Retrospective assessment of family screening in Fabry disease

Objective:Fabry disease is a rare hereditary lysosomal storage disease caused by the deficiency of alpha-galactosidase A (α-GLA). Although sensorineural hearing loss is common in Fabry disease, there are no studies in the literature that have screened a population with sensorineural hearing loss for Fabry disease. In this study, we aimed to screen a group of patients who were diagnosed with sensorineural hearing loss and underwent a hearing test for Fabry disease.Methods:One hundred sixty eight patients who were aged 18–75 years and diagnosed with idiopathic hearing loss between July 2019 and January 2020 were included. In male patients, α-GLA enzyme activity was analyzed. Patients with low enzyme activity were identified and genetic testing was performed for mutations in the GLA gene. In females, only genetic testing was performed.Results:Eighty four women and 84 men were included in the study. α-GLA enzyme activity was low in 11 of the 84 male patients (13%). One out of these 11 patients had a gene mutation for Fabry disease. Moreover, four relatives of this index patient were diagnosed with Fabry disease in family screening. GLA gene mutation was also found in one of the 84 female patients. Consequently, two (1.2%) of our 168 patients were diagnosed with Fabry disease by screening with enzyme activity and genetic testing.Conclusion:Our study showed that screening for Fabry disease in patients with idiopathic sensorineural hearing loss without other specific findings might be a useful strategy for detecting new cases.

Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk. A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7 ng/mL suggested classical Fabry mutations in most of the patients (93%). Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A. This determines an accumulation of globotriaosylceramide within lysosomes. The clinical picture is highly variable and depends on cellular storage deposition. Renal, cardiac and nervous system are the most frequent organs involved. Gastrointestinal involvement is also present, associated with other clinical signs of Fabry disease and sometimes can be a prominent clinical manifestation. We describe a Fabry disease case in which gastrointestinal involvement was the first and the only clinical sign of Fabry disease and a diagnosis of Fabry disease was made by chance during a family screening. Enzyme replacement therapy was started and after 3 months, there was a complete disappearance of signs.

BackgroundFabry disease (FD) remains poorly recognized, especially in children in China. Considering the diversity and nonspecific clinical manifestations accompanying with life-threatening aspect of this disease, methods to improve effective screening and management of the suspects are needed. This study aims to explore how it can be done effectively from a multidisciplinary perspective for children with FD at a tertiary children’s hospital in China.MethodsA multidisciplinary team (MDT) of pediatric FD experts was launched at Children’s Hospital of Fudan University. Children with high-risk characteristics were referred by the MDT screening team using the dried blood spot (DBS) triple-test (α-galactosidase A, globotriaosylsphingosine, GLA gene). For newborns who were undergoing genetic testing in the hospital, the GLA gene was listed as a routine analysis gene. Evaluation, family screening, and genetic counselling were implemented after screening by the MDT management team.ResultsBefore the establishment of the MDT, no case was diagnosed with FD in the hospital. However, twelve months following the MDT program's implementation, thirty-five children with high-risk profiles were referred for screening by DBS triple-test, with a yield of diagnosis of 14.3% (5/35). These 5 diagnosed children were referred due to a high-risk profile of pain accompanied by dermatological angiokeratoma and hypohidrosis (n = 2), pain accompanied by abnormal liver function (n = 1), pain only (n = 1), and unexplained renal tubular dysfunction (n = 1). Two neonates were detected early with GLA mutations in the hospital, with a yield of detection of 0.14% (2/1420). Furthermore, another 3 children diagnosed with FD were referred from other hospitals. Family screening of these 10 diagnosed children indicated that 9 boys inherited it from their mothers and 1 girl inherited it from her father. Four of them started to receive enzyme replacement therapy.ConclusionScreening and management of children with FD is effective based on a defined screening protocol and a multidisciplinary approach. We should pay more attention to the high-risk profiles of pain, angiokeratoma, decreased sweating, and unexplained chronic kidney disease in children.

