scholarly journals Fabry Disease that Phenocopies Hypertrophic Cardiomyopathy: a thorough Genetic ‘Detective’ Identifies the ‘Rogue’ Hidden in the GLA Gene

2019 ◽  
Vol 49 (5) ◽  
pp. 464 ◽  
Author(s):  
Soonil Kwon ◽  
Seung-Pyo Lee ◽  
Seung Shin Park ◽  
Beom Joon Kim ◽  
Hyung-Kwan Kim ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Gla Gene

Dual therapy with migalastat and agalsidase-beta in a patient with Fabry disease with progressing hypertrophic cardiomyopathy

2021 ◽  
Vol 132 (2) ◽  
pp. S103
Author(s):  
Chanan Stauffer ◽  
Manisha Balwani ◽  
Robert J. Desnick ◽  
Luca Fierro ◽  
Jaya Ganesh
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
Dual Therapy ◽  
Agalsidase Beta

scholarly journals Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology

2016 ◽  
Vol 311 (5) ◽  
pp. F1015-F1024 ◽  
Author(s):  
Ester M. Pereira ◽  
Anatália Labilloy ◽  
Megan L. Eshbach ◽  
Ankita Roy ◽  
Arohan R. Subramanya ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Human Kidney ◽  
Premature Death ◽  
Antibody Array ◽  
Cell Models ◽  
Lysosomal Storage ◽  
Protein Levels ◽  
Gla Gene ◽  
Fabry Nephropathy ◽  
And Control

Fabry nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD), a rare X-linked lysosomal storage disorder. Gb3, the main substrate of α-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD.

MO061IS THE PM290I MUTATION RELATED TO ORGAN INVOLVEMENT OF FABRY DISEASE?

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Francisca Silva ◽  
Nicole Pestana ◽  
José Durães ◽  
Nuno Guimarães Rosa ◽  
Gil Silva
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Genetic Variant ◽  
Clinical Manifestations ◽  
Mutant Enzyme ◽  
Enzyme Replacement ◽  
Screening Study ◽  
Gla Gene

Abstract Background and Aims Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy improved the natural course of this disease, but an early diagnosis is crucial for a successful treatment. Method A screening study for GLA gene mutations was conducted for all patients under dialysis, from a single centre. All the probands with a detectable mutation were analysed individually. Data on the patient's family and personal pathological history were retrospectively collected, by consulting the clinical file. Results 35 years-old female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite optimal medical treatment the disease progressed, and she started renal replacement therapy with peritoneal dialysis. Five years later she was enrolled in a pilot screening study for FD and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon 6 of the GLA gene was found. The proband didn’t meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index, a new ischemic cerebral lesion and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to the decision to initiate enzyme replacement therapy. Until now there are only a few descriptions of this genetic variant in the scientific literature. A Portuguese study analysed a total of 11 FD patients and described 2 patients with p.M290I mutation, without detectable Gb3 accumulation. Another study was designed to evaluate the genotype-phenotype relationship in 73 Chinese FD patients. Contrary to other reports, the p.M290I mutation was not associated to the classic FD phenotype. A Swiss investigation with a similar design analysed 69 FD patients during their routine annual examinations. M290I mutant enzyme was found in a 48-year-old heterozygous female with a classic FD phenotype but with a low serum LysoGb3. A Spanish newborn screening identified one male patient with FD and the p.M290I genetic variant but was unable to provide any information about the clinical expression of this mutation, since the diagnosis was made between the third and fifth days of life. The study describing the most patients carrying the M290I mutant enzyme is Brazilian and screened a total of 25,223 dialysis patients. Among 89 FD-positive patients, the p.M290I mutation was present in 22. However, the authors did not provide detailed information about the clinical manifestations or α-Gal A activity and LysoGb3 levels of these patients. Finally, a recent Portuguese screening of 150 hypertrophic cardiomyopathy patients found 25 patients with FD. Of these, one female carried the GLA gene variant p.M290I, with a non-detectable LysoGb3 plasma level. Conclusion We describe a case of FD due to a previously known but still poorly described GLA mutation, which offers strong evidence of its pathogenicity. To our knowledge, this is the first report of p.M290I mutation-associated disease activity evidenced by elevated levels of serum LysoGb3. Despite the absence of classic FD symptoms such as neuropathic pain, cornea verticillata and angiokeratoma, the presence of severe multiple organ evolvement, characterized by renal failure, cardiac disease and ischaemic stroke, strongly suggests a classic phenotype. Consequently, it is our opinion that the presence of a p.M290I GLA mutation should require a strict ongoing patient follow-up, as it may cause clinically significant disease.

Use of Myocardial T1 Mapping at 3.0 T to Differentiate Anderson-Fabry Disease from Hypertrophic Cardiomyopathy

Radiology ◽  
2018 ◽  
Vol 288 (2) ◽  
pp. 398-406 ◽  
Author(s):  
Gauri R. Karur ◽  
Sean Robison ◽  
Robert M. Iwanochko ◽  
Chantal F. Morel ◽  
Andrew M. Crean ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Fabry Disease ◽  
T1 Mapping ◽  
Myocardial T1 ◽  
3.0 T

First case of late onset cardiac phenotype Fabry disease due to an AluYb8 insertion in exon 7 of the GLA gene

2019 ◽  
Vol 20 (10) ◽  
pp. 1182-1182
Author(s):  
Constantin Gatterer ◽  
Dietrich Beitzke ◽  
Raute Sunder-Plassmann ◽  
Gere Sunder-Plassmann ◽  
Senta Graf
Keyword(s):  
Fabry Disease ◽  
Late Onset ◽  
Cardiac Phenotype ◽  
First Case ◽  
Gla Gene
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