Hindawi Case Reports in Genetics Volume 2022, Article ID 3208810, 7 pages https://doi.org/10.1155/2022/3208810 Case Report The Benefits of Early versus Late Therapeutic Intervention in Fabry Disease Mónica Furlano ,1 Elisabet Ars ,2 Anna Matamala,3 Vicens Brossa ,4 Joan Martı́ ,5 Maria del Prado-Venegas ,6 Jaume Crespi,7 Esther Roe,8 and Roser Torra 1 1 Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Medicine Department-Universitat Autónoma de Barcelona, Barcelona, Spain 2 Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB Sant Pau), Barcelona, Spain 3 Inherited Kidney Diseases, Nursing Department, Fundació Puigvert, Barcelona, Spain 4 Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 5 Department of Neurology (Stroke Unit), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 6 Department of Otorhinolaryngology, Hospital de la Sta Creu i Sant Pau, Barcelona, Spain 7 Ophtalmology Department, Hospital de Sant Pau-Universitat Autonoma Barcelona, Barcelona, Spain 8 Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Correspondence should be addressed to Roser Torra; rtorra@fundacio-puigvert.es Received 17 August 2022; Revised 30 September 2022; Accepted 10 November 2022; Published 30 December 2022 Academic Editor: Balraj Mittal Copyright © 2022 Mónica Furlano et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants of the GLA gene. Heterozygous female patients may show much more variability in clinical manifestations, ranging from asymptomatic to full- blown disease. Because of this heterogeneous clinical picture in women, the diagnosis of FD has typically been delayed for more than a decade, and the optimal time to initiate treatment remains controversial. Case Presentation. Here, we present two unrelated female patients diagnosed with FD harbouring the same pathogenic GLA variant. We discuss the implications of initiating specifc therapy at diferent stages of the disease, with and without organ involvement (early versus late therapeutic intervention). Conclusions. Tese clinical cases suggest that initiating specifc treatment at an earlier age in women with FD may prevent organ involvement and associated clinical events. 1. Introduction (angiokeratoma), recurrent burning pain (acropar- aesthesias), cornea verticillata, hypohidrosis, cardiac and Fabry disease (FD) is a lysosomal storage disorder with X- renal injury, and cerebral ischaemia, and a generally linked transmission caused by pathogenic variants in the milder nonclassical phenotype, also referred to as late- GLA gene encoding α-galactosidase A (α-Gal A). Defciency onset FD, characterised by a more variable disease course or decreased activity of this enzyme results in accumulation [4, 5]. Heterozygous females have variable clinical mani- of its main unmetabolized substrate (globotriaosylceramide festations, depending on the inactivation pattern of the X [GL-3]) and its derivatives (e.g., lyso-Gb3) in various tissues chromosome, ranging from asymptomatic to full-blown and organs [1–3]. disease [6]. α-Gal A levels in females may be within the Te disease can be divided into a severe, classical normal range, so FD diagnosis relies on the sequencing of phenotype clinically characterised by skin lesions the GLA gene [7]. 2 Case Reports in Genetics Migalastat was approved in 2016. It is an oral phar- In October 2010, after confrming eligibility criteria, she macological chaperone, which stabilises α-Gal A when it has was included in a clinical trial to receive migalastat for an amenable mutation (an estimated 35–50% of patients 24 months (FACETS study [8]) (Figure 3). with FD overall), increasing enzyme trafcking to lysosomes Her glomerular fltration rate (GFR) at baseline, mea- and thus intracellular α-Gal A activity [8–10]. sured by plasma clearance of iohexol, was normal, and her Tere are more than 1,000 diferent disease-causing GL-3 in urine was >4 times the upper limit of normal, variants known in the GLA gene to be associated with FD fulflling the criteria for the clinical trial. At enrolment, the (Human Gene Mutation Database, https://www.hgmd. number of GL-3 inclusions in interstitial capillary cells (KIC org/). Te occurrence of disease complications is GL-3) obtained from a kidney biopsy sample was 0.236. highly age-dependent. Timely diagnosis and early ther- Likewise, GL-3 inclusions were documented in podocytes apeutic intervention are favourable