Patient-reported experience with Fabry disease and its management in the real-world setting: results from a double-blind, cross-sectional survey of 280 respondents.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.

Vericiguat improves cardiac function and microcirculation of a male patient with Fabry disease: A case report.

Fabry disease (FD) is a rare X chromosome-linked disorder and can be easily misdiagnosed. Here, we report the case of a 69-year-old male patient with FD who developed heart failure and showed extremely high pulmonary artery pressure. His initial symptom was recurrent atrial fibrillation. The left and right atrial inner diameters were large, and the ventricular wall was thick. Gene analysis which showed GLA c.215T>C p.Met72Thr mutation and single photon emission computed tomography indicated the diagnosis of FD with coronary microvascular dysfunction. The patient was prescribed anti-heart failure drugs, including vericiguat. Following the treatment, his heart function and microvascular perfusion significantly improved, which might be due to the beneficial effects of vericiguat.

Elevated interleukin-8 expression by skin fibroblasts as a potential contributor to pain in women with Fabry disease.

Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an in vitro model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, KCNN4) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.

[Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree].

Objective: To investigate the clinical phenotype and genetic characteristics of patients with Fabry disease caused by a GLA variant, IVS4+919G>A. Methods: It was a prospective study. Fabry disease screening was conducted among high-risk population in Ninghai from October 2021 to August 2023. Those children with decreased α-galactosidase enzyme activity<2.40 µmol/(L·h) or elavated Lyso-GL-3 level>1.10 µg/L in dried blood spot (DBS) method underwent GLA genetic testing for diagnosis confirmation. Meanwhile, family screening was carried out. A proband and his family members diagnosed with Fabry disease were research subjects. The clinical and genetic characteristics of patients with Fabry disease caused by the GLA variant (IVS4+919G>A) were analyzed. Results: The female proband aged 9.8 years with pain in both lower limbs as the initial symptom was found to have a heterozygous GLA variant IVS4+919G>A among 102 patients. In family screening, there were 4 family members (proband's father, elder sister, elder male cousin and elder female cousin) with Fabry disease and a family member (proband's fifth aunt) with a GLA variant. Among these 4 diagnosed family members, the elder male cousin of the proband, a boy aged 13.2 years had a heterozygous GLA variant, IVS4+919G>A with intermittent pain in both lower limbs as the initial symptom. The proband's father had knee joint pain. The proband's elder sister had decreased vision and his elder female cousin had no obvious symptoms. The proband's fifth aunt with a GLA variant had decreased vision. Conclusions: High-risk screening in children and family screening are helpful for early diagnosis and treatment of Fabry disease. Neuropathic pain may be a early symptom in children with Fabry disease caused by the GLA variant, IVS4+919G>A.

Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China.

Fabry disease (FD), an X-linked disorder resulting from dysfunction of α-galactosidase A, can result in significant complications. Early intervention yields better outcomes, but misdiagnosis or delayed diagnosis is common, impacting prognosis. Thus, early detection is crucial in the clinical diagnosis and treatment of FD. While newborn screening for FD has been implemented in certain regions, challenges persist in enzyme activity detection techniques, particularly for female and late-onset patients. Further exploration of improved screening strategies is warranted. This study retrospectively analyzed genetic screening results for pathogenic GLA variants in 17,171 newborns. The results indicated an estimated incidence of FD in the Nanjing region of China of approximately 1 in 1321. The most prevalent pathogenic variant among potential FD patients was c.640-801G > A (46.15 %). Furthermore, the residual enzyme activity of the pathogenic variant c.911G > C was marginally higher than that of other variants, and suggesting that genetic screening may be more effective in identifying potential female and late-onset patients compared to enzyme activity testing. This research offers initial insights into the effectiveness of GLA genetic screening and serves as a reference for early diagnosis, treatment, and genetic counseling in FD.

What should rheumatologists know about Gaucher disease and Fabry disease? Connecting the dots for an overview.

Gaucher and Fabry diseases are lysosomal storage disorders in which deficient enzyme activity leads to pathological accumulation of sphingolipids. These diseases have a broad phenotypic presentation. Musculoskeletal symptoms and pain complaints are frequently reported by patients. Thus, rheumatologists can be contacted by these patients, contributing to the correct diagnosis, earlier indication of appropriate treatment and improvement of their prognosis. This review describes important concepts about Gaucher and Fabry diseases that rheumatologists should understand to improve patients' quality of life and change the natural history of these diseases.

