Heart failure in two male patients with late-onset Fabry mutation (IVS4 + 919G > A)

Abstract

Fabry disease is a metabolic disorder that can affect multiple organ systems, with the heart being one of the most commonly affected organs, particularly in late-onset cases. The prevalence of Fabry disease may be as high as 10% in patients with unexplained myocardial hypertrophy. Diagnosis relies on specific screening tests and genetic testing; however, misdiagnosis rates are high, leading to many patients being identified only after significant cardiac impairment has occurred. Enzyme replacement therapy and other drug treatments have limited effectiveness for these patients, making heart transplantation a potential option.

In the first case, a 62-year-old male with worsening chest distress was admitted to our hospital in 2021. He had underwent electrocardiography and echocardiography as part of a physical examination 20 years ago, which revealed hypertrophic non-obstructive cardiomyopathy without any symptoms. However, no further comprehensive screening was conducted at that time. Six years ago, he presented with chest tightness and shortness of breath following a shower and subsequently underwent coronary angiography in an external hospital, which did not reveal any significant abnormalities. Electrocardiography showed marked changes in the ST segment and T-wave (Figure 1A). Coronary artery angiography demonstrated non-obstructive coronary arteries. Cardiac magnetic resonance (CMR) in 2015 indicated diffused cardiac hypertrophy and late gadolinium enhancement (LGE) in the interventricular septum and under the epicardium of the cardiac apex and lateral wall of left ventricle (Figure 1B). Subsequently, his exercise tolerance decreased, and his heart function was assessed as New York Heart Association (NYHA) class II. Half a year ago, he started experiencing progressively worsening episodes of chest tightness and shortness of breath. A re-examined CMR showed significant enlargement of the left ventricle but less myocardial hypertrophy compared with previous result (Figure 1C). Dynamic electrocardiogram findings were indicative of paroxysmal ventricular tachycardia, leading to implantable cardioverter defibrillator implantation, and heart transplantation was recommended.

Physical examination, laboratory tests and imaging examination in our hospital altogether supported the diagnosis of heart failure with reduced ejection fraction (EF), with an estimated EF of 30%, left heart dilation, asymmetric myocardium hypertrophy (Figure 1D), premature ventricular contractions (Figure 1A), increased level of troponin I (TnI) and B-type natriuretic peptide (BNP) and normal renal function (Table 1). Gene panel sequencing indicated a pathogenic mutation IVS4 + 919 G > A in the alpha-galactosidase A (GLA) gene (Table 1), suggesting a diagnosis of Fabry disease. Serum alpha-galactosidase A activity (α-Gal A) was 0.79 μmol/L/h (reference interval: 2.40–17.65 μmol/L/h), and globotriaosylsphingosine (lyso-GL-3) level was 8.37 ng/mL (reference interval: <1.11 ng/mL) detected via dried blood spot (DBS), indicating the α-Gal deficiency and GL-3 accumulation. No extracardiac manifestations of Fabry disease were detected. Following an assessment of the patient's cardiopulmonary performance through a comprehensive exercise test, it was determined that the peak oxygen uptake (peak VO2) fell below 10 mL kg⁻¹ min⁻¹, meeting the criteria for heart transplantation. Consequently, a cardiac transplant procedure was conducted. Myocardial pathology showed glycosphingolipid deposition in interventricular septum, consistent with the location of LGE showed in CMR (Figure 2A). Haematoxylin eosin staining showed a reduced amount and disorganized arrangement of cardiomyocytes, accompanied by increased collagen and adipose tissue (Figure 2B). In addition, Toluidine blue staining showed a large amount of blue granules in cardiomyocytes, indicating accumulation of globotriaosylceramide (GL-3) (Figure 2C). Typical histological feature of osmiophilic myeloid bodies between myofibrils was observed under transmission electron microscopy (TEM), indicating glycolipid storage in lysosomes (Figure 2D). After heart transplantation, his symptoms were completely alleviated, and postoperative echocardiography showed normal EF, ventricular wall thickness and cardiac chamber dimension. Mycophenolate mofetil (MMF) combined with tacrolimus (FK506) were used to prevent anti-transplant rejection and echocardiography was conducted regularly. Three months after heart transplantation, mild hypertrophy of interventricular septum was discovered, and agalsidase beta was added for enzyme replacement therapy (ERT). During subsequent follow-up, the patient's left ventricular wall thickness returned to normal and has remained within the physiological range ever since.

In the second case, a 60-year-old male diagnosed with left ventricular hypertrophy (LVH) for 30 years was admitted to our hospital in 2023. An echocardiogram in 2018 revealed an EF of 68% with a ventricular septal thickness measuring 12.7 mm, and in 2017, an EF of 58% with an advanced ventricular septal thickness of 15.7 mm. Despite receiving cardiac resynchronization therapy for left bundle branch block and reduced EF, his cardiac function has gradually deteriorated over the past 5 years. Since 2019, the patient has exhibited pronounced left ventricular dilation and thinning of the left ventricular wall, with a left ventricular end-diastolic diameter of 60 mm and an interventricular septal thickness of 11 mm detected by echocardiogram. He was diagnosed with Fabry disease with decreased serum α-Gal A activity and the IVS4 + 919 G > A mutation of GLA gene in 2022. Echocardiogram and laboratory tests demonstrated significant enlargement of left heart and impairment of ventricular systolic and diastolic function, with a left ventricular end-diastolic diameter of 62 mm, an EF of 35%, and N-terminal-proBNP > 9000 pg/mL (Table 1). No non-sustained ventricular tachycardia was documented, and no extracardiac manifestations of Fabry disease were detected. Due to uncontrolled heart failure and intolerance towards cardiopulmonary exercise test, he underwent heart transplantation in our hospital, and pathological examination of myocardium, aorta and cardiac valves was performed. Evident myocardial tissue loss and the formation of scar were observed in the middle layer of left ventricular wall and interventricular septum, with myelin figures were seen under TEM, consistent with the first case (Figure 3A,C). In addition, the same pathological alterations of frothy cardiomyocytes, increased interstitial components including fibrous and adipose tissues, and infiltration of lymphocytes were shown (Figure 3B). Myeloid bodies were also seen in the smooth muscle cells of the aorta except for cardiomyocytes (Figure 3D). However, no myeloid bodies was observed in valve-derived tissues (Figure 3E,F). However, 15 days after cardiac transplantation, the patient died due to acute graft rejection.

