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.
Type 1 Classic Phenotype
The signs and symptoms of males with type 1 classic phenotype typically begin in childhood or adolescence. Symptoms increase with age due to the progressive glycolipid accumulation in the vascular system, kidneys, and heart leading to kidney failure, heart disease, and/or strokes. Early and progressive clinical symptoms include:
Common Manifestations in Type 1 and 2 Males:
With advancing age in type 1 males, typically in the third to fourth decades, and in type 2 males in the third to sixth decades, the progressive GL-3/Gb3 glycolipid deposition leads to renal and heart manifestations as described below. Many of the type 2 later-onset males who lack the early manifestations in the type 1 boys, are detected in renal, heart, or stroke clinics. Patients with the type 2 later-onset subtype typically do not have the skin lesions (angiokeratoma), sweat normally, do not experience the Fabry pain or crises, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in adult life.
Signs of progressive organ involvement include:
Renal dysfunction. Progressive decrease in renal function is due to the progressive accumulation of GL-3/Gb3 in the kidneys. There is histological evidence of this accumulation and ensuing cellular and vascular injury to renal tissue beginning in childhood and adolescence (Tondel 2008, Najafian 2013, Wijburg 2015.) in type 1 classic males and females. In the type 1 classic males the decline in kidney function progresses to kidney failure and the need for dialysis or transplantation typically by 35 to 45 years of age. In type 2 males, kidney involvement typically occurs in the fourth decade and later. Kidney involvement in type 1 female heterozygotes is more variable. Only about 10-15% of type 1 females develop kidney failure. It is not clear what percentage of type 2 females develop renal dysfunction, if any.
Cardiac disease. GL-3/Gb3 deposition can be found in all cardiac tissues, including myocytes, nerves, and coronary arteries. Heart disease includes heart enlargement, typically left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM), rhythm abnormalities (arrhythmias), and heart failure. LVH occurs in about 20% of males and females with an average age of diagnosis in the early 40s among males and late 40s among females. Early heart involvement in type 1 males typically includes arrhythmias and mitial insufficiency in their twenties followed by LVH leading to HCM. Type 2 later-onset males develop the same heart manifestations as type 1 males and may be first diagnosed in cardiac clinics among patients with LVH or HCM. Heterozygous females with the type 1 phenotype often have sinus bradycardia as an early finding leading to LVH and HCM. It is not clear if type 2 heterozygotes develop heart disease or if they have additionally autosomal dominant HCM due to sarcomere mutations (Desnick, et al., 2014).
Cerebrovascular complications. As a result of the progressive GL-3/Gb3 deposition in the small blood vessels in the brain, about 7% of males and 4% of females with Fabry disease, particularly those with the type 1 phenotype, experience ischemic or hemorrhagic strokes, occurring typically in the fourth decade of life or later (Wilcox 2008).
Fabry disease is caused by mutations (alterations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Chromosomes are found in the nucleus of all cells. They carry the genetic characteristics of each individual in thousands of specific segments, called “genes”, that span the length of the chromosomes. Each of these genes has a specific function in the body. Human chromosomes are organized in pairs, numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Individuals inherit one chromosome in each pair from each parent. Therefore, in X-linked disorders including Fabry disease, disease traits on the X chromosome can be masked in females by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). This means that in X-linked disorders some cells will have the X chromosome with the mutated gene activated and some will have the X chromosome with the functioning gene activated. Therefore, in Fabry disease the symptoms and severity of organ involvement are dependent on what tissues/organs have the X chromosome with the GLA gene mutation activated, which partially explains why the disease severity in females is more variable than in their affected male relatives. Since males have only one X chromosome, if a male has the X chromosome with the GLA gene mutation, he will be affected with the disorder. Therefore, males with Fabry disease are more uniformly affected, whereas females, due to random X-inactivation, may be asymptomatic or as severely affected as males.