Anderson-Fabry disease management: role of the cardiologist.

Anderson-Fabry disease (AFD) is a lysosomal storage disorder characterized by glycolipid accumulation in cardiac cells, associated with a peculiar form of hypertrophic cardiomyopathy (HCM). Up to 1% of patients with a diagnosis of HCM indeed have AFD. With the availability of targeted therapies for sarcomeric HCM and its genocopies, a timely differential diagnosis is essential. Specifically, the therapeutic landscape for AFD is rapidly evolving and offers increasingly effective, disease-modifying treatment options. However, diagnosing AFD may be difficult, particularly in the non-classic phenotype with prominent or isolated cardiac involvement and no systemic red flags. For many AFD patients, the clinical journey from initial clinical manifestations to diagnosis and appropriate treatment remains challenging, due to late recognition or utter neglect. Consequently, late initiation of treatment results in an exacerbation of cardiac involvement, representing the main cause of morbidity and mortality, irrespective of gender. Optimal management of AFD patients requires a dedicated multidisciplinary team, in which the cardiologist plays a decisive role, ranging from the differential diagnosis to the prevention of complications and the evaluation of timing for disease-specific therapies. The present review aims to redefine the role of cardiologists across the main decision nodes in contemporary AFD clinical care and drug discovery.

What Is Hidden in Patients with Unknown Nephropathy? Genetic Screening Could Be the Missing Link in Kidney Transplantation Diagnosis and Management.

Between 15-20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (PAX2: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant.

Differences Between Two Distinct Hypertrophic Cardiac Conditions: Fabry Disease versus Hypertrophic Cardiomyopathy. / Diferenças entre Duas Condições Cardíacas Hipertróficas Distintas: Doença de Fabry Versus Cardiomiopatia Hipertrófica.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) and Fabry disease (FD) are genetically inherited diseases with left ventricular hypertrophy (LVH) phenotype characteristics that cause adverse cardiac outcomes. OBJECTIVES: To investigate the demographic, clinical, biochemical, electrocardiographic (ECG), and echocardiographic (ECHO) differences between HCM and FD. METHODS: 60 HCM and 40 FD patients were analyzed retrospectively as a subanalysis of the 'LVH-TR study' after excluding patients with atrial fibrillation, pace rhythm, bundle branch blocks, and second and third-degree atrioventricular (AV) blocks. The significance level was accepted as <0.05. RESULTS: Male gender (p=0.048) and creatinine (p=0.010) are significantly higher in favor of FD; however, ST depression (p=0.028), QT duration (p=0.041), interventricular septum thickness (IVSd) (p=0.003), posterior wall thickness (PWd) (p=0.009), moderate-severe mitral regurgitation (MR) (p=0.013), and LV mass index (LVMI) (p=0.041) are significantly higher in favor of HCM in the univariate analyses. In multivariate analysis, statistical significance only continues in creatinine (p=0.018) and QT duration (0.045). FD was positively correlated with creatinine (rho=0.287, p=0.004) and HCM was positively correlated with PWd (rho=0.306, p=0.002), IVSd (rho=0.395, p<0.001), moderate-severe MR (rho=0.276, p<0.005), LVMI (rho=0.300, p=0.002), relative wall thickness (RWT) (rho=0.271, p=0.006), QT duration (rho=0.213, p=0.034) and ST depression (rho=0.222, p=0.026). CONCLUSION: Specific biochemical, ECG, and ECHO characteristics can aid in the differentiation and early diagnosis of HCM and FD.

