020, as the patient’s mutations were non-amenable to treatment with chaperone therapy, she was included in the ERT qualification process. A detailed medical examination focused on FD symptoms revealed acroparaesthesia, anhidrosis, and angiokeratomas. All of these symptoms had been present since childhood but were never previously associated with FD. A brain MRI, required for the ERT program, revealed multiple lesions in the white matter and pons, as well as post-ischemic cavities in the right lenticular nucleus, right internal capsule (15×15×6 mm), and the left side of the thalamus (12×13×4 mm). Similar abnormalities are often seen in patients with lysosomal storage disorders. However, prior to the OHT, no brain MRI or CT was performed.

Finally, she received approval for ERT with the standard agalsidase-beta dose of 1 mg/kg. The first administration of this drug took place in June 2020. This infusion lasted 3.5 hours, and no adverse effects were observed. Therefore, the duration of following infusions was shortened to 1 hour 45 minutes. Until now, the patient has received over 100 doses of ERT, and the therapy has been ongoing for over 50 months. No adverse effects of ERT have been noticed. Throughout ERT administration, regular clinical and laboratory assessments have been performed every 6 months. Additionally, the patient remains under the care of a heart transplant center. Deferred analysis of the endomyocardial biopsy performed 5 years after the heart transplant did not reveal any accumulation of glycosphingolipids (Figure 3). Regular echocardiographic check-ups showed no abnormalities, with a left ventricular ejection fraction of 66% and cardiac wall thickness within the normal range. Moreover, levels of high-sensitivity troponin and NT-proBNP have remained low since the OHT (Figure 2). Interestingly, since the beginning of ERT, a progressive reduction in lyso-Gb3 has been observed (Figure 2). Due to the limited availability of tests for anti-drug antibodies (ADA) against ERT, we have not evaluated the presence or levels of ADA. The course of therapy was complicated in June 2022 by CMV infection-related meningitis. Typical antiviral treatment with ganciclovir was successfully conducted. The immunosuppressive treatment was probably the underlying cause of this infection.

Despite ERT, the patient is currently treated with tacrolimus (1 mg twice a day), mycophenolate mofetil (500 mg twice a day), ramipril (2.5 mg), lacidipine (2 mg), atorvastatin (10 mg), acetylsalicylic acid (75 mg), and pantoprazole (40 mg). No interactions between ERT and the immunosuppressive drugs have been observed. The tacrolimus blood concentration remains stable.

Discussion

The presented case of this female patient is an example of late-onset FD with cardiac involvement. Despite treatment, the progression of Fabry cardiomyopathy in the patient was extremely unfavorable and quickly led to severe heart failure, which was managed with cardiac transplantation. The 6-year post-transplant follow-up, including ERT administration starting in 2022, has been successful.

Heart failure is diagnosed in about 20% of untreated females with FD and in about 15% of females with late-onset FD [21]. The literature contains only a few cases of heart transplantations in patients with FD, mostly reported in men. In all described cases, no signs of FD-related heart involvement were observed in the years following OHT, and most patients received ERT (Table 1). These reports are consistent with our observations. Our patient’s biochemical markers levels, cardiac functions assessments, and imaging tests did not reveal any abnormalities, which corresponded well with the patient’s good clinical status. However, heart involvement in FD typically takes years to develop, and the follow-up periods in the aforementioned case reports might have been too short. It is also important to consider that the heart donor was likely free of FD, so the graft’s cardiomyocytes may produce enough alpha-galactosidase to cause a protective effect, but this hypothesis requires further research.

The clinical course of patients with FD after heart transplantation may be influenced by 2 therapeutic components: ERT and post-transplant immunosuppression. ERT usually decelerates the progression of FD but rarely leads to a complete cessation of the disease [22]. However, post-transplant patients who received ERT presented noticeably better graft function compared to those who did not receive ERT [23]. Interestingly, a report described a patient with FD who received only immunosuppressive drugs (without ERT), and 4 years after the transplant, there was no evidence of cardiac involvement [20]. A similar situation was observed in our patient, who received immunosuppressive treatment without ERT for more than 3 years, and combined ERT and immunosuppressive therapy for more than 4 years. During this period, her cardiac biomarkers remained low. Moreover, a similar phenomenon was observed in patients who underwent renal transplants. In this population, individuals who received ERT and anti-rejection drugs rarely presented pathological renal changes related to FD [17,24–27]. It is important to note that the follow-up periods in the aforementioned reports might be insufficient. Nonetheless, observing such a phenomenon appears to be a promising area for further investigation regarding the role of immunosuppressive therapy in FD progression.

