Enzyme replacement therapy in two patients with classic Fabry disease from the same family tree:Two case reports

BACKGROUND The pathophysiology of Fabry disease(FD)-induced progressive vital organ damage is irreversible.Disease progression can be delayed using enzyme replacement therapy(ERT).In patients with classic FD,sporadic accumulation of globotriaosylceramide(GL-3)in the heart and kidney begins in utero;however,until childhood,GL-3 accumulation is mild and reversible and can be restored by ERT.The current consensus is that ERT initiation during early childhood is paramount.Nonetheless,complete recovery of organs in patients with advanced FD is challenging.CASE SUMMARY Two related male patients,an uncle(patient 1)and nephew(patient 2),presented with classic FD.Both patients were treated by us.Patient 1 was in his 50s,and ERT was initiated following end-organ damage;this was subsequently ineffective.He developed cerebral infarction and died of sudden cardiac arrest.Patient 2 was in his mid-30s,and ERT was initiated when the patient was diagnosed with FD,during which the damage to vital organs was not overtly apparent.Although he had left ventricular hypertrophy at the beginning of this treatment,the degree of hypertrophy progression was limited to a minimal range after>18 years of ERT.CONCLUSION We obtained discouraging ERT outcomes for older patients but encouraging outcomes for younger adults with classic FD.

Hydroxychloroquine-induced renal phospholipidosis resembling Fabry disease in undifferentiated connective tissue disease: A case report

BACKGROUND Fabry disease is a kind of lysosomal storage disease resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A(GLA). A mutation in the GLA gene leads to a loss of activity of alpha-galactosidase A. Some drugs,such as hydroxychloroquine, can cause pathological changes similar to those usually seen in Fabry disease.CASE SUMMARY We report the case of a 41-year-old female patient who was diagnosed with undifferentiated connective tissue disease in 2008. Hydroxychloroquine treatment started 2 years ago, and proteinuria and hematuria increased. Renal biopsy demonstrated renal phospholipidosis. Zebra bodies and myelin figures were found by renal electron microscopy and were initially thought to be indicators of Fabry disease. A genetic analysis of the patient and her family members did not reveal mutations in the GLA gene, supporting a diagnosis of hydroxychloroquine-induced renal phospholipidosis.CONCLUSION This report reveals one of the adverse effects of hydroxychloroquine. We should pay more attention to hydroxychloroquine-induced renal phospholipidosis.

Screening of Fabry disease in patients with end-stage renal disease of unknown etiology:the first Thailand study

We aimed to explore the prevalence of Fabry disease in Thai patients who were diagnosed with end-stage renal disease（ESRD） of an unknown origin.Venous blood samples were collected from ESRD patients for biochemical and molecular studies.Alpha-galactosidase A（a-GAL A） screening was performed from dried-blood spots using fluorometry.Molecular confirmation was performed using DNA sequencing of the GLA gene.A total of 142 male and female patients were included in this study.Ten patients（7.04%） exhibited a significant decrease in a-GAL A activity.There were no definitive pathogenic mutations observed in the molecular study.However,four patients revealed a novel nucleotide variant at c.l-10 C〉T,which was identified as a benign variant following screening in the normal population.In conclusion,the a-GAL A assay utilizing dried-blood spots revealed a significant false positive rate.There was no definitive Fabry disease confirmed in Thai patients diagnosed with ESRD of unknown etiology.

Fabry Disease with Aseptic Meningitis:A Case Series and Literature Review of an Underestimated Clinical Presentation

Objective Fabry disease(FD)is an X-linked lysosomal storage disease caused by the mutation in theα-galactosidase A gene that leads to a consequently decreasedα-galactosidase A enzyme activity and a series of clinical presentations.However,FD accompanied with aseptic meningitis can be relatively scarce and rarely reported,which leads to significant clinical misdiagnosis of this disease.Methods Sixteen patients diagnosed with FD based on a decreased activity ofα-galactosidase A enzyme and/or genetic screening were identified through a 6-year retrospective chart review of a tertiary hospital.Clinical presentations,brain magnetic resonance imaging,cerebrospinal fluid analysis,treatment and outcome data were analyzed in cases of aseptic meningitis associated with FD.Results Three out of 16 cases exhibited aseptic meningitis associated with FD.There was one female and two male patients with a mean age of 33.3 years.A family history of renal failure or hypertrophic cardiomyopathy was found in 3 cases.All cases presented with a persistent or intermittent headache and recurrent ischemic stroke.The cerebrospinal fluid analyses showed mild pleocytosis in 2 patients and an elevated level of protein in all patients.Cerebrospinal fluid cytology revealed activated lymphocytes,suggesting the existence of aseptic meningitis.In the literature review,up to 9 cases presenting with FD and aseptic meningitis were found,which bore a resemblance to our patients in demographic and clinical characteristics.Conclusion Our cases suggested that aseptic meningitis in FD might be under-detected and easily misdiagnosed,and should be more thoroughly examined in further cases.