FUNDAMENTO: A cardiomiopatia hipertrófica (CMH) e a doença de Fabry (DF) são doenças herdadas geneticamente com características fenotípicas de hipertrofia ventricular esquerda (HVE) que causam resultados cardíacos adversos. OBJETIVOS: Investigar as diferenças demográficas, clínicas, bioquímicas, eletrocardiográficas (ECG) e ecocardiográficas (ECO) entre CMH e DF. MÉTODOS: 60 pacientes com CMH e 40 pacientes com DF foram analisados retrospectivamente como uma subanálise do "estudo LVH-TR" após exclusão de pacientes com fibrilação atrial, ritmo de estimulação, bloqueios de ramo e bloqueios atrioventriculares (AV) de segundo e terceiro graus. O nível de significância foi aceito como <0,05. RESULTADOS: O sexo masculino (p=0,048) e a creatinina (p=0,010) são significativamente maiores a favor da DF; entretanto, infradesnivelamento do segmento ST (p=0,028), duração do QT (p=0,041), espessura do septo interventricular (SIVd) (p=0,003), espessura da parede posterior (PWd) (p=0,009), insuficiência mitral moderada a grave (IM) (p=0,013) e o índice de massa ventricular esquerda (IMVE) (p=0,041) são significativamente maiores a favor da CMH nas análises univariadas. Na análise multivariada, a significância estatística apenas permanece na creatinina (p=0,018) e na duração do intervalo QT (0,045). A DF foi positivamente correlacionada com a creatinina (rho=0,287, p=0,004) e a CMH foi positivamente correlacionada com o PWd (rho=0,306, p=0,002), IVSd (rho=0,395, p<0,001), IM moderada-grave (rho= 0,276, p<0,005), IMVE (rho=0,300, p=0,002), espessura relativa da parede (ERP) (rho=0,271, p=0,006), duração do QT (rho=0,213, p=0,034) e depressão do segmento ST (rho =0,222, p=0,026). CONCLUSÃO: Características bioquímicas, ECG e ECO específicas podem auxiliar na diferenciação e no diagnóstico precoce da CMH e da DF.

Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry.

BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

Fabry Disease: Cardiac Implications and Molecular Mechanisms.

PURPOSE OF REVIEW: This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes. RECENT FINDINGS: Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited. Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease-related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease.

[Clinical analysis of 10 patients with Fabry disease].

We aimed to analyze the clinical data of 10 patients (6 male and 4 female) with Fabry disease (FD). The mean age of the patients was (28.80±9.27) years. Seven patients had classical FD and three had delayed onset FD. Among the 10 patients, six had skin involvement and cutaneous angiokeratoma; five had hypohidrosis or anhidrosis; nine had intermittent neuralgia; and three had supraorbital ridge protrusion, forehead bulge, and lip thickening. Five patients had proteinuria, including one with chronic kidney disease stage 3 and one with chronic kidney disease stage 5. Cardiac involvement occurred in three patients, two had myocardial hypertrophy and one had valvular insufficiency. The activity of galactosidase decreased in seven patients (2.80-1.55 µmol·L-1·h-1). Plasma deacetyl-GL-3 was elevated in all 10 patients(3.12-120.00 ng/ml). Three patients underwent renal biopsy, wherein two cases of focal segmental glomerulosclerosis and one of mesangial proliferative glomerulonephritis was found. A large number of myeloid and zebra bodies were found in the podocytes in three patients, including a small number of myeloid and zebra bodies in the renal tubular epithelial cells in one patient with occasional zebra bodies in the renal interstitium. Nine patients had GLA gene mutations. One patient was c.102T>A, a de novo mutation. Four patients were treated with agalsidase α injection (0.2 mg/kg, intravenous infusion every 2 weeks), and their prognosis was good. FD has various clinical manifestations and multi-system involvement, which requires multidisciplinary cooperation. Detection of galactosidase activity, plasma globotriaosylsphingosine, and GLA gene mutation can help for accurate diagnosis.

[Neuro-otological manifestations in Fabry disease-a retrospective single center study]. / Neurootologische Manifestationen bei Morbus Fabry ­ eine retrospektive Analyse.

