NORD gratefully acknowledges R.J. Desnick, PhD, MD, Dean for Genetic and Genomic Medicine, Professor and Chairman Emeritus, and Dana Doheny, MS, Research Coordinator and Genetic Counselor, International Center for Fabry Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, for assistance in the preparation of this report.
Fabry disease is a rare inherited disorder of lipid (fat) metabolism resulting from the deficient activity of the enzyme, alpha-galactosidase A (a-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by mutations (or alterations) in the a-Gal A gene (abbreviated as GLA
) that instructs cells to make the a-Gal A enzyme. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. a-Gal A functions to break down specific complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect the heart and kidneys.
gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Males are typically more severely affected than females. Females have a more variable course and may be asymptomatic or as severely affected as males (see Genetics section below).
There are two major disease phenotypes: the type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death (Desnick 2001). Type 1 males have little or no functional a-Gal A enzymatic activity (<1% of normal mean), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. These include the acroparesthesia (excruciating pain in the hands and feet which occur with exercise, fevers, stress, etc.); angiokeratomas (clusters of red to blue rash-like discolorations on the skin); anhidrosis or hypohidrosis (absent or markedly decreased sweating); gastrointestinal symptoms including abdominal pain and cramping, and frequent bowel movements; and a characteristic corneal dystrophy (star-burst pattern of the cornea seen by slit-lamp ophthalmologic examination) that does not affect vision (Desnick 2001, Desnick 2009, Germain 2010). With increasing age, the systemic GL-3/Gb3 deposition, especially in the heart leads to arrhythmias, left ventricular hypertrophy (LVH) and then hypertrophic cardiomyopathy (HCM), and in the kidneys to progressive insufficiency then to renal failure, and/or to cerebrovascular disease including transient ischemic attacks (TIAs) and strokes. Prior to renal replacement therapy (i.e., dialysis and transplantation) and enzyme replacement therapy (ERT), the average age of death of affected males with the type 1 classic phenotype was ~40 years (Columbo et al. 1967). The incidence of males with the type 1 classic phenotype is about 1 in 40,000 males, but varies with demography and race, ranging from about ~1 in 18,000 to 1 in 95,000 based on newborn screening studies (Liao 2014, Uribe 2013, Mechtler 2012, Whittman 2012, Scott 2013, Inoue 2013, Hwu 2009, Spada 2006).
In contrast, males with the type 2 “later-onset” phenotype (previously called cardiac or renal variants) have residual a-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not manifest the early manifestations of type 1 males (i.e., the acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy, etc). They experience an essentially normal childhood and adolescence. They typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics (e.g., Linthorst 2010, Elliott 2011, Herrera 2013, Baptista 2014), and recently by newborn screening. Based on these screening studies (e.g., Liao 2014, Uribe 2013, Mechtler 2012, Whittman 2012, Scott 2013, Inoue 2013, Hwu 2009, Spada 2006) the incidence of type 2 later-onset males varies by demography, ethnicity, and race, but is at least 10 times more frequent than that of the type 1 males from the same region, ethnic group, or race.
Clinical manifestations in heterozygous females from families with the type 1 classic phenotype are variable due to random X-chromosomal inactivation (Dobrovolny 2011) and range from asymptomatic to as severe as type 1 classic males (Desnick, 2009, Germain 2015). Type 2 heterozygotes may be asymptomatic or develop renal or cardiac manifestations later in life. At least 90% of type 1 heterozygotes have the characteristic corneal findings, while the type 2 heterozygous females typically lack the characteristic corneal findings or other early type 1 manifestations (Desnick, 2009, 2014). However, the frequency of manifestations in type 2 heterozygotes has not been systematically investigated to date.
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