globotriaosylceramide and Hypertrophy--Left-Ventricular

Fabry disease is a rare, progressive, X-linked inherited storage disorder due to absent or deficient of lysosomal alfa galactosidase A activity. Deficient activity of alfa-galactosidase A results in progressive accumulation of globotriaosylceramide in a variety of tissues and organs including myocardium, kidney and nerve system. This disorder predominantly affects males; however, female heterozygotes may also be affected with a less severe clinical picture. Classic Fabry disease is usually diagnosed in early age of childhood because of multiorgan involvement whereas cardiac and renal variants of Fabry are manifested in 30-50 years of age because of late onset of clinical picture in which other organs involvement are uncommon. Although Fabry is known as a very rare disease, its prevalence is reported to be higher in patients with ventricular hypertrophy, chronic kidney disease and cryptogenic stroke. From the cardiology point of view, the most important key finding of the disease is unexplained ventricular hypertrophy. However, in clinical practice, ventricular hypertrophy is usually thought to be due to hypertrophic cardiomyopathy in the absence of hypertension or aortic stenosis and Fabry disease is often undiagnosed or overlooked. Early diagnosis and enzyme replacement therapy have been shown to significantly improve prognosis. The aim of this paper is to provide a comprehensive review including epidemiology, prognosis, clinical presentation, diagnosis and therapeutic approaches of cardiac variant of Fabry based on the available data in the literature.

Topics: Age of Onset; alpha-Galactosidase; Arrhythmias, Cardiac; Cardiomegaly; Early Diagnosis; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Enzyme Replacement Therapy; Fabry Disease; Female; Heart Diseases; Heterozygote; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Male; Pedigree; Prognosis; Sex Factors; Symptom Assessment; Trihexosylceramides

Fabry disease resulting from a deficiency of α-galactosidase A leads to the accumulation of globotriaosylceramide in various organs. Because the disease is an X-linked recessive disorder, males tend to develop more symptoms and more severe symptoms than females. There are also some variants of Fabry disease, and cardiac variant (cardiac Fabry disease) has the dysfunctions only in heart. Cardiac manifestations in Fabry disease are initially symmetrical and concentric left ventricular hypertrophy, and later progressive cardiac dysfunction with localized thinning of the basal posterior wall. In recent years, enzyme replacement therapy has been performed as a treatment for Fabry disease, and the initiation of this therapy is expected before the cardiac fibrosis develops. Therefore, early diagnosis of Fabry disease is essential, and echocardiography is an indispensable tool for clinical practice of this disease. Then, it is necessary to remember this disease as a differential diagnosis when encountering unexplained left ventricular hypertrophy.

Topics: Adult; Age of Onset; Child; Child, Preschool; Early Diagnosis; Early Medical Intervention; Echocardiography; Enzyme Replacement Therapy; Fabry Disease; Fibrosis; Humans; Hypertrophy, Left Ventricular; Myocardium; Trihexosylceramides; Ventricular Dysfunction

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

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

Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.. The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes.. The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased.. Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Topics: 1-Deoxynojirimycin; Adolescent; Adult; Aged; alpha-Galactosidase; Diarrhea; Double-Blind Method; Fabry Disease; Female; Glomerular Filtration Rate; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Kidney; Male; Middle Aged; Mutation; Trihexosylceramides; Ultrasonography; Young Adult

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

Left ventricular hypertrophy (LVH) is a frequent echocardiographic feature in Fabry disease (FD) and in severe cases may be confused with hypertrophic cardiomyopathy (HCM) of other origin. The prevalence of FD in patients primarily diagnosed with HCM varies considerably in screening and case finding studies, respectively. In a significant proportion of patients, presenting with only mild or moderate LVH and unspecific clinical signs FD may remain undiagnosed. Urinary Gb3 isoforms have been shown to detect FD in both, women and men. We examined whether this non-invasive method would help to identify new FD cases in a non-selected cohort of patients with various degree of LVH.. Consecutive patients older than 18 years with a diastolic interventricular septal wall thickness of ≥12mm determined by echocardiography were included. Referral diagnosis was documented and spot urine was collected. Gb3 was measured by mass spectroscopy. Subjects with an elevated Gb3-24:18 ratio were clinically examined for signs of FD, α-galactosidase-A activity in leukocytes was determined and GLA-mutation-analysis was performed. We examined 2596 patients. In 99 subjects urinary Gb3 isoforms excretion were elevated. In these patients no new cases of FD were identified by extended FD assessment. In two of three patients formerly diagnosed with FD Gb3-24:18 ratio was elevated and would have led to further diagnostic evaluation.. Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method.

