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International Journal of Molecular... Feb 2022Fabry disease is an X-linked lysosomal multisystem storage disorder induced by a mutation in the alpha-galactosidase A (GLA) gene. Reduced activity or deficiency of... (Review)
Review
Fabry disease is an X-linked lysosomal multisystem storage disorder induced by a mutation in the alpha-galactosidase A (GLA) gene. Reduced activity or deficiency of alpha-galactosidase A (AGAL) leads to escalating storage of intracellular globotriaosylceramide (GL-3) in numerous organs, including the kidneys, heart and nerve system. The established treatment for 20 years is intravenous enzyme replacement therapy. Lately, oral chaperone therapy was introduced and is a therapeutic alternative in patients with amenable mutations. Early starting of therapy is essential for long-term improvement. This review describes chaperone therapy in Fabry disease.
Topics: 1-Deoxynojirimycin; Fabry Disease; Humans; Male; Mutation; Time-to-Treatment; Trihexosylceramides; alpha-Galactosidase
PubMed: 35163813
DOI: 10.3390/ijms23031887 -
Anatolian Journal of Cardiology Apr 2023
Topics: Humans; Artificial Intelligence; Fabry Disease
PubMed: 36995060
DOI: 10.14744/AnatolJCardiol.2023.4 -
Clinical Genetics Sep 2021Fabry (or Anderson-Fabry) is a rare pan-ethnic disease affecting males and females. Fabry is an X-linked lysosomal storage disease, affecting glycosphingolipid... (Review)
Review
Fabry (or Anderson-Fabry) is a rare pan-ethnic disease affecting males and females. Fabry is an X-linked lysosomal storage disease, affecting glycosphingolipid metabolism, that is caused by mutations of the GLA gene that codes for α-galactosidase A. Fabry disease (FD) can be classified into a severe, classical phenotype, most often seen in men with no residual enzyme activity, that usually appear before 18 years and a usually milder, nonclassical (later-onset) phenotype that usually appear above 18 years. Affected patients show multifactorial complications, including renal failure, cardiovascular problems, and neuropathy. In this review, we briefly report the clinical trials so far performed with the available therapies, and then we focus on the in vitro and the in vivo experimental models of the disease, to highlight the relevance in improving the existing therapeutics and understand the mechanism of this rare disorder. Current available in vivo and in vitro models can assist in better comprehension of the pathogenesis and underlying mechanisms of FD, thus the existing therapeutic approaches can be optimized, and new options can be developed.
Topics: Animals; Disease Models, Animal; Enzyme Replacement Therapy; Fabry Disease; Genetic Therapy; Humans
PubMed: 33997974
DOI: 10.1111/cge.13999 -
Postgraduate Medical Journal Dec 2018Fabry disease is a rare inborn error of the enzyme α-galactosidase (α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical... (Review)
Review
Fabry disease is a rare inborn error of the enzyme α-galactosidase (α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years, in particular since enzyme replacement therapy (ERT) has become widely available in 2001. With rising awareness and rising numbers of (diagnosed) patients, physicians encounter new challenges. Over 900 α-Gal gene mutations are currently known, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician and a lot of uncertainty for patients. Another challenge are patients who develop neutralising antibodies to ERT, which possibly leads to reduced therapy effectiveness. In this article, we summarise the latest developments in the science community regarding diagnostics and management of this rare lysosomal storage disorder and offer an outlook to future treatments.
Topics: Biomarkers; Enzyme Replacement Therapy; Fabry Disease; Genetic Therapy; Humans
PubMed: 30559317
DOI: 10.1136/postgradmedj-2018-136056 -
Heart (British Cardiac Society) Dec 2023The cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Disease-specific therapy, including enzyme replacement therapy...
OBJECTIVE
The cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Disease-specific therapy, including enzyme replacement therapy (ERT) and chaperone therapy (migalastat), is recommended for patients exhibiting cardiovascular involvement, but its efficacy for modulating cardiovascular disease expression and optimal timing of initiation remains to be fully established. We therefore aimed to systematically review and evaluate the effectiveness of disease-specific therapy compared with placebo, and to no intervention, for the cardiovascular manifestations of Fabry disease.
METHODS
Eight databases were searched from inception using a combination of relevant medical subject headings and keywords. Randomised, non-randomised studies with a comparator group and non-randomised studies without a comparator group were included. Studies were screened for eligibility and assessed for bias by two independent authors. The primary outcome comprised clinical cardiovascular events. Secondary outcomes included myocardial histology and measurements of cardiovascular structure, function and tissue characteristics.
RESULTS
72 studies were included, comprising 7 randomised studies of intervention, 16 non-randomised studies of intervention with a comparator group and 49 non-randomised studies of intervention without a comparator group. Randomised studies were not at serious risk of bias, but the others were at serious risk. Studies were highly heterogeneous in their design, outcome measurements and findings, which made assessment of disease-specific therapy effectiveness difficult.
CONCLUSION
It remains unclear whether disease-specific therapy sufficiently impacts the cardiovascular manifestations of Fabry disease. Further work, ideally in larger cohorts, with more standardised clinical and phenotypic outcomes, the latter measured using contemporary techniques, are required to fully elucidate the cardiovascular impact of disease-specific therapy.
PROSPERO REGISTRATION NUMBER
CRD42022295989.
