ACRT Journal

Introduction

Fabry Disease (FD) is an X-linked lysosomal storage disorder with multiple organ involvement. A deficiency in the enzyme alphagalactosidase A (α-Gal A) results in intracellular accumulation of glycosphingolipids. Progressive fibrosis causes neurological dysfunction, myocardial hypertrophy, and heart and kidney failure. In the end, FD patients require dialysis and organ transplants. Preventing irreversible organ damage requires timely diagnosis and treatment. In addition to supportive care, migalastat (for patients with amenable gene mutations i.e., 35%-50% of patients) and enzyme replacement therapy (ERT) are currently available for FD [1]. FD is a rare disease with recent screening studies revealing higher frequencies than previously estimated. These studies, which focused on male newborns, found incidence rates ranging from 1:316 to 1:7575 [2,3]. In some geographical areas, the presence of founder mutations has further increased the local prevalence of FD. The S238N mutation previously described in isolated cases [4], was later found to be the most prevalent mutation in Spanish females with FD, constituting 31% of cases [5]. One study, conducted in Alicante’s Elda Health Department involving 42 patients with the S238N mutation, confirmed its high prevalence in the region [6]. S238N (NM_000169.3:c.713G>A; p.Ser238Asn; GRCh38) is a missense mutation in exon 5 of the GLA gene that substitutes Serine for Asparagine at position 238 of α-Gal A [4]. FD caused by the S238N mutation has been described as a later onset variant affecting the heart and kidneys [4,6].

Fabry patients with this specific mutation are prevalent in Spain, particularly Alicante. Considering the non-standardized nature of follow-up of this disease, as well as the lack of real-world data relating to switching from ERT to migalastat [7,8], a more extensive analysis of this population may be necessary. Therefore, in this study we describe the results of the multidisciplinary evaluation in seven FD patients who share the same mutation and their outcomes after switching to migalastat.

Materials and Methods

This is a descriptive case series of seven male patients with FD from the Hospital General Universitario Dr. Balmis de Alicante (Alicante, Spain), aged ≥18 years and carrying the S238N mutation. The patients had all been treated with ERT (agalsidase alfa) for at least 18 months and subsequently with migalastat for at least two years. We evaluated the outcomes of switching from ERT to migalastat at baseline and at 6, 12 and 24 months after starting migalastat. Information was collected from patients’ medical charts, including demographics, personal medical histories, comprehensive organ-specific investigations, and laboratory and instrumental exams to assess the organ involvement in FD patients.

As part of clinical practice in our hospital, the following methodology was used: α-Gal A enzyme activity and plasma levels of Lyso-Gb3 were measured in dried blood spots; until 2018, renal function was measured by changes in urine albumin-creatinine ratio, and by eGFR quantified by the Modification of Diet in Renal Disease-4 [MDRD4] equation [9], and then by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula [10]); a combination of echocardiography (thickness of cardiac structures, left ventricular volume, measures of systolic and diastolic function, heart rate) and electrocardiography, as well as plasma troponin T and pro–brain natriuretic peptide (NT-proBNP) concentration were used to assess cardiac changes.

Results

The characteristics of patients are described in Table 1. Seven men, three of whom were unrelated, plus two sets of brothers, all from five unrelated families, were assessed with a mean (range) of follow-up (pre- and post-switch) of 9.2 (4.3-14.9) years. Four patients switched to migalastat due to progression or lack of cardiologic response, two due to the patient’s own choice, and one due to poor venous access. Clinical and biochemical findings at ERT and migalastat start are described in (Table 2). All patients, except one who did not have the measurement at migalastat start, had decreased α-Gal A activity in white blood cells with levels below 80% of the reference value (≥15.3 μmol/L/h), with three patients with almost no residual activity (patients 2, 3 and 6), and increased plasma Lyso-Gb3 levels, reference value: ≤1.8 ng/ mL). The eGFR prior to the commencement of migalastat was normal (>90 mL/min/1.73 m2) in five patients, and there were two patients with baseline CKD stages 2 (60-89 mL/min/1.73 m2) and 3 (30-59 mL/min/1.73 m2). Six out of seven patients registered microalbuminuria (30-300 mg/g) before migalastat was initiated, one of them had undergone a kidney transplant. Cardiac magnetic resonance imaging revealed increased thickness of the interventricular septum (IVS) (normal ≤12 mm) and left ventricular hypertrophy (LVH) in four patients, with a left ventricular mass index (LVMi) ranging from 142 to 260 g/m2 (normal: 115 g/m2). In four patients, an early transmitral velocity/tissue Doppler early diastolic mitral annular velocity (E/Ea) >15 indicated increased pulmonary capillary pressure (PCP), reflecting the left atrial pressure or elevation in left ventricular filling pressure. Elevated cardiac troponin T and NT-proBNP (normal range: 0-14 ng/L and 0-150 pg/mL, respectively) indicated advanced heart disease in three.

In all patients, enzyme activity increased 6-12 months after migalastat start, and the achieved levels of enzyme activity were maintained with the exception of one patient, who returned to almost residual baseline levels at month 24 with an increase in plasma Lyso-Gb3 (Figure 1).

After 24 months of treatment with migalastat, the stage of CKD remained the same in all the patients. Microalbuminuria values also remained stable during the treatment period, with a slight reduction in most patients (Figure 1). The patient with proteinuria presented a slight reduction in the levels from baseline (1279 mg/g creatinine [Cr]) to 24 months after treatment with migalastat (1104 mg/g Cr). In the case of the kidney-transplanted patient, renal parameters remained stable, and no adjustments to immunosuppressive treatments were necessary.

All patients showed stable LVH and cardiac function during treatment with migalastat (Figure 1). In four patients, the diastolic function marker E/Ea decreased and, specifically, in patient 7, whose baseline E/Ea was 17.8, at month 24 it was below 14, indicating an improvement of diastolic function with lowered LV filling pressure than before treatment with migalastat. There were only two cases in which E/Ea increased; one patient remained stable (Figure 1). Treatment with migalastat was generally safe and well tolerated. Patients did not experience any cardiological clinical events during follow-up.

Figure 1: Effect of the switch from ERT to migalastat. Evolution of α-Gal A, Lyso-Gb3, eGFR, microalbuminuria, IVS, LVMi, E/Ea ratio, cardiac TnT, proBNP after 2 years of migalastat. α‐Gal A activity expressed as a percentage of normal. Normal white blood cell activity (µmol/L/h): ≥15.3. α-Gal A, α alpha galactosidase A; Cr, Creatinine; E/Ea, Mitral peak Doppler E-wave to peak mitral annulus velocity ratio; eGFR, estimated glomerular filtration rate; IVS, interventricular septum; LVMi left-ventricular mass index; Lyso-Gb3, deacylated globotriaosylsphingosine; proBNP, pro–brain natriuretic peptide; TnT, troponin-T; UACR, Urine Albumin-to-Creatinine Ratio.

Table 1: Patient demographics and medical history characteristics at switch.

Table 2: Clinical and biochemical findings in the seven patients at ERT start/treatment period (T1)† and at migalastat start (T2).