One study suggests that cardiac involvement in FD can be caused by autoimmune cardiomyositis [28]. The authors propose that the production of anti-heart and anti-myosin antibodies is triggered by the necrosis of lyso-Gb3-loaded myocytes. However, this study is limited by its small sample size, and further research is needed on this topic. Other studies suggest that lyso-Gb3 accumulation by itself, as well as the oxidative stress it causes, can trigger an inflammatory response [29]. These mechanisms could potentially be targets for immunosuppressive agents.

The reduction of ADA levels, the presence of which can diminish the effectiveness of ERT, may also be an important explanation for this observation [30]. Reports describe successful reduction of ADA levels in patients undergoing immunosuppressive therapy and in a mouse model of FD [31,32]. Although there are insufficient data to confirm that hypothesis, the administration of anti-rejection drugs administration may contribute to a reduction in ADA levels, leading to a better response to ERT.

This case report has significant limitations, primarily due to limited access to medical documentation and laboratory tests from the period when the patient was not under our team’s care. The cMRI images obtained before OHT were saved in limited sequences and low quality; therefore, we primarily relied on the radiological description. The histopathological samples were incomplete and of poor quality, which limited our analysis and the material available for illustration. Since anti-drug antibody testing is not available in our center’s laboratory, we were unable to monitor its levels during follow-up.

Conclusions

Severe heart failure not responding to medical therapy in patients with FD can be managed effectively with cardiac transplantation. Although the risk of disease recurrence in the transplanted organ appears to be relatively low, this observation requires further investigation with extended follow-up and a larger study sample. The anti-inflammatory effects of post-transplant immunosuppressive therapy could potentially contribute to this outcome, but additional research is needed.

References:

1.. Zarate YA, Hopkin RJ, Fabry’s disease: Lancet, 2008; 372(9647); 1427-35

2.. Germain DP, Levade T, Hachulla E, Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease: Clin Genet, 2022; 101(4); 390-402

3.. Cianci V, Pascarella A, Gasparini S: Metab Brain Dis, 2022; 37(8); 3023-26

4.. Rajan JN, Ireland K, Johnson R, Stepien KM, Review of mechanisms, pharmacological management, psychosocial implications, and holistic treatment of pain in Fabry disease: J Clin Med, 2021; 10(18); 4168

5.. Dinu IR, Firu ŞG, Fabry disease – current data and therapeutic approaches.: Rom J Morphol Embryol, 2021; 62(1); 5-11

6.. Michaud M, Mauhin W, Belmatoug N, When and how to diagnose Fabry disease in clinical pratice: Am J Med Sci, 2020; 360(6); 641-49

7.. Beck M, Ramaswami U, Hernberg-Ståhl E, Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry: Orphanet J Rare Dis, 2022; 17(1); 238

8.. Ortiz A, Germain DP, Desnick RJ, Fabry disease revisited: Management and treatment recommendations for adult patients: Molecular Genetics and Metabolism, 2018; 123(4); 416-27

9.. Echevarria L, Benistan K, Toussaint A, X-chromosome inactivation in female patients with Fabry disease: Clin Genet, 2016; 89(1); 44-54

10.. Hossain MA, Yanagisawa H, Miyajima T, The severe clinical phenotype for a heterozygous Fabry female patient correlates to the methylation of non-mutated allele associated with chromosome 10q26 deletion syndrome: Mol Genet Metab, 2017; 120(3); 173-79

11.. Hossain MA, Wu C, Yanagisawa H: Mol Genet Metab Rep., 2019; 20; 100497

12.. Yanagisawa H, Hossain MA, Miyajima T: Mol Genet Metab, 2019; 126(4); 460-65

13.. Averbuch T, White J, Fine N, Anderson-Fabry disease cardiomyopathy: An update on epidemiology, diagnostic approach, management and monitoring strategies: Front Cardiovasc Med, 2023; 10; 1152568

14.. Azevedo O, Cordeiro F, Gago MF, Fabry disease and the heart: A comprehensive review: Int J Mol Sci, 2021; 22; 4434

15.. Ditaranto R, Chiti C, Milandri A, Atypical subendocardial late gadolinium enhancement in Anderson-Fabry cardiomyopathy: Circ Cardiovasc Imaging, 2024; 12; e016865

16.. Verocai F, Clarke JT, Iwanochko RM, Case report: Long-term outcome post-heart transplantation in a woman with Fabry’s disease: J Inherit Metab Dis, 2010; 33(S3); 385-87

17.. Kyem G, Okorozo A, Hamdan H, Tuffaha AM, A case report of kidney after heart transplant in patient with Fabry disease: Transplant Proc, 2023; 55(8); 1975-77