Topics: Adult; Aged; Aged, 80 and over; alpha-Galactosidase; Echocardiography; Fabry Disease; Female; Glycolipids; Humans; Hypertrophy, Left Ventricular; Male; Mass Spectrometry; Middle Aged; Spectrometry, Mass, Electrospray Ionization; Trihexosylceramides

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

Topics: Algorithms; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Electrocardiography; Enzyme Therapy; Fabry Disease; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Male; Myocardium; Sex Factors; Trihexosylceramides; Vascular Diseases

Fabry disease is an X-linked lysosomal disorder that results from a deficiency of the lysosomal enzyme alpha-galactosidase A leading to accumulation of glycolipids, mainly globotriaosylceramide in the cells from different tissues. Classical Fabry disease affects various organs. Clinical manifestations start at early age and include angiokeratoma, acroparesthesia, hypohydrosis, heat/exercise intolerance, gastrointestinal pain, diarrhea, and fever. The main complications of Fabry disease are more prominent after the age of 30 when kidney, heart, and/or cerebrovascular disorders appear. Most of the heterozygous females are symptomatic. Enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated. Quality of life of patients receiving ERT is improved. Enzyme replacement stabilizes or slows the decline in renal function and reduces left ventricular hypertrophy. Fabry disease may be underdiagnosed because of nonspecific and multiorgan symptoms. Different screening strategies have been carried out in different at-risk populations in order to detect undiagnosed Fabry patients. An increasing knowledge about Fabry disease within the medical community increases the chances of patients to receive a timely diagnosis and, consequently, to access the appropriate therapy.

Topics: alpha-Galactosidase; Enzyme Replacement Therapy; Fabry Disease; Female; Genetic Testing; Heterozygote; Humans; Hypertrophy, Left Ventricular; Infant, Newborn; Male; Neonatal Screening; Pregnancy; Prenatal Diagnosis; Quality of Life; Trihexosylceramides

Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb(3)) accumulates in Fabry patients as a result of alpha-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb(3) levels in plasma and urine, and clinical symptoms is not firmly established.. Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy.. Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb(3) was found to be more elevated in plasma samples from male (n = 26; median 6.27 micromol/L (1.39-9.74)) than female Fabry patients (n = 37; median 2.16 (0.77-4.18)). This was also observed for urinary Gb(3): males (n = 22) median 1851 nmol/24 h (40-3724); females (n = 29) median 672 (86-2052). Plasma and urinary Gb(3) levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb(3) levels and clinical symptoms could be detected.. Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb(3) levels, limiting their value as surrogate disease markers.

Topics: Adolescent; Aged; Cohort Studies; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Netherlands; Phenotype; Quality of Life; Retrospective Studies; Sex Factors; Surveys and Questionnaires; Trihexosylceramides

Fabry disease is an underdiagnosed, treatable, X-linked, multisystem disorder.. To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials.. Prospective, cross-sectional, observational study.. Referral to the National Institutes of Health.. Twenty-five male children with Fabry disease (mean age: 12.3 +/- 3.5 years) and 21 age-matched control subjects.. Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test).. Quality of life scores for pediatric patients <10 years of age with Fabry disease, compared with published normative values, were 55 +/- 17 vs 83 +/- 19 for bodily pain and 62 +/- 19 vs 80 +/- 13 for mental health. Bodily pain scores for patients > or =10 years of age were 54 +/- 22 vs 74 +/- 23. Sweat volume in the Fabry disease group was 0.41 +/- 0.46 microL/mm2, compared with 0.65 +/- 0.44 microL/mm2 in the control group. Renal function, urinary protein excretion, and cardiac function and structure were normal for the majority of patients. The 3 patients with residual alpha-galactosidase A activity > or =1.5% of normal values were free of cornea verticillata and had normal serum and urinary globotriaosylceramide levels. All other children had glycolipid levels comparable to those of adult patients with Fabry disease. Acroparesthesia and cardiac abnormalities were generally present before anhidrosis and proteinuria. Mapping of the missense mutations on the crystallographic structure of alpha-galactosidase A revealed that the mutations were partially surface-exposed and distal to the active site among individuals with residual enzyme activity. Mutations associated with left ventricular hypertrophy (defined as left ventricular mass index of >51 g/m2.7) were localized near the catalytic site of the enzyme.. Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy.

Topics: Adolescent; alpha-Galactosidase; Blood Cell Count; Body Size; Case-Control Studies; Child; Cross-Sectional Studies; Fabry Disease; Glomerular Filtration Rate; Humans; Hypertrophy, Left Ventricular; Male; Mental Health; Mutation; Pain; Quality of Life; Sweating; Trihexosylceramides