globotriaosylceramide and Cardiomyopathies

Anderson-Fabry disease (AFD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme α-galactosidase A (α-Gal A). Anderson-Fabry cardiomyopathy is characterized by structural, valvular, vascular and conduction abnormalities, and is now the most common cause of mortality in patients with AFD. Large-scale metabolic and genetic screening studies have revealed AFD to be prevalent in populations of diverse ethnic origins, and the variant form of AFD represents an unrecognized health burden. Anderson-Fabry disease is an X-linked disorder, and genetic testing is critical for the diagnosis of AFD in women. Echocardiography with strain imaging and cardiac magnetic resonance imaging using late enhancement and T1 mapping are important imaging tools. The current therapy for AFD is enzyme replacement therapy (ERT), which can reverse or prevent AFD progression, while gene therapy and the use of molecular chaperones represent promising novel therapies for AFD. Anderson-Fabry cardiomyopathy is an important and potentially reversible cause of heart failure that involves LVH, increased susceptibility to arrhythmias and valvular regurgitation. Genetic testing and cardiac MRI are important diagnostic tools, and AFD cardiomyopathy is treatable if ERT is introduced early.

Topics: Adult; alpha-Galactosidase; Cardiomyopathies; Disease Management; Echocardiography; Enzyme Replacement Therapy; Fabry Disease; Female; Genetic Testing; Genetic Therapy; Heart Failure; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Risk Factors; Sex Factors; Trihexosylceramides

Fabry disease (FD) is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs.. Being X-chromosomal-linked, most studies in the past have focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and thus need to be treated, respectively.. This review wants to give a systematical overview of the typical organ involvement in female patients with FD. Moreover, therapy recommendations especially for female patients are discussed.

Topics: Adult; alpha-Galactosidase; Brain Diseases; Cardiomyopathies; Fabry Disease; Female; Glycosphingolipids; Humans; Kidney Diseases; Middle Aged; Patient Care Team; Severity of Illness Index; Trihexosylceramides; Young Adult

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. Intracellular accumulation of globotriaosylceramide starts in utero and progressively develops in various tissues and organs. Cardiac involvement is frequent, and its presentation as concentric nonobstructive left ventricular hypertrophy serves as a model for other hypertrophic cardiomyopathies. This review describes the Fabry cardiomyopathy, its treatment, and multidisciplinary patient care models. These models will help clinicians in diagnosing, assessing, and treating patients with Fabry disease. As the models can be extrapolated to other diseases, they might contribute to more optimal clinical management of patients with other cardiac disorders.

Topics: alpha-Galactosidase; Cardiomyopathies; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Male; Treatment Outcome; Trihexosylceramides

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of alpha-galactosidase A. The subsequent accumulation of globotriaosylceramide (Gb3) in cells and tissues of the body has multisystemic effects and significantly impacts upon quality of life and survival of individuals with this condition. In general, Anderson-Fabry disease is more severe in male patients; however, despite X-linkage, females may develop severe signs and symptoms of the disease, although there is considerable phenotypic heterogeneity, which correlates most closely with age. Histological analyses of biopsies have shown evidence of Gb3 storage in the kidney and heart in female patients. Gb3 levels are also elevated in the urine of females, although plasma Gb3 levels are not reliably elevated. The efficacy of enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A has been demonstrated in females in a clinical trial and in observational studies, including those using data from outcome surveys. Benefits include a reduction in left ventricular mass, stabilization of renal function and improvements in pain and quality of life.. If early intervention with ERT in females is to be advocated, it is necessary to demonstrate not only that females with Anderson-Fabry disease have clinical and biochemical features of alpha-galactosidase A deficiency and respond to ERT, but also that early intervention prevents the onset of the later manifestations of the disorder. Any strategy for early therapy should also balance future advantages against any impact on quality of life.