BACKGROUND: Fabry disease (FD) is one of the X­linked lysosomal storage diseases that can affect any organ. They have a specific lysosomal dysfunction in common, which results in substrate accumulation in lysosomes instead of metabolite degradation. Due to the deficiency/absence of α­galactosidase, globotriaosylceramides (Gb3) are deposited in lysosomes of the organs. In addition to acroparesthesia, angiokeratomas, autonomic dysfunction, vortex keratopathies, ischemic cerebral or cardiac complications and chronic renal failure, also vestibulocochlear dysfunctions with sudden or progressive asymmetric hearing loss, tinnitus and vertigo may be observed. PATIENTS AND METHODS: In this retrospective study, 33 patients (men = 16 and women = 17) with FD were evaluated. All patients presented to us in interdisciplinary cooperation as part of routine examinations by the specialized center for lysosomal storage diseases of the in-house department of nephrology. This presentation is carried out as a screening examination independent of neuro-otological symptoms. RESULTS: The mean age at diagnosis was 34.76 (±11.55) years. The first presentation in our ENT department was at 40.45 (±11.71) years. We were able to demonstrate a significant correlation between neurological symptoms or apoplexy and hearing loss (p = 0.001) and between cardiac manifestations and hearing loss (p = 0.024). CONCLUSION: Hearing loss is a potential symptom of Fabry disease and is not limited to the classic male phenotype. Due to possible positive correlations with neurological and cardiological manifestations of the disease, routine ENT screening examinations should be carried out to be able to identify and treat neuro-otological deficits at an early stage. In addition, FD should also be considered and tested as a differential diagnosis, especially in younger patients with sudden unilateral or bilateral hearing loss and a family history.

Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis?

INTRODUCTION: Fabry disease (FD) can be undiagnosed in the context of multiple sclerosis (MS) due to similar clinical and paraclinical features. Our study aimed to determine the prevalence (and the necessity of screening) of FD among patients with possible or definite MS. METHODS: In this prospective monocentric observational study, we included consecutive patients enrolled between May 2017 and May 2019 after the first clinical event suggestive of MS. All patients underwent FD screening using dried blood spots in a stepwise manner combining genetic and enzyme testing. Patients were followed until May 2022. RESULTS: We included 160 patients (73.1% female, mean age 33.9 years). The 2017 revised McDonald's criteria for definite MS were fulfilled by 74 (46.3%) patients at the time of study recruitment and 89 (55.6%) patients after 3-5 years of follow-up. None of the patients had a pathogenic GLA variant, and four (2.5%) had a variant of unknown significance (p.A143T, p.S126G, 2 × p.D313Y). In two of these patients, the intrathecal synthesis of oligoclonal bands was absent, and none had hyperproteinorachia or pleocytosis in cerebrospinal fluid. Detailed examination of FD organ manifestations revealed only discrete ocular and kidney involvement in two patients. CONCLUSION: The prevalence of FD in the population of suspected or definite MS patients does not appear to be high. Our results do not support routine FD screening in all patients with a possible diagnosis of MS, but there is an urgent need to search for red flags and include FD in the differential diagnosis of MS.

Impact of GLA Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies.

BACKGROUND: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data. REGISTRATION: URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.

A Classical Phenotype of Fabry Disease with Novel Mutation Found by Kidney Biopsy, A Case Report.

Fabry disease (FD) is a multi-organ disorder caused by a deficiency of alpha-galactosidase (α-GLA) or reduced activity of the enzyme due to mutations in the GLA gene on the X chromosome, making it an X-linked hereditary disease. A 37-year-old man previously diagnosed with sudden deafness and cardiac hypertrophy was referred to our department after an abnormal urine finding during a public health checkup. A renal biopsy revealed characteristic findings, and he was diagnosed with FD with a novel GLA abnormality (c.714dupT (p.I239Yfs*11)). We are currently administering enzyme replacement therapy (ERT) with agalsidase α. This case shows that a novel genetic abnormality in FD can be overlooked for 37 years, even in the presence of typical symptoms. The significance of a renal biopsy in diagnosing FD is emphasized, highlighting the crucial role of nephrologists.  DOI: 10.52547/ijkd.7595.

[Multisystem lesions in orphan diseases: rheumatological aspects of Fabry's disease. Case report].

Fabry-Andersen disease is a genetically determined, progressive disease related to lysosomal storage diseases, linked to the X chromosome, characterized by impaired glycosphingolipid metabolism, due to the deficiency or absence of the enzyme α-galactosidase A. Fabry disease is a multisystem disease and is characterized by damage to vital organs - kidneys, heart, brain, with the occurrence of complications that cause an unfavorable prognosis. Autoinflammation mechanisms with signs of chronic inflammation are involved in the pathogenesis of the disease. One of the features of Fabry disease are clinical manifestations in the form of arthralgia, fever, skin lesions, which are similar to rheumatological diseases. The article presents a clinical observation of the classical type of Fabry disease with multiple organ manifestation, which required differential diagnosis with rheumatological diseases. Rheumatologists are specialists who are involved in the early diagnosis of Fabry disease, so they should have a high awareness of this sphingolipidosis.