Although Fabry disease was identified a century ago, it is still a challenging condition to diagnose and treat. Registries data suggest that at least 10% of patients may first present with a cardiac event and that cardiac disease is 1 of the 3 major causes of morbidity and mortality in affected males and females. Cardiac involvement in Fabry disease may be expressed as left ventricular hypertrophy (LVH), coronary disease, atrioventricular conduction disturbances, arrhythmias, and valvular involvement. The exact mechanism by which hypertrophy and fibrosis in the heart occur is not fully understood. Lysosomal globotriaosylceramide accumulation in the myocardium is responsible for only 3% of the mass in the hypertrophic heart, indicating that the LVH is not a direct result of substrate infiltration. One of the most important contributions that cardiologists can make is to consider the diagnosis of Fabry disease in patients with cardiac manifestations preceding the development of LVH and conduct family screen...

<h3>Background</h3> Testing for genetic causes of cardiomyopathy is useful for diagnosis, guiding treatment and family screening. Historically in the UK, genetic testing was carried out by specialist teams in inherited cardiac conditions (ICC) clinics. ICC and genetics services are not resourced to provide these services to the general heart failure population and so genetic testing for cardiomyopathy has been taken into mainstream heart failure teams. There is little data on the frequency of positive genetic tests in this setting and whether tests are requested appropriately. <h3>Methods</h3> We retrospectively analysed genetic tests requested by a heart failure team (3 consultants) at a tertiary cardiac centre from March 2024 to February 2025. We excluded patients known to the local ICC team. We explored whether testing followed current NHS national genomic test directory (NGTD) eligibility criteria. Clinical data including LVEF, coronary angiogram and cMRI results were reviewed. <h3>Results</h3> A total of 62 genetic panels were sent for 57 patients, The mean age was 52 years and comprised of 38 males and 19 females. 31 tests were sent as an inpatient, and 31 as an outpatient. The most common genetic panels were R132 dilated and arrhythmogenic cardiomyopathy DCM/ACM (n=37) and R131 hypertrophic cardiomyopathy HCM (n=20). Other testing (n=5) was performed for familial hypercholesterolaemia, hereditary amyloidosis, Fabry disease, haemochromatosis and thoracic aortic aneurysm. 10 positive results and 1 high polygenic risk score were identified. 4 were positive from a clinical phenotype of DCM/ACM R132 (3 for TTN and 1 VCL) and 2 from HCM phenotype R131 (MYBPC3 and CSRP-3). Other positive finding were 2 cases of TTR (amyloid), and one each of APOB (high cholesterol) and HFE (haemochromatosis). 59 of the 62 tests followed NGTD criteria, with deviations due to older age or borderline LVEF. 48 patients underwent cMRI, 27 patients underwent coronary angiography. 17 (30%) individuals had a significant family history and yielded 5 positive results and one high polygenic risk score. 5 further positives were obtained from the 40 (70%) individuals who had no significant family history. No variants of uncertain significance were identified. <h3>Conclusion</h3> Mainstreaming of genetic testing for cardiomyopathy is practical and feasible within a heart failure service but does generate significant results which require action. The most common indication is a clinical phenotype of dilated or arrhythmogenic cardiomyopathy (60%) followed by unexplained left ventricular hypertrophy (32%). The rate of positive tests is around 16% and higher in those with a positive family history (30%) compared to those without (12.5%). Education and training of heart failure teams who provide counselling to patients about genetic testing in heart failure is critical to manage these patients and their families optimally.