Topics: Age Factors; alpha-Galactosidase; Cardiomyopathies; Cardiovascular Diseases; Disease Progression; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Trihexosylceramides

Anderson-Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb(3)) in the lysosomes of cells throughout the body that ultimately results in premature death from renal, cardiac or cerebrovascular complications. Until recently, there was no effective therapy available for this disease. The present study was designed to assess the safety and efficacy of enzyme replacement therapy with agalsidase alfa on the cardiac manifestations of Anderson-Fabry disease.. The effects of therapy with agalsidase alfa on cardiac structure and function were assessed in a randomised, double-blind, placebo-controlled study of 15 adult male patients with Anderson-Fabry disease. The following parameters were measured at baseline and 6 months: left ventricular mass, QRS duration and levels of Gb(3) in cardiac tissue, urine sediment and plasma. After 6 months of the randomised trial patients were enrolled in a 2-year open-label extension study.. Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041). A mean 20% reduction in myocardial Gb(3) content as assessed by serial transvenous endomyocardial biopsies was demonstrated over the 6 months of enzyme replacement compared to a mean 10% increase in patients receiving placebo (p = 0.42). Enzyme replacement therapy with agalsidase alfa resulted in regression of the hypertrophic cardiomyopathy associated with Anderson-Fabry disease.

Topics: Adult; Aged; alpha-Galactosidase; Cardiomyopathies; Chromatography, High Pressure Liquid; Double-Blind Method; Echocardiography; Electrocardiography; Fabry Disease; Heart Conduction System; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Angiography; Male; Middle Aged; Myocardium; Trihexosylceramides; Ventricular Dysfunction, Left

Topics: alpha-Galactosidase; Arrhythmias, Cardiac; Biopsy; Cardiomyopathies; Fabry Disease; Humans; Lysosomes; Trihexosylceramides

Fabry disease is an X-linked disease caused by mutations in α-galactosidase A (GLA); these mutations result in the accumulation of its substrates, mainly globotriaosylceramide (Gb3). The accumulation of glycosphingolipids induces pathogenic changes in various organs, including the heart, and Fabry cardiomyopathy is the most frequent cause of death in patients with Fabry disease. Existing therapies to treat Fabry disease have limited efficacy, and new approaches to improve the prognosis of patients with Fabry cardiomyopathy are required.. We generated induced pluripotent stem cell (iPSC) lines from a female patient and her son. Each iPSC clone from the female patient showed either deficient or normal GLA activity, which could be used as a Fabry disease model or its isogenic control, respectively. Erosion of the inactivated X chromosome developed heterogeneously among clones, and mono-allelic expression of the GLA gene was maintained for a substantial period in a subset of iPSC clones. Gb3 accumulation was observed in iPSC-derived cardiomyocytes (iPS-CMs) from GLA activity-deficient iPSCs by mass-spectrometry and immunofluorescent staining. The expression of ANP was increased, but the cell surface area was decreased in iPS-CMs from the Fabry model, suggesting that cardiomyopathic change is ongoing at the molecular level in Fabry iPS-CMs. We also established an algorithm for selecting proper Gb3 staining that could be used for high-content analysis-based drug screening.. We generated a Fabry cardiomyopathy model and a drug screening system by using iPS-CMs from a female Fabry patient. Drug screening using our system may help discover new drugs that would improve the prognosis of patients with Fabry cardiomyopathy.

Topics: alpha-Galactosidase; Cardiomyopathies; Drug Evaluation, Preclinical; Fabry Disease; Female; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Patients; Trihexosylceramides; X Chromosome Inactivation

To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry.. We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing.. Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause.. We describe a novel familial Gb3-associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.

Topics: Adult; Biopsy, Needle; Cardiomyopathies; Diagnosis, Differential; Disease Progression; Fabry Disease; Female; Heart Failure; Heterozygote; Humans; Hypertrophy, Left Ventricular; Immunohistochemistry; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Prognosis; Risk Assessment; Sampling Studies; Survival Rate; Trihexosylceramides