Topics: Humans; Fabry Disease; Cardiovascular Diseases
PubMed: 37640453
DOI: 10.1136/heartjnl-2023-322712 -
Heart (British Cardiac Society) Aug 2003
Topics: Cardiomyopathy, Hypertrophic; Diagnosis, Differential; Fabry Disease; Humans; Hypertrophy, Left Ventricular; Male
PubMed: 12860841
DOI: 10.1136/heart.89.8.819 -
Biochimica Et Biophysica Acta. General... Jan 2020Fabry disease is caused by α-galactosidase A deficiency. Substrates of this lysosomal enzyme accumulate, resulting in cellular dysfunction. Patients experience... (Review)
Review
BACKGROUND
Fabry disease is caused by α-galactosidase A deficiency. Substrates of this lysosomal enzyme accumulate, resulting in cellular dysfunction. Patients experience neuropathic pain, kidney failure, heart disease, and strokes.
SCOPE OF REVIEW
The clinical picture and molecular features of Fabry disease are described, along with updates on disease mechanisms, animal models, and therapies.
MAJOR CONCLUSIONS
How the accumulation of α-galactosidase A substrates, mainly glycosphingolipids, leads to organ damage is incompletely understood. Enzyme replacement and chaperone therapies are clinically available to patients, while substrate reduction, mRNA-based, and gene therapies are on the horizon. Animal models exist to optimize these therapies and elucidate disease mechanisms for novel treatments.
GENERAL SIGNIFICANCE
Recent newborn screening studies demonstrate that Fabry disease is the most common lysosomal storage disease. As many countries now include Fabry disease in their screening panels, the number of identified patients is expected to increase significantly. Better knowledge of disease pathogenesis is needed to improve treatment options.
Topics: Animals; Disease Models, Animal; Enzyme Replacement Therapy; Fabry Disease; Glycosphingolipids; Humans; Lysosomal Storage Diseases; RNA, Messenger; alpha-Galactosidase
PubMed: 31526868
DOI: 10.1016/j.bbagen.2019.129437 -
Clinical Journal of the American... Apr 2020
Review
Topics: Early Diagnosis; Enzyme Replacement Therapy; Fabry Disease; Genetic Predisposition to Disease; Humans; Isoenzymes; Kidney Diseases; Mutation; Phenotype; Predictive Value of Tests; Prognosis; Recombinant Proteins; Risk Assessment; Risk Factors; alpha-Galactosidase
PubMed: 32132142
DOI: 10.2215/CJN.09480819 -
Genes Sep 2020Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the... (Review)
Review
Progressive nephropathy is one of the main features of Fabry disease, which largely contributes to the overall morbidity and mortality burden of the disease. Due to the lack of specific biomarkers, the heterogeneity of the disease, and unspecific symptoms, diagnosis is often delayed. Clinical presentation in individual patients varies widely, even in patients from the same family carrying the same pathogenic variant. Therefore, it is reasonable to anticipate that additional genomic, transcriptomic, proteomic, and metabolomics factors influence the manifestation and progression of the disease. The aim of this article is to provide an overview of nephropathy in Fabry patients and the biomarkers currently used in the diagnosis and follow-up. Current biomarkers are associated with late signs of kidney damage. Therefore, there is a need to identify biomarkers associated with early stages of kidney damage that would enable early diagnosis, which is crucial for effective treatment and prevention of severe irreversible complications. Recent advances in sequencing and -omics technologies have led to several studies investigating new biomarkers. We will provide an overview of the novel biomarkers, critically evaluate their clinical utility, and propose future perspectives, which we believe might be in their integration.
Topics: Animals; Biomarkers; Computational Biology; Fabry Disease; Genomics; Humans; Kidney Diseases; Metabolomics; Proteomics
PubMed: 32962051
DOI: 10.3390/genes11091091 -
Genes Dec 2023Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the gene on the X chromosome, leading to a deficiency in α-galactosidase A (AGAL) enzyme... (Review)
Review
Fabry Disease (FD) is a rare lysosomal storage disorder caused by mutations in the gene on the X chromosome, leading to a deficiency in α-galactosidase A (AGAL) enzyme activity. This leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in vital organs such as the kidneys, heart, and nervous system. While FD was initially considered predominantly affecting males, recent studies have uncovered that heterozygous Fabry women, carrying a single mutated gene, can manifest a wide array of clinical symptoms, challenging the notion of asymptomatic carriers. The mechanisms underlying the diverse clinical manifestations in females remain not fully understood due to X-chromosome inactivation (XCI). XCI also known as "lyonization", involves the random inactivation of one of the two X chromosomes. This process is considered a potential factor influencing phenotypic variation. This review delves into the complex landscape of FD in women, discussing its genetic basis, the available biomarkers, clinical manifestations, and the potential impact of XCI on disease severity. Additionally, it highlights the challenges faced by heterozygous Fabry women, both in terms of their disease burden and interactions with healthcare professionals. Current treatment options, including enzyme replacement therapy, are discussed, along with the need for healthcare providers to be well-informed about FD in women, ultimately contributing to improved patient care and quality of life.
Topics: Male; Humans; Female; Fabry Disease; Quality of Life; Kidney; Lysosomal Storage Diseases; Biomarkers
PubMed: 38254927
DOI: 10.3390/genes15010037