Fabry disease is an X-linked inherited lysosomal storage disorder caused by deficiency of α-galactosidase A activity and characterized by accumulation of GL-3 in affected tissues including kidney, heart, skin, neural tissue, gastrointestinal tract, ophthalmic tissue and so on.¹ Cardiac involvement is the primary cause of impaired quality of life and mortality in patients with Fabry disease.² It is an under-identified cause of heart failure with preserved EF and ventricular arrhythmias in men and women over 30 and 40 years old, respectively.³ Approximately 0.5%–1% of patients older than 35–40 years old with idiopathic LVH or hypertrophic cardiomyopathy (HCM) are eventually diagnosed with Fabry disease.^{4, 5} In patients with cardiac variant Fabry disease, differential diagnosis from other HCMs is more challenging in the absence of systemic manifestations, because all patterns of LVH have been reported in Fabry disease.⁶ The utilization of CMR is indispensable for the initial diagnosis, and continuous monitoring of cardiomyopathy associated with Fabry disease and typical findings include concentric LVH, disproportionate hypertrophy of papillary muscles and A basal inferolateral pattern of LGE.⁷ A large longitudinal study reported severe heart failure (NYHA class ≥ 3) in 10% of patients.⁸ Heart failure is related to age and disease progression. In the terminal stage of Fabry cardiomyopathy, the myocardium undergoes fibrosis, the heart enlarges, and the ejection fraction decreases.⁹

More than 1000 GLA variants have been identified² and are categorized as pathogenic, benign without clinical relevance, or of unclear significance.¹⁰ Genetic variants associated with the cardiac variant include p.N215S (prevalent in North America and Europe), p.F113L (prevalent in Portugal) and IVS4 + 919G > A (prevalent in Chinese Taiwan).⁶ Up to 86% of newborns with Fabry disease in Chinese Taiwan were confirmed at least carriers of IVS4 + 919G > A.¹¹ Patients with IVS4 + 919G > A were mainly the late onset phenotype and manifest as progressive impairment of cardiac function,^{12, 13} with the prevalence of LVH 2%–3% under the age of 40 and significant elevation to about 32% and 67% in female and male patients respectively above 40 years old.¹²

The pharmacological treatment of Fabry disease includes disease-specific therapies, among which enzyme replacement therapy (ERT) is longest-used in clinical practice, and therapies to alleviate cardiovascular symptoms and prevent major adverse cardiovascular events. Recombinant α-Gal A for ERT is administered intravenously every 2 weeks to male patients or symptomatic female patients with an established Fabry disease diagnosis. Regression of LV mass and wall thickness has been reported in patients with both classic and cardiac phenotypes, although evidence for late-onset cardiac involvement phenotypes is limited.¹

Heart transplantation is often considered as the ultimate therapeutic option for patients with refractory end-stage cardiomyopathy, unresponsive to pharmacological and device interventions. Dilated cardiomyopathy (DCM) is a prevalent indication for heart transplantation, accounting for 40%–50% of all heart transplants.¹⁴ The post-transplantation survival rates are relatively favourable, with an approximate 85%–90% 1-year survival rate, a 70%–75% 5-year survival rate, and a 50%–60% 10-year survival rate.¹⁵ Mild left ventricular hypertrophy was observed 3 months after cardiac transplantation. The primary concern lies in early transplant rejection. However, the possibility of a recurrence of cardiac damage similar to that observed in Fabry disease cannot be disregarded, as indicated by previous report.¹⁶ Therefore, ERT utilizing agalsidase beta was initiated. Although heart transplantation is less frequently indicated for hypertrophic cardiomyopathy (HCM), it may be necessary for patients with refractory heart failure unresponsive to other surgical interventions. The prognosis for HCM patients after transplantation is comparable with that of DCM patients, although there might be a slightly higher incidence of postoperative complications such as transplant vasculopathy.¹⁷ Thus, heart transplantation is a viable option for end-stage Fabry cardiomyopathy. Previous literature has reported that four patients with Fabry disease underwent heart transplantation.¹⁸ Among them, three individuals underwent a 1-year follow-up, and their ventricular structure and cardiac function were normal upon completion of the follow-up period. Although one patient exhibited sustained normal cardiac function after 14 years, long-term follow-up is required to determine clinical outcomes.

In conclusion, we report two cases of Fabry disease patients with the IVS4 + 919 G > A mutation of the GLA gene undergoing heart transplantation due to advanced heart failure. The first patient exhibited transient myocardial hypertrophy, and the second patient succumbed to a severe rejection reaction following heart transplantation. In both cases, the dynamic changes in ventricular wall structure were evident throughout the progression of heart function impairment, with scar-like alterations within the middle layer of the left ventricular wall in dissected specimens. Ultrastructural examination revealed characteristic myeloid bodies associated with Fabry disease.

The authors declare no conflict of interest.