for disease prognosis endothelial cells (data not shown). α-Gal A activity in white and can prevent the occurrence of or even partially re- blood cells was decreased by almost 40% [8] and plasma verse organ lesions caused by FD [3]. However, much of lyso-Gb3 was increased (Figure 4(a)). Te protein excretion the published literature describe outcomes after late rate was within the normal reference values (Figure 4(b)). treatment initiation once substantial organ damage has Te echocardiographic evaluation confrmed preserved di- already occurred. mension and function (Figure 4(c)). Here, we report the case of two women with the p. Te patient’s pain (Brief Inventory Pain (BPI)) [14] and Ile270Tr pathogenic variant who have been treated with gastrointestinal symptoms (Gastrointestinal Symptom Rat- migalastat for 11 and 5 years, respectively, and the difer- ing Scale (GSRS)) [15] remained stable throughout the ences in functional class deterioration depending on early follow-up. therapeutic intervention. After 6 months, migalastat treatment reduced KIC GL-3 inclusions, urine GL-3, and plasma lyso-Gb3. Importantly, 2. Case presentation enzyme activity was fully restored (Figure 4(a)). Renal and cardiac parameters were kept at physiological values 2.1. Case 1. We present the case of a 38-year-old female (Figures 4(b) and 4(c)). Six months later (12 months after with 10 years of follow-up since migalastat initiation. Her migalastat initiation), plasma lyso-Gb3 levels remained previous medical history included gastrointestinal stable without further reduction, while urine GL-3 con- symptoms, including episodes of diarrhoea at 18 years of centration showed a meaningful decrease. In addition, α-Gal age. An intestinal biopsy was performed to relate the A activity remained stable. Renal biopsy revealed a slight gastrointestinal symptoms to FD, but no GL-3 deposits increase in KIC GL-3 inclusions (Figure 4(a)), but overall were detected. Terefore, the patient was diagnosed with renal function remained normal (Figure 4(b)). Notably, irritable bowel syndrome. She also noticed acropar- a decrease in the left ventricular mass index and in left aesthesia and whorled opacities in the cornea (cornea ventricular posterior wall thickness parameters were ob- verticillata). Sequence analysis of the GLA gene in the served (Figure 4(c)). At the end of the trial (24 months after patient, in comparison with the wild-type sequence migalastat initiation), the patient remained stable, with (Figure 1), revealed a single nucleotide point mutation in unremarkable changes (Figures 4(a)–4(c)). heterozygosis at nucleotide c.809T >C p.(Ile270Tr) In 2012, after completing the pivotal study, the patient (GLA variant: NM_000169.3). Tis variant results in the was enrolled in the open-label extension (OLE) study change from isoleucine to threonine at position 270 of the (AT1001-041) to receive migalastat for an additional exon 6 [11] Tis variant has not been found in the 24 months (Figure 3). Forty-eight months (4 years) after population database gnomAD, and it is predicted to be migalastat initiation, all scores related to renal and cardiac pathogenic by most computational predictive programs parameters fell within normal reference values (Figures 4(b) (BayesDel_addAF, DANN, DEOGEN2, FATHMM-MKL, and 4(c)). LIST-S2, M-CAP, MVP, MutationAssessor, Muta- In 2014, at age 30. Te patient was included in the second tionTaster, SIFT) as well as by the meta-predictor REVEL extension of the study (AT1001-042), where she received (score = 0.97). Tis variant has been associated with the migalastat for another 36 months (Figure 3). At the end of classic Fabry phenotype, and its amenability to migalastat this period (7 years on migalastat treatment), renal and therapy has been confrmed in the GLP HEK cell-based cardiac values were still within physiological ranges assay [12]. Taking into account all this evidence and (Figures 4(b) and 4(c)). following the American College of Medical Genetics and Since 2017, our patient has continued treatment with Genomics guidelines for the interpretation of sequence migalastat in its marketed form. Currently, she remains variants [13], the variant GLA c.809T >C p. (Ile270Tr) is stable, with no signifcant albuminuria and no organ in- pathogenic. volvement (Figures 3, 4(b), and 4(c)). Regarding her family history, her father had classical FD