18.. Rajagopalan N, Dennis DR, O’Connor W, Successful combined heart and kidney transplantation in patient with Fabry’s disease: A case report: Transplant Proc, 2019; 51(9); 3171-73

19.. Karras A, De Lentdecker P, Delahousse M, Combined heart and kidney transplantation in a patient with Fabry disease in the enzyme replacement therapy era: Am J Transplant, 2008; 8(6); 1345-48

20.. Tran Ba SN, Lidove O, Dorent R, [Combined heart and kidney transplantation in Fabry’s disease: Long-term outcomes in two patients.]: Rev Med Interne, 2017; 38(2); 137-42 [in French]

21.. Azevedo O, Cordeiro F, Gago MF, Fabry disease and the heart: A comprehensive review: Int J Mol Sci, 2021; 22(9); 4434

22.. Germain DP, Charrow J, Desnick RJ, Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease: J Med Genet, 2015; 52(5); 353-58

23.. Cybulla M, Walter KN, Schwarting A, Kidney transplantation in patients with Fabry disease: Transplant International, 2009; 22(4); 475-81

24.. Dziemianko I, Jezior D, Boratyńska M, Kidney transplantation and enzyme α-Galactosidase a therapy in patient with Fabry disease: A case report: Transplant Proc, 2007; 39(9); 2925-27

25.. Taneda S, Honda K, Nakajima I, Renal transplantation between siblings with unrecognized Fabry disease: Transplant Proc, 2013; 45(1); 115-18

26.. Kato T, Nishimura K, Ichikawa Y, Deceased renal transplantation in patient with Fabry’s disease maintained by enzyme replacement therapy: Int J Urol, 2009; 16(7); 650

27.. Ersözlü S, Desnick RJ, Huynh-Do U, Long-term outcomes of kidney transplantation in Fabry disease: Transplantation, 2018; 102(11); 1924-33

28.. Frustaci A, Verardo R, Grande C, Immune-mediated myocarditis in Fabry disease cardiomyopathy: J Am Heart Assoc, 2018; 7(17); e009052

29.. Pieroni M, Ciabatti M, Graziani F, The heart in Fabry disease: Mechanisms beyond storage and forthcoming therapies: Rev Cardiovasc Med, 2022; 23(6); 196

30.. Stappers F, Scharnetzki D, Schmitz B, Neutralising anti-drug antibodies in Fabry disease can inhibit endothelial enzyme uptake and activity: J Inherit Metab Dis, 2020; 43(2); 334-47

31.. Garman RD, Munroe K, Richards SM, Methotrexate reduces antibody responses to recombinant human alpha-galactosidase A therapy in a mouse model of Fabry disease: Clin Exp Immunol, 2004; 137(3); 496-502

32.. Lenders M, Oder D, Nowak A, Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease: J Intern Med, 2017; 282(3); 241-53

In Press

Case report  Poland

AMH and Kisspeptin Receptor Expression in Rare Hydropic Leiomyoma: A Case Study

Am J Case Rep In Press; DOI: 10.12659/AJCR.947953  

Case report  China

Fatal Acute Necrotizing Encephalopathy in a 17-Year-Old Girl with COVID-19: A Case Report

Am J Case Rep In Press; DOI: 10.12659/AJCR.946932  

Case report  Italy

Cardiac Tamponade and Pneumonitis as Indicators of Systemic Cobaltosis in Metal-on-Polyethylene Hip Implants

Am J Case Rep In Press; DOI: 10.12659/AJCR.947854  

Case report  USA

Psoas Quartus and Femoral Nerve Branching: A Case Report and Potential Clinical Implications

Am J Case Rep In Press; DOI: 10.12659/AJCR.945927  

Most Viewed Current Articles

21 Jun 2024 : Case report  China (mainland) 96,778

Intracranial Parasitic Fetus in a Living Infant: A Case Study with Surgical Intervention and Prognosis Anal...

DOI :10.12659/AJCR.944371

Am J Case Rep 2024; 25:e944371

0:00

07 Mar 2024 : Case report  USA 52,393

Neurocysticercosis Presenting as Migraine in the United States

DOI :10.12659/AJCR.943133

Am J Case Rep 2024; 25:e943133

0:00

20 Nov 2023 : Case report  Saudi Arabia 31,818

Azithromycin Treatment for Acne Vulgaris: A Case Report on the Risk of Clostridioides difficile Infection

DOI :10.12659/AJCR.941424

Am J Case Rep 2023; 24:e941424

0:00

18 Feb 2024 : Case report  Japan 23,483

A Case of Thoracic Empyema Caused by Actinomyces naeslundii

DOI :10.12659/AJCR.943030

Am J Case Rep 2024; 25:e943030

0:00

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923