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.

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.

Treatment of Anderson-Fabry Disease

2020 ◽  
Vol 26 (40) ◽  
pp. 5089-5099 ◽  
Author(s):  
Irene Simonetta ◽  
Antonino Tuttolomondo ◽  
Mario Daidone ◽  
Salvatore Miceli ◽  
Antonio Pinto
Keyword(s):  
Fabry Disease ◽  
Treatment Strategies ◽  
Signs And Symptoms ◽  
Current Treatment ◽  
Viral Gene ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Cell Based Therapy ◽  
Organ Manifestations ◽  
Alpha Galactosidase

: Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry’s disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. : This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.

scholarly journals Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease

2019 ◽  
Vol 60 (1) ◽  
pp. 208-214
Author(s):  
Miki Tsujiuchi ◽  
Mio Ebato ◽  
Hideyuki Maezawa ◽  
Takuya Mizukami ◽  
Ayaka Nogi ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Long Term Effects ◽  
Enzyme Replacement

scholarly journals Kidney Transplant in Fabry Disease: A Revision of the Literature

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 284 ◽  
Author(s):  
Irene Capelli ◽  
Valeria Aiello ◽  
Lorenzo Gasperoni ◽  
Giorgia Comai ◽  
Valeria Corradetti ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Transplantation ◽  
Fabry Disease ◽  
Therapeutic Option ◽  
Gene Mutations ◽  
Disease Recurrence ◽  
Long Term Effects ◽  
Enzyme Replacement ◽  
Fabry Nephropathy

Fabry disease is classified as a rare X-linked disease caused by a complete or partial defect of enzyme alpha-galactosidase, due to GLA gene mutations. This disorder leads to intracellular globotriaosylceramide (Gb3) deposition associated with increased Gb3 plasma levels. Most of the symptoms of the disease, involving kidneys, heart and nervous system, result from this progressive Gb3 deposition. The incidence is estimated in 1/50,000 to 1/117,000 in males. Fabry nephropathy begins with microalbuminuria and/or proteinuria, which, in the classic form, appear from childhood. Thus, a progressive decline of renal function can start at a young age, and evolve to kidney failure, requiring dialysis or renal transplantation. Enzyme replacement therapy (ERT), available since 2001 for Fabry disease, has been increasingly introduced into the clinical practice, with overall positive short-term and long-term effects in terms of ventricular hypertrophy and renal function. Kidney transplantation represents a relevant therapeutic option for Fabry nephropathy management, for patients reaching end-stage renal disease, but little is known about long-term outcomes, overall patient survival or the possible role of ERT after transplant. The purpose of this review is to analyze the literature on every aspect related to kidney transplantation in patients with Fabry nephropathy: from the analysis of transplant outcomes, to the likelihood of disease recurrence, up to the effects of ERT and its possible interference with immunosuppression.

scholarly journals Ocular findings in Fabry disease in Colombian patients

Biomédica ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 434-439 ◽  
Author(s):  
Katherine Rothstein ◽  
Jubby M. Gálvez ◽  
Ángela M. Gutiérrez ◽  
Laura Rico ◽  
Eveling Criollo ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Multidisciplinary Treatment ◽  
Case Series ◽  
Clinical History ◽  
Diagnosis And Treatment ◽  
Ophthalmologic Examination ◽  
Alpha Galactosidase ◽  
Prompt Diagnosis ◽  
Ocular Signs

Fabry disease is a rare X-linked disorder caused by an alpha-galactosidase enzyme deficiency, which leads to a progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye.This case series describes the first ophthalmological Colombian report of Fabry disease highlighting the importance of ocular signs as markers of the disease, useful in diagnosis and treatment to avoid long-term complications that lead to a morbi-mortality increment.We describe five cases of Fabry disease from Bogotá, Colombia, including a complete clinical history, ophthalmologic, optometric examination, and photographs. We found that all patients had refractive defects and that in all cases corneal verticillata pattern was found. Four patients presented with posterior capsule lens brown-beige deposits and four patients had conjunctival and retinal tortuous vessels. A complete ophthalmologic examination is important for prompt diagnosis, which is key to starting a multidisciplinary treatment and reducing morbi-mortality.

scholarly journals Circulating microRNAs in Fabry Disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ke Xiao ◽  
Dongchao Lu ◽  
Jeannine Hoepfner ◽  
Laura Santer ◽  
Shashi Gupta ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Premature Death ◽  
Circulating Mirnas ◽  
Serum Samples ◽  
Significant Differential Expression ◽  
Enzyme Replacement ◽  
Beneficial Effects ◽  
Mirna Sequencing ◽  
Continuous Progress ◽  
Alpha Galactosidase