and, after undergoing a kidney and heart transplant, fnally died at age 42. Her 43-year-old sister was also diagnosed 2.2. Case 2. We present the case of a 65-year-old woman with the disease and remains asymptomatic. Her 13-year-old diagnosed with FD and severe organ involvement treated son was found to be unafected in a prenatal diagnosis with migalastat for the last 3 years. Te patient had a long (Figure 2). medical history, including multiple conditions such as Case Reports in Genetics 3 G T T A G T G A T T G G CA A C T T G T T A G T G A Y T G G CA A C T T 22 29 36 22 29 36 Control: WT Patient (1 and 2): GLA c. [809T>C]; [=] p. (Ile270Thr) (a) (b) Figure 1: Sanger sequencing of exon 6 of the GLA gene. (a) Normal control showing wild-type (WT) sequence. (b) Patient sequence with GLA variant c.809T >C p.(Ile207Tr) in heterozygosity. Te arrow indicates the nucleotide position with the sequence variant. Patient 1 Patient 2 Figure 2: Pedigrees. Te proband is indicated with an arrow. Striped boxes represent males with Fabry disease; striped circles represent females with Fabry disease; slash indicates deceased. cardiac hypertrophy with preserved left ventricular ejection had ischaemic heart disease and sensorineural hearing loss, fraction (LVEF) and diastolic dysfunction, exertional genetic testing was negative for FD (Figure 2). dyspnoea, cutaneous lupus disease, primary anti- In 2018, the patient requested to be switched from ERT phospholipid syndrome, dyslipidaemia, hypertension, and to migalastat. During follow-up, the patient experienced atrophic gastritis. She is currently being treated with tor- unexplained syncopes and conduction disturbances (frst- asemide, amiodarone, enalapril, bisoprolol, acenocoumarol, degree auriculoventricular blockade with right ventricle and pravastatin. In 2016, she sufered a stroke of the right bundle branch block and left anterior hemiblock), which middle cerebral artery along with paroxysmal atrial fbril- were confrmed by a pathological electrophysiological study lation. At that time, typical FD manifestations (severe showing a prolonged Hiss-Ventricular (HV) interval, and sensorineural hypoacusis, cornea verticillata, and angio- the patient was ftted with a permanent dual chamber keratomas) were also detected (Figure 3). Genetic testing pacemaker in 2019 (Figure 3). demonstrated the presence of a pathogenic sequence variant Currently, the patient continues on migalastat and is in the GLA gene: c.809T >C p.(Ile270Tr), the same as the stabilised with moderate systolic dysfunction (LVEF 41%), previous case although not a relative (Figure 1). Plasma an IVSD of 17 mm, a preserved, stable eGFR of 61 mL/min/ α-Gal A activity was decreased (less than 30%) (Figure 4(a)). 1.73 m2 (Figures 3, 4(b), and 4(c)) and no microalbuminuria. Cardiac hypertrophy was then attributed to FD. Fabry- specifc therapy was immediately initiated with enzyme 3. Discussion replacement therapy (ERT) (agalsidase beta) (Figure 3). Regarding her family history, although her mother had Tis report describes two unrelated female patients with FD a hypertrophic cardiomyopathy and her father and brother harbouring the same GLA p. Ile270Tr pathogenic variant 4 Case Reports in Genetics Patient 1/early treated Current status: FACETS studya OLEb OLEc Marketed form No organ involvement eGFR (96 mL/min/1.73 m2) Diagnosis of FD: Acroparaesthesia and GI symptoms cornea verticillata (IBD) Migalastat 18 years-old 26 years-old 38 years-old 2001 2002 2009 2010 2012 2014 2016 2017 2018 2019 2021 60 years-old 65 years-old Agalsidase beta Migalastat Normal ECG Hearing aids AV blockade pacemaker Stroke Atrial fibrillation Current status: stabilised LVH: Septum (17 mm) Diagnosis of FD: Systolic dysfunction Exertional dyspnoea, sensorineural hypoacusis, (LVEF 41%) eGFR (61 cornea verticillata and angiokeratomas mL/min/1.73 m2) Patient 2/late treated Figure 3: Medical history and occurrence of events over time in two female patients treated at diferent stages of FD. aAT1001-011 (NCT00925301), bAT1001-041 (NCT01458119), and cAT1001-042 (NCT02194985). AV, atrioventricular; ECG, echocardiogram; eGFR, estimated glomerular fltration rate, normal: >90 and >60 for omen >50 years15; FD, Fabry disease; GI, gastrointestinal; IBD, irritable bowel syndrome; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; OLE, open-label extension. and the efect of early