Background and Aims Fabry disease is a rare genetic disorder that affects multiple organs, including the kidneys. It is characterized by the accumulation of globotriaosylceramide (Gb3) in various tissues and organs, leading to progressive interstitial fibrosis and renal dysfunction. We aim to determine the renal manifestations of Fabry disease in particular the histological aspects. Method This study analyzed 9 patients with Fabry disease and renal involvement in a retrospective, single-center analysis. Clinical and biological data, as well as histologic findings, were collected based on patient's observations. Results Data was collected from 9 patients, including 7 males and 2 females, with an average age at diagnosis of 25.2 years (ranging from 17 to 32 years). All patients showed depleted activity of alpha 1 glycosidase, confirming the diagnosis. Acrosyndrome and vascular cutaneous lesions (angiokeratomas) were the dominant signs at admission with respectively (n=7; n=4), with only 3 patients being identified through familial screening without symptoms. Uncontrolled Hypertension was noted in 2 patients. Renal manifestations included renal hyperfiltration in 2 cases, isolated proteinuria in 4 patients, and renal failure in 3 others with a mean serum creatinine levels of 240 ± 36 µmol/l. Four patients underwent renal biopsy, which showed characteristic lesions of Fabry disease with sphingolipid accumulation and tubular cell vacuolization. Thickening of the glomerular capillary walls was observed in one patient. Interstitial fibrosis and tubular atrophy were noted in 3 patients. All patients received enzyme replacement therapy. Angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin II receptors blockers (ARB) were uses in 6 patients. Five patients progressed to terminal stage of renal failure requiring dialysis after an average follow-up period of 13±2.7 years. Four patients died from cardiovascular complications. Conclusion Early recognition and diagnosis of Fabry disease from the onset of glomerular hyperfiltration and albuminuria are crucial for the initiation of appropriate treatment and management, which can help to delay the progression of renal and other organ damage.

Introduction Fabry disease (FD) is an X-linked rare lysosomal storage disease caused by mutations in the GLA gene which lead to decrease in α Gal A enzyme activity and tissue accumulation of lysosomal globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Due to X linked transmission, males are hemizygous, and females are heterozygous and were initially thought to be unaffected. However, women with FD can vary from asymptomatic, mildly symptomatic, to severely symptomatic as males. The aim of this study is to evaluate the particularities of FD presentation, cardiac imaging and management in females from the full Romanian FD cohort as compared to male patients. Methods This study included all consecutive patients diagnosed in or referred to our center with FD between 2014–2021. All patients had a complete clinical, biological and cardiac imaging workup. Results During the inclusion interval, data from 66 consecutive Romanian FD patients (37 women and 29 men) from 29 unrelated families were collected. Diagnosing mode in FD women differs compared to men (p&amp;lt;0.001): most women were diagnosed through family screening or by a cardiologist, while most men were diagnosed by nephrologists. Women had higher levels of α Gal A levels (1.3±0.8 μmol/L/h vs 0.5±0.7 μmol/L/h, normal cutoff &amp;gt;1.2) (p&amp;lt;0.001) and smaller levels of lyso-GB3 (5.8±2.6 ng/ml vs 110±35.6 ng/ml, normal cutoff&amp;lt;3.8) (p&amp;lt;0.001). More women are asymptomatic carriers than men (27% vs 3.4%), but when symptoms were present, they could be as severe as in men. Enrolled women were older (50.9±16.3 vs 41±14.9 years, p=0.014), diagnosed later (46.8±16.8 vs 32.7±14.3 years, p&amp;lt;0.001) and had later symptom onset of the disease compared with men (38.1±14.4 vs 20.3±14.9 years, p&amp;lt;0.001). Women had less angiokeratomas (p=0.001) and hypohydrosis (p=0.04), with no difference in cornea verticillata or ENT involvement. Both women and men developed cardiac symptoms starting from the fifth decade, with no differences in terms of angina, NYHA class, syncope between sexes. Women tend to have a lower prevalence of LVH compared to men (p=0.052), with no differences regarding ejection fraction or global longitudinal strain between genders. Regarding other organs involved, women were equally affected as men from acroparesthesia and stroke, with similar age at first cerebrovascular event. Women had milder kidney involvement (stages 1 and 2) when compared to men (56.8% vs 37.9%, p=0.004). Regardless of these findings, it appeared that women were less treated with pathogenic therapy comparing to men (48.6% vs 82.7%) (p=0.004). Conclusions Women with FD are not merely genetic carriers as they can be as affected as men. However, they benefit later from diagnosis and less of pathogenic therapy. Further studies with more female participations are needed to better understand the Fabry burden and needs in women. Funding Acknowledgement Type of funding sources: None.

The benefits, challenges and regional differences of family screening in rare genetic diseases: Lessons from Fabry disease