Abstract Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.

scholarly journals Cell Transplantation Combined with Recombinant Collagen Peptides for the Treatment of Fabry Disease

2020 ◽  
Vol 29 ◽  
pp. 096368972097636
Author(s):  
Daisuke Kami ◽  
Masashi Yamanami ◽  
Takahiro Tsukimura ◽  
Hideki Maeda ◽  
Tadayasu Togawa ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Cell Transplantation ◽  
Financial Burden ◽  
Kidney Injury ◽  
The Body ◽  
Term Survival ◽  
Enzyme Replacement ◽  
Continuous Release ◽  
Alpha Galactosidase

Fabry disease is caused by a decrease in or loss of the activity of alpha-galactosidase, which causes its substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) to accumulate in cells throughout the body. This accumulation results in progressive kidney injury due to glomerulosclerosis and in heart failure due to hypertrophy. Enzyme replacement therapy (ERT) has been used as the standard therapy for Fabry disease, but it causes a significant financial burden, and regular administration is inconvenient for patients. Because of the short half-life of alpha-galactosidase in vivo, therapeutic methods that can supplement or replace ERT are expected to involve continuous release of alpha-galactosidase, even at low doses. Cell transplantation therapy is one of these methods; however, its use has been hindered by the short-term survival of transplanted cells. CellSaic technology, which utilizes cell spheroids that form after cells are seeded simultaneously with a recombinant collagen peptide scaffold called a μ-piece, has been used to improve cell survival upon implantation. In this study, syngeneic murine embryonic fibroblasts were used to generate CellSaic that were transplanted into Fabry mice. These spheroids survived for 28 days in the renal subcapsular space with forming blood vessels. These results indicate CellSaic technology could be a platform to promote cellular graft survival and may facilitate the development of cell transplantation methods for lysosomal diseases.

Long-Term and Sustained Correction of the α-Galactosidase A Deficiency in Fabry Mice and Patient Cells Receiving Lentivirally Transduced Hematopoietic Stem/Progenitor Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1285-1285
Author(s):  
Makoto Yoshimitsu ◽  
Christopher Siatskas ◽  
Sheng-Ben Liang ◽  
Vanessa I. Rasaiah ◽  
Koji Higuchi ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Stable Gene ◽  
Inherited Disorders ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Enzyme Replacement ◽  
Vector Systems

Abstract Fabry disease is a lysosomal storage disease caused by a defect in α-galactosidase A (α-gal A). Currently enzyme replacement therapy is available; however frequent infusions are required and long-term outcome in key organs remain to be established. Stable gene augmentation by virus-based delivery can correct cells and offers considerable potential as an effective, long-term therapeutic approach. Our goal is to engineer life-long correction of the disorder with a single treatment. Transplantation of genetically modified autologous hematopoietic stem/progenitor cells (HSPCs), which can self-renew and differentiate multiple cell types, is thus an attractive target in this context. Previously we have demonstrated long-term correction mediated by gene transfer into HSPCs by oncoretroviral vectors both with pre-selection of transduced cells prior to transplantation and without. In the interest of minimizing the effect on the graft by reducing ex vivo culture time and possibly reducing deleterious integration events, we are pursuing other integrative vector systems. It is well known that recombinant lentiviral vectors (LVs) can efficiently transduce not only dividing cells but also non-dividing or less-cycling cells like HSPCs. The aim of this study is to evaluate whether VSV-g pseudotyped LV-mediated gene modification of HSPCs can systemically treat affected organs in Fabry disease mouse model (Fabry mice). We first demonstrated sustained LV-mediated marking of peripheral blood (PB) cells by transducing bone marrow mononuclear cells (BMMNCs) with an LV which encodes enGFP cDNA at an MOI of 30 and transplanting into Fabry mice. Stable and robust enGFP expression (n=5, 65.8±5.8%) in PB cells was observed for >250 days. Next, we transplanted Fabry mice with BMMNCs transduced with an LV encoding the human α-gal A cDNA. Sustained expression of functional α-gal A in Fabry mice was observed over 24 weeks. Plasma α-gal A activity from treated Fabry mice (n=9) was two-fold higher than wild-type controls (n=8). Increased α-gal A activity, often above normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed including heart and kidney which are life-threatening in Fabry disease. To determine whether true HPSCs were transduced by LVs, secondary BM transplantations were performed. PB from secondary transplanted Fabry mice showed multilineage enGFP marking of PB, splenocytes, and BMMNCs, along with therapeutic levels of α-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34+ cells from a Fabry patient with corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease. These studies provide confirmation of the utility of this system for research and therapy for a variety of inherited disorders including Fabry disease.

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