treatment, not only on symptoms and diagnosed late in the course of the disease, when cardiac surrogates, including LVM and GFR, but also on clinical hypertrophy was already severe. Although she started ERT events. Te literature has extensively described this variant immediately upon diagnosis and was later switched to in association with the classic Fabry phenotype [11, 16–21]. migalastat, her cardiac hypertrophy did not improve, and Specifc features of advanced disease, such as cardiac fbrosis she even required a pacemaker. Te patient’s many or severe renal dysfunction, are hallmarks of irreversible comorbidities may have also played a role in her poorer organ damage. Tus, it is mandatory to start treatment outcome. However, she has not developed Fabry ne- before the occurrence of irreversible manifestations to phropathy, as although her eGFR is not optimal, she shows achieve better outcomes [22–24]. Tis is in line with the two no microalbuminuria, a hallmark of the disease. Tis may be cases described here. In the frst case, treatment was initiated an example of how FD therapy does not reverse organ in- at an early stage of the disease, before renal or cardiac in- volvement but may prevent damage to other organs, such as volvement, while in the second case, treatment was started at the kidney. a late stage, with severe and irreversible cardiac involvement. Even so, it cannot be ruled out that the diferent disease As previously mentioned, the patient in the frst case severity in the two cases stems from a diferent X inactivation initiated FD-specifc therapy upon inclusion in the phase III pattern. According to previous studies, preferential in- FACETS study at the age of 26 years, before any evident activation of the wild-type GLA allele is associated with an organ damage. After 6 months of migalastat treatment, KIC early onset of disease and rapid progression, compared to GL-3 inclusions, urine GL-3, and plasma lyso-Gb3 were a milder disease when the mutated allele is preferentially reduced, and α-Gal A activity was fully restored. Tese inactivated [26, 27]. Conversely, other studies [28, 29] re- results are consistent with recent fndings from the miga- ported that X inactivation patterns in symptomatic females lastat phase III ATTRACT study [8, 25]. Moreover, the did not difer from those of female controls of the same age. patient remained asymptomatic with no organ involvement Some of these discrepancies may arise from the fact that for the whole follow-up. Tis is doubly remarkable when disease progression is also related to a cross-correction talking about a variant associated with a classic phenotype, mechanism that degrades over time, explaining why given that these females are more likely to develop com- women with FD develop more symptoms with age [28]. Tis plications than nonclassical ones [5]. Te second patient was highlights the need for a larger series to support our fndings. Case Reports in Genetics 5 Patient 1 Patient 2 FACETS studya FACETS studya Agalsidase beta 100 150 146.2 0.300 0.236 Number per KIC Absolute value Absolute value 100.0 100.0 100.0 100 0.200 50 93.5 61.1 0.097 29.8 50 38.9 0.100 0.028 12.8 9.7 8.6 8.7 8.0 0 0.000 0 Start of 6m 12 m 24 m Baseline 6m 12 m Start of 18 m treatment treatment GL3 inclusions α-Gal A Activity (%) α-Gal A Activity (%) Lyso-Gb3 (nmol/L) Urine GL-3 (ng/mL creatinine) (a) Patient 1 Patient 2 FACETS studya OLEb OLEc Marketed formd Agalsidase beta Migalastat 150 100 136.0 120.0 120.0 108.0 99.0 106.0 70.9 95.0 92.0 90.0 91.0 97.0 100.0 63.6 61.9 61.3 100 88.0 Absolute value Absolute value 103.5 56.3 99.0 94.8 99.0 52.8 88.0 90.0 85.0 50 84.0 71.0 70.0 68.0 50 4.1 1.3 1.9 2.8 3.1 2.4 0.6 1.3 1.3 6.6 2.5 3.2 3.2 4.9 1.4 1.1 0 0 Start of 6 m 12 m 24 m 48 m 5y 6y 7y 8y 9y 10 y 11 y Start of 1y 2y 3y 4y 5y treatment treatment Proteinuria 24 h (mg) eGFR (mL/min/1.73 m2) eGFR (mL/min/1.73 m2) UACR (mg/mmol) UACR (mg/mmol) (b) Patient 1 Patient 2 Agalsidase beta Migalastat FACETS study a OLE b OLE c Marketed form d 200 50 167.0 154.5 150 97.0 142.6 134.4 127.6 131.5 Absolute value Absolute value 104.3 106.3 103.5 98.0 100 88.0 84.0 85.4 22.0 22.0 81.5 73.4 69.7 71.7 18.0 17.2 17.3 17.0 57.9 59.0 59.5 52.0 50 1.4 16.0 11.0 9.6 11.0 12.1 8.0 8.5 8.1 7.2 7.1 8.2 6.8 7.7 7.2 8.7 8.7 7.4 11.0 8.1 8.9 7.1 10.0 0 0 Start of 6m 12 m 24 m 48 m 5y 6y 7y 8y 10 y 11 y Start of 1y 2y 3y 4y 5y