Males with X-linked Fabry disease transmit the GLA gene mutation to all their daughters, who are heterozygotes, but never to their sons. Female heterozygotes have a 50 percent risk of transmitting the disease to each of their children, both daughters and sons, with each pregnancy.
The GLA gene normally instructs the body’s cells to make the α-Gal A enzyme, which breaks down globotriaocylceramide (GL-3/Gb3) in the cell’s lysosomes. Fabry disease is caused by mutations in the GLA gene. There are over 770 mutations in the GLA gene that are responsible for Fabry disease, causing the Type 1 or 2 phenotypes. Thus, the severity and range of symptoms may vary among individuals depending on the GLA mutation in their family. Some mutations markedly alter the enzyme such that it has little to no activity. These mutations cause the type 1 Classic subtype, while other mutations result in a small amount of residual enzyme activity and the type 2 later-onset subtype. The signs and symptoms of Fabry disease develop due to deficient or low activity of α-Gal A. Patients with the type 1 classic phenotype, who have no or very low activity levels (less than 1% of normal), accumulate the GL-3/Gb-3 glycolipid substance (and related glycolipids) in most tissues of the body, especially small blood vessels, and certain cells in the heart and kidneys. Patients with the type 2 later-onset phenotype have residual enzyme activity (1-10% of normal), and also accumulate GL-3/Gb3, but to a lesser extent and at a slower rate. They tend to have a somewhat less severe form of the disease, but males with the type 2 subtype ultimately develop severe cardiac disease and/or renal failure.
Fabry disease is a rare pan ethnic disorder, meaning that it occurs in all racial and ethnic populations affecting males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males.
The diagnosis of Fabry disease is frequently made by physicians who recognize the pain in the extremities, absent or decreased sweating (anhidrosis or hypohidrosis), typical skin lesions (angiokeratoma), gastrointestinal abnormalities, corneal involvement, renal insufficiency, and heart symptoms present in childhood, adolescence or adulthood. The diagnosis is confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in males and females.
Prenatal diagnosis of Fabry disease is made by measuring a-Gal A activity and demonstrating the family-specific GLA mutation in cells that are removed from the amniotic fluid surrounding the developing fetus at about 15 weeks of pregnancy. Early prenatal diagnosis at about 10 weeks of pregnancy can be made by a-Gal A enzyme and gene analyses of villi obtained by chronic villus sampling.
The U.S. Food and Drug Administration (FDA) approved an enzyme replacement therapy called agalsidase beta (Fabrazyme®) as a treatment for patients with Fabry disease in 2003. Fabrazyme®, which is administered intravenously, is a form of the human enzyme produced by recombinant DNA technology. This replacement of the missing enzyme reduces the accumulation of the accumulated glycolipids in cells, including the cells of the kidney and other organs. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of Fabrazyme® enzyme replacement therapy for Fabry disease.
Fabrazyme® had been designated an orphan drug and was approved by the FDA under an accelerated or early approval mechanism. One of the requirements of the accelerated approval is that the sponsor complete a post-market study verifying that patients will benefit from the product, which was accomplished and reported in 2007.
For additional information on Fabrazyme®, contact the manufacturer:
One Kendall Square
Cambridge, MA, 02139
Tel: (617) 252-7500
Fax: (617) 252-7600
Low doses of diphenylhydantoin, carbamazepine, or neurontin, may help to prevent the acroparesthesias- the discomfort in the hands and feet. Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of people with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment is supportive.
The FDA has granted orphan drug status to AT1001, manufactured by Amicus Therapeutics, Inc., for the treatment of Fabry disease. This oral therapy was designed to enhance an individual’s residual alpha-galactosidase A activity. Studies are being conducted to determine its safety and effectiveness. For information, contact:
Amicus Therapeutics, Inc.
6 Cedar Brook Drive
Cranbury, NJ 08512
Phone: (609) 662-2000
Fax: (609) 662-2001
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about Fabry disease:
International Center for Fabry Disease
Icahn School of Medicine at Mount Sinai
Fifth Avenue at 100th Street
New York, NY 10029
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