Autopsy Findings of Heterozygous Fabry Disease with the Severe Phenotype: A Case Report

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Maki Hiratsuka ◽  
Katsushi Koyama ◽  
Makoto Ito ◽  
Ryo Sato ◽  
Kodai Suzuki ◽  
...  
Keyword(s):  
Renal Failure ◽  
Fabry Disease ◽  
Cerebral Hemorrhage ◽  
Lysosomal Storage ◽  
Severe Phenotype ◽  
Autopsy Findings ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
End Stage

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder, with hemizygous males being more severely affected than heterozygous females. Herein, we report a rare case of FD in a heterozygous female with a severe phenotype. The patient had obesity and hyperlipidemia and had her first cerebral infarction at the age of 33 years. She underwent renal biopsy and was diagnosed with FD with morphological features of focal segmental glomerulosclerosis nephropathy at the age of 34 years. Her leukocyte alpha-galactosidase A activity was 2.3 Agal/U (normal: >20 Agal/U), and genetic analysis revealed the presence of the classical phenotype. Enzyme replacement therapy (ERT) was initiated at the age of 35 years; however, peritoneal dialysis owing to end-stage renal failure occurred at the age of 37 years. The patient died of a cerebral hemorrhage at the age of 44 years. Her Mainz Severity Score Index at the time of death was 48/76, suggestive of the severe phenotype. Autopsy findings revealed remarkable globotriaosylceramide accumulation on electron microscopy, particularly in the major organs and their vascular smooth muscle cells. Regarding the vertebral arteries which sourced the cerebral hemorrhage, the effects of FD-induced vascular thickening and long-term renal failure-induced atherosclerosis were confirmed. Furthermore, the patient’s vascular sclerosis was modified with acquired factors such as lifestyle-related disease associated with obesity. We recommend intensified treatment for metabolic factors simultaneous with ERT to help in delaying the progression of FD.

Conjunctival lymphangiectasia associated with classic Fabry disease

2017 ◽  
Vol 102 (1) ◽  
pp. 54-58 ◽  
Author(s):  
Melanie D Sivley ◽  
Eric L Wallace ◽  
David G Warnock ◽  
William J Benjamin
Keyword(s):  
Fabry Disease ◽  
Dry Eye ◽  
Imaging System ◽  
University Of Alabama ◽  
Multisystem Disease ◽  
Enzyme Replacement ◽  
Clinical Presentations ◽  
Alpha Galactosidase ◽  
The University

BackgroundFabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival lymphangiectasia (CL) has not previously been associated with FD.MethodsWe examined the eyes of a cohort of 13 adult patients, eight men and five women, with documented classic FD, all treated with enzyme replacement therapy (ERT) at the University of Alabama at Birmingham between February 2014 and April 2015. The average age was 48 years with a range of 35–55 years for men and 21–71 years for women. The mean duration of ERT was 8.4 years (men 8.9 years, women 7.6 years) with a range of 4–14 years. Classical Fabry mutations included Q283X, R227X, W236X and W277X. A high resolution Haag-Streit BQ-900 slit lamp with EyeCap imaging system was used to record conjunctival images.ResultsCL was observed in 11 of the 13 patients (85%) despite long-term ERT. Clinical presentations included single cysts, beaded dilatations and areas of conjunctival oedema. Lesions were located within 6 mm of the corneal limbus. Ten of the 13 subjects (77%) had Fabry-related cataracts and all 13 demonstrated bilateral corneal verticillata. Twelve of the 13 patients had evidence of dry eye, 9 of whom were symptomatic, and 10 had peripheral lymphoedema.ConclusionCL represents a common but under-recognised ocular manifestation of FD, which persists despite ERT, and is often accompanied by peripheral lymphoedema and dry eye syndrome.

scholarly journals ANDERSON-FABRY DISEASE: MANIFESTATION AND PROGNOSIS

2017 ◽  
pp. 46-50
Author(s):  
N. O. Pichkur
Keyword(s):  
Fabry Disease ◽  
Activity Level ◽  
Social Adaptation ◽  
Disease Manifestation ◽  
Enzyme Replacement ◽  
Renal Manifestation ◽  
Patient State ◽  
Alpha Galactosidase ◽  
Stage Renal Disease ◽  
End Stage

The aim of the study was to describe diagnostic and treatment experience of Fabry disease in Ukraine, rare inherited multisystem metaboliс disorder with chronic kidney insufficiency as one of signs. The diagnosis was found in nine years old boy with acroparestesia and multiply angiokeratomas after enzymodiagnostic test (determination of lysosomal enzyme alpha-galactosidase A activity level in peripheral blood leucocytes). The parents gave consent to examine of the other child in family, 19 years old boy with myeloradiculonevritis and inferior paraparesis, and glomerulonephritis presented by proteinuria. Fabry disease was confirmed in proband by special enzymodiagnostic test. Clinical-genealogical analysis was exposed by the "phenomenon of grandfather": grandfather exitus from End Stage Renal Disease, probably due renal manifestation of Fabry disease. Enzyme replacement therapy was stabilized patient state, decreased the proteinuria level and saved the renal function. Early and classic signs of Fabry disease which allows to suspect a genetic anomaly were presented in article. Information about Fabry disease physician followed by in-time diagnosis and onset of specific therapy those provide favorable disease course, social adaptation and rehabilitation of patient, effective medical-genetic consultation in gen-compromised families.