treatment treatment LVMi (g/m2) IVSD (mm) IVSD (mm) LVM (g) LVPWT (mm) LVPWT (mm) (c) Figure 4: Changes in (a) Metabolism. (b) Renal. (c) Cardiac Parameters with treatment at diferent stages in two cases of FD. α-Gal A is expressed as a percentage of normal (% normal). Normal white blood cell activity: 22 nmol free 4 MU released/mg protein/h7 (patient 1); normal laboratory reference activity on dried blood spots samples: 4.7–18.8 μmol/L/h (patient 2); normal Lyso-Gb3: ≤0.6 nm/L; normal urine GL-3: <33.8 ng/mL; normal protein excretion rate: <150 mg/24 hours; normal eGFR: >90 mL/min/1.73 m2; normal UACR: <3 mg/ mmol; normal LVMI: 43–95 g/m2; normal LVPWT: 6–10 mm; normal IVSD: 6–9 mm. Dotted lines defne the end of study (case 1) or treatment switch (case 2). In the cardiac parameters graph of case 1, gaps indicate a diferent method of measurement. Case 1: urine GL-3 and GL-3 inclusions were measured up to month 12 of the FACETS study; LVMI and LVM not measured at 8, 9, and 10 months; LVPWT measured upto 12 months of the FACETS study; case 2: UACR and LVPWT not measured at years 3 and 4. aNCT00925301, bAT1001-041; c AT1001-042. α-Gal A, alpha-galactosidase A; eGFR, estimated glomerular fltration rate; FD, Fabry disease; GL-3, globotriaosylceramide; IVSD, interventricular septal thickness at end diastole; LVMI, left ventricular mass index; LVPWT, left ventricular posterior wall thickness; Lyso-Gb3, globotriaosylsphingosine; OLE, open-label extension; UACR, urine albumin-to-creatinine ratio. 6 Case Reports in Genetics In conclusion, these clinical cases at diferent stages of References disease progression highlight the importance of early di- agnosis and timely treatment initiation in patients with FD [1] O. Azevedo, M. Gago, G. Miltenberger-Miltenyi, P. Gaspar, and provide further evidence of the long-term efcacy and N. Sousa, and D. Cunha, “Mild left ventricular hypertrophy unravels a novel nonsense mutation of the GLA gene associated with the classical phenotype of Fabry disease,” Cardiology, vol. 137, no. 2, pp. 67–73, 2017. Data Availability [2] A. Mehta, J. T. R. Clarke, R. Giugliani et al., “Natural course of Fabry disease: changing pattern of causes of death in FOS - Te datasets during and/or analysed during the current Fabry Outcome Survey,” Journal of Medical Genetics, vol. 46, study are available from the corresponding author upon no. 8, pp. 548–552, 2009. request. [3] A. Ortiz, D. P. Germain, R. J. Desnick et al., “Fabry disease revisited: management and treatment recommendations for Conflicts of Interest adult patients,” Molecular Genetics and Metabolism, vol. 123, no. 4, pp. 416–427, 2018. MF has received honoraria for lectures, presentations, [4] R. El-Abassi, D. Singhal, and J. D. England, “Fabry’s disease,” speaker bureaus, manuscript writing, or educational events Journal of the Neurological Sciences, vol. 344, no. 1-2, pp. 5–19, from Reata and Otsuka, and for attending meetings and/or 2014. traveling from Otsuka, Sanof Genzyme, and Amicus. EA, [5] M. Arends, C. Wanner, D. Hughes et al., “Characterization of classical and nonclassical Fabry disease: a multicenter study,” AM, VB, JM, MPV, JC, and ER declare that they have no Journal of the American Society of Nephrology, vol. 28, no. 5, conficts of interest. RT has received medical writing support pp. 1631–1641, 2017. for the present manuscript from Amicus, consulting fees [6] C. Whybra, C. Kampmann, I. Willers et al., “Anderson–Fabry from Amicus, Takeda, Chiesi, and Sanof Genzyme, hono- disease: clinical manifestations of disease in female hetero- raria for lectures, presentations, speakers bureaus, manu- zygotes,” Journal of Inherited Metabolic Disease, vol. 24, no. 7, script writing, or educational events from Amicus, Takeda, pp. 715–724, 2001. Chiesi, and Sanof Genzyme, and is a council member of the [7] R. J. Desnick, R. Brady, J. Barranger, A. J. Collins, European Renal Association (ERA). D. P. Germain, and M. Goldman, “Fabry disease, an under- recognized multisystemic disorder: expert recommendations Authors’ Contributions for diagnosis, management, and enzyme replacement ther- apy,” Annals of Internal Medicine, vol. 138, no. 4, pp. 338–346, MF investigated and visualized the study and reviewed and 2003. edited the article. EA conceptualized, validated, investigated, [8] D. P. Germain, D. A. Hughes, K. 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