Anderson-Fabry disease presenting with atrial fibrillation as earlier sign in a young patient:A case report

BACKGROUND Anderson-Fabry disease(AFD)is an X-linked lysosomal storage disorder that results from a deficiency ofα-galactosidase A enzyme activity in which glycosphingolipids gradually accumulate in multi-organ systems.Cardiac manifestations are the leading cause of mortality in patients with AFD.Among them,arrhythmias comprise a large portion of the heart disease cases in AFD,most of which are characterized by conduction disorders.However,atrial fibrillation as a presenting sign at the young age group diagnosed with AFD is uncommon.CASE SUMMARY We report a case of a 26-year-old man who was admitted with chest discomfort.Left ventricular hypertrophy was fulfilled in the criteria by the Sokolow-Lyon index and atrial fibrillation on the 12 Leads-electrocardiography(ECG)that was documented in the emergency room.After spontaneously restored to normal sinus rhythm,relationships between P and R waves,including a shorter PR interval on the ECG,were revealed.The echocardiographic findings showed thickened interventricular septal and left posterior ventricular walls.Based on the clues mentioned earlier,we realized the possibility of AFD.Additionally,we noticed the associated symptoms and signs,including bilateral mild hearing loss,neuropathic pain,anhidrosis,and angiokeratoma on the trunk and hands.He was finally diagnosed with classical AFD,which was confirmed by the gene mutation and abnormal enzyme activity ofα-galactosidase A.CONCLUSION This case is a rare case of AFD as a presentation with atrial fibrillation at a young age.Confirming the relationship between P and Q waves on the ECG through sinus rhythm conversion may help in differential diagnosis of the cause of atrial fibrillation and hypertrophic myocardium.

Novelα-galactosidase A gene mutation in a Chinese Fabry disease family:A case report

BACKGROUND Fabry disease(FD)is a rare X-linked lysosomal storage disease caused by a deficiency of the enzymeα-galactosidase A.CASE SUMMARY Herein,we analyzed a four-generation Chinese family.The proband is a 57-yearold woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago.Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm,left ventricular end-diastolic diameter of 63.1 mm,and moderate-to-severe mitral regurgitation.Cardiac magnetic resonance indicated an enlarged left heart and right atrium,decreased left ventricular systolic and diastolic function,a left ventricular ejection fraction of 20%,and thickening of the left ventricular septum.In March 2019,gene and enzyme activity tests confirmed the diagnosis of FD.Her son was diagnosed with FD after gene and enzyme activity assay,and was prescribed agalsidase-βfor enzyme replacement therapy in July 2020.Two sisters of the proband were also diagnosed with FD by genetic testing.Both of them had a history of atrial fibrillation.CONCLUSION A novel mutation was identified in a Chinese family with FD,in which the male patient had a low level of enzyme activity,early-onset,and severe organ involvement.Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.

Neurological manifestations in Fabry disease

Fabry disease(FD)is a rare,progressive,multisystem and highly debilitating disease.FD is an X-linked lysosome storage disorder that results inα-galactosidase A deficiency.The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells.The resulting effect of the deposition is generalized inflammation and vasculopathy,which can also affect the central and peripheral nervous system.FD progresses with kidney dysfunction,angiokeratoma of the skin,cardiomyopathy,cerebrovascular events and neurological disorders.In the present review,the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy,cochlear nerve dysfunction,psychiatric and cognitive symptoms,autonomic dysfunction and peripheral neuropathy.Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life,which make it essential to diagnose FD as soon as possible.

The Diagnostic and Therapeutic Challenges of Fabry Nephropathy—A Review of the Literature, Illustrated by a Clinical Case

Fabry Disease (FD) is a rare lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) enzyme deficiency, resulting in glycosphingolipid accumulation. Its clinical spectrum ranges from severe classical to milder nonclassical or late-onset phenotypes. Renal involvement, termed Fabry Nephropathy (FN), can vary from mild proteinuria to kidney failure. FN diagnosis, especially in nonclassical cases with a genetic Variant of Unknown Significance (VUS) in the GLA gene, poses challenges. Measurement of plasma lyso-Gb3 levels is gaining importance in FN diagnosis, while renal biopsy with electron microscopy remains the gold standard in equivocal cases. Treatment options include Enzyme Replacement Therapy (ERT) and chaperone therapy, demanding careful candidate selection due to high treatment costs. Research has predominantly focused on classical FD, revealing modest treatment benefits. However, evidence for treating patients, especially females, with milder nonclassical or late-onset phenotypes is scarce, emphasizing the necessity for placebo-controlled clinical trials in these subgroups. Meanwhile, participation in global FD registries can improve our understanding of disease management. Case Presentation: A woman in her late sixties presented with moderate chronic kidney disease, mild proteinuria, and microscopic hematuria. Her family history included a prevalence of renal, cardiac and cerebrovascular diseases. Kidney biopsy revealed characteristic myelin figures and zebra bodies in podocytes, strongly suggestive of FN. Genetic analysis identified a VUS in the GLA gene (c.655A > C, p.Ile219Leu), introducing diagnostic uncertainty. Further investigations revealed severe cardiac involvement. Considering the recurring difficulty presented by the finding of a VUS in the GLA gene during FN assessments, along with the uncertainty regarding the need for treatment in nonclassical or late-onset FD phenotypes, especially in women, this case becomes a central focus for a thorough review of the literature. This review aims to propose a practical algorithm that integrates clinical, biochemical, and genetic markers for FN screening and diagnosis. Additionally, it explores treatment benefits in nonclassical or late-onset FD phenotypes, with a focus on female patients.