Rare presentation of Fabry disease as ‘burnt-out’ hypertrophic cardiomyopathy

2021 ◽  
Vol 14 (9) ◽  
pp. e243604
Author(s):  
Sam Williams ◽  
Ahmed El-Medany ◽  
Angus Nightingale ◽  
Yasmin Ismail
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Left Ventricular ◽  
Diagnostic Tools ◽  
Lysosomal Storage ◽  
Rare Presentation ◽  
Enzyme Replacement ◽  
End Stage Heart Failure ◽  
End Stage

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow-up, before presenting with end-stage heart failure. This was initially suspected as dilated cardiomyopathy and then ‘burnt-out phase’ of HCM but subsequently the underlying diagnosis was Fabry disease. Fabry disease is an uncommon lysosomal-storage disease due to reduced or absent activity of the alpha-galactosidase A enzyme. Cardiac involvement most frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabry can progress to a ‘burnt out’ phase, whereby initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle.

scholarly journals Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5784
Author(s):  
Sanne J. van der Veen ◽  
Wytze J. Vlietstra ◽  
Laura van Dussen ◽  
André B.P. van Kuilenburg ◽  
Marcel G. W. Dijkgraaf ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Treatment Prediction ◽  
Multiple Variables ◽  
Male Patients ◽  
Pre Treatment ◽  
Alpha Galactosidase ◽  
Development Risk ◽  
Associated Variables

Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

scholarly journals Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-Up

2021 ◽  
Vol 10 (8) ◽  
pp. 1664
Author(s):  
Clara Carnicer-Cáceres ◽  
Jose Antonio Arranz-Amo ◽  
Cristina Cea-Arestin ◽  
Maria Camprodon-Gomez ◽  
David Moreno-Martinez ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Fabry Disease ◽  
Clinical Manifestations ◽  
Organ Injury ◽  
Lysosomal Storage ◽  
Pathogenic Mechanisms ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
Gla Gene ◽  
Response Biomarkers

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

scholarly journals Fabry Cardiomyopathy: Current Treatment and Future Options

2021 ◽  
Vol 10 (14) ◽  
pp. 3026
Author(s):  
Irfan Vardarli ◽  
Manuel Weber ◽  
Christoph Rischpler ◽  
Dagmar Führer ◽  
Ken Herrmann ◽  
...  
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
Left Ventricular ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Alpha Galactosidase ◽  
Nerve System ◽  
Future Therapy ◽  
Reduced Activity

Fabry disease is a multisystem X-linked lysosomal storage disorder caused by a mutation in the alpha-galactosidase A gene. Deficiency or reduced activity of alpha-galactosidase A (GLA) is leading to progressive intracellular accumulation of globotriaosylceramide (GL3) in various organs, including the heart, kidney and nerve system. Cardiac involvement is frequent and is evident as concentric left ventricular hypertrophy. Currently, the standard treatment is enzyme replacement therapy or chaperone therapy. However, early starting of therapy, before myocardial fibrosis has developed, is essential for long-term improvement of myocardial function. For future treatment options, various therapeutic approaches including gene therapy are under development. This review describes the current and potential future therapy options for Fabry cardiomyopathy.

P0081IMPACT OF RENAL FAILURE ON OVERALL SURVIVAL OF PATIENTS WITH FABRY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ekaterina Karovaikina ◽  
Sergey Moiseev ◽  
Nikolay Bulanov ◽  
Alexey Moiseev ◽  
Agunda Kuchieva ◽  
...  
Keyword(s):  
Overall Survival ◽  
Renal Failure ◽  
Fabry Disease ◽  
Survival Function ◽  
Chronic Hemodialysis ◽  
Dialysis Initiation ◽  
Rank Test ◽  
Enzyme Replacement ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims End-stage renal disease (ESRD) is associated with significant morbidity and mortality among patients with Fabry disease (FD). The aim of our study was to evaluate impact of renal failure on overall survival of patients with FD. Method We recruited 117 adult (&gt;18 years) patients with FD that was confirmed by enzymatic and genetic studies. ESRD was defined according to the KDIGO guidelines (2012). Kaplan-Meyer analysis and Log Rank test were used to estimate overall survival of patients with FD. Results Thirty-seven (36 males and 1 female) of 117 patients had ESRD. Thirty-three of them were treated with chronic hemodialysis, whereas four patients have undergone renal transplantation. Among patients with ESRD eleven (29.7%) patients died at the median age of 43 (37; 46) years. All deceased patients were males. The median time from dialysis initiation to death was 32 (6; 67) months. The causes of death included sudden cardiac death (n=9), stroke (n=1) and peritonitis (n=1). Only 2 deceased patients received enzyme replacement therapy over 3 and 11 months. There were deaths only in the ESRD group (Table). There was a decline in survival function after the age of 30 years in patients with ESRD. In Kaplan-Meyer analysis overall survival was 51.2 years (95% Confidence interval 47.7-54.7) and was lower in patients with ESRD (Log Rank (mantel-Cox) χ2=17.5, df 1, р&lt;0.0001, Figure). Five- and 10-year survival after dialysis initiation was 72.5% and 54.1%, respectively. Conclusion ESRD was the major factor associated with low survival of patients with FD in Russia. One out of every 3 dialysis patients died in 5 years after dialysis initiation.

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