globotriaosylceramide and Cardiovascular-Diseases

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD's development and progression that could become useful targets for therapeutics. This review discusses FD's cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

Topics: alpha-Galactosidase; Animals; Cardiovascular Diseases; Fabry Disease; Humans; Inflammation; Mitochondria; Mutation; Phenotype; 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 disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity (acroparesthesia, angiokeratoma, autonomic dysfunction, cardiomyopathy and deafness), and mortality from early onset strokes, heart attack and renal failure in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most heterozygotes present with a cardiac, renal or neurological symptomatology, although to a lesser extent than what is observed in hemizygotes. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of possible carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 200 mutations have been identified. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to clinical studies and enzyme replacement therapy has recently been validated as a therapeutic agent for FD patients in clinical trials. Long term safety and efficacy of replacement therapy are currently being investigated.

Topics: alpha-Galactosidase; Amino Acid Substitution; Cardiovascular Diseases; Disease Progression; Eye Diseases; Fabry Disease; Female; Genetic Carrier Screening; Genetic Counseling; Genotype; Humans; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Mutation; Pregnancy; Prenatal Diagnosis; Trihexosylceramides; X Chromosome