About fabry disease

What is fabry disease?

Fabry disease is caused by the lack of or faulty enzyme needed to metabolize lipids, fat-like substances that include oils, waxes, and fatty acids. The enzyme is known as ceramide trihexosidase, also called alpha-galactosidase-A. A mutation in the gene that controls this enzyme causes insufficient breakdown of lipids, which build up to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. Since the gene that is altered is carried on a mother's X chromosome, her sons have a 50 percent chance of inheriting the disorder and her daughters have a 50 percent chance of being a carrier.

What are the symptoms for fabry disease?

Type 1 Classic Phenotype

The signs and symptoms of males with the type 1 classic phenotype typically begin in childhood or adolescence (Desnick 2001, Desnick and Brady 2004). Symptoms increase with age primarily due to the progressive glycolipid accumulation in the micro-vascular system, kidney podocytes, and cardiomyocytes leading to kidney insufficiency and failure, heart disease, and/or strokes. Early and progressive clinical symptoms include:

  • Acroparesthesias. Pain is an early symptom of the type 1 Classic subtype and may occur as early as 2-8 years of age in males, and can occur during childhood or adolescence in female heterozygotes, particularly associated with fevers. Affected individuals may experience episodes of severe Burning pain in the hands and the feet (acroparesthesia). Severe episodes of Pain (Fabry’s crises) may last for hours to days and are frequently triggered by exercise, fatigue, stress, and/or Fever (Burlina 2011).
  • Anhidrosis or hypohidrosis. Type 1 males and some type 1 females have decreased or absent sweat production (hypohidrosis or anhidrosis) and Discomfort (heat intolerance) in warm temperatures, with exercise, or fevers.
  • Angiokeratomas. Early symptoms also include the appearance of a reddish to dark-blue skin rash, especially in the area between the hips and the knees. These skin Lesions may be flat or raised. They often are found in the umbilical area or genitals of type 1 males. Typically, males and females with the type 2 later-onset phenotype do not have these characteristic skin lesions.
  • Gastrointestinal problems. GI symptoms are an early manifestation of type 1 Fabry Abdominal cramping, frequent bowel movements, and Diarrhea may also occur, particularly after a large meal.
  • Corneal dystrophy. Patients with the type 1 classic phenotype have abnormal deposits of glycolipids in their corneas resulting in a characteristic whorl-like opacity, which can be seen by slit-lamp examination by an experienced ophthalmologist. These changes do not affect vision. Blood vessels in the eyes may appear twisted (cork screw-like; contorted) and/or slightly enlarged (dilated) due to the glycolipid accumulation in the vessel walls.
  • Additional Type 1 symptoms. Other symptoms that may be associated with Fabry disease include chronic fatigue, dizziness, headache, generalized weakness, nausea, and/or vomiting, delayed puberty, lack of or Sparse hair growth, and rarely malformation of the joints of the fingers. Some type 1 classic males have abnormal accumulation of lymph in the feet and legs associated with Swelling (lymphedema). In these patients, lymph, a body fluid containing certain white blood cells, fats, and proteins, accumulates outside blood vessels in spaces between cells and drains or flows back into the bloodstream via lymph vessels. Lymphedema results from disruption of lymph’s normal drainage due to the glycolipid accumulation in the lymphatic vessels and lymph nodes.

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/or heart manifestations as described below (Desnick 2001, Arends 2017). Many of the type 2 later-onset males who lack the early manifestations seen in the type 1 males, are detected in renal, heart, or stroke clinics (Nakao 1995, 2003; Doheny 2018). 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, particularly in the endothelial cells, smooth muscle cells and podocytes (Najafian 2013; Tondel 2008, 2013). There is histological evidence of this accumulation and ensuing cellular and vascular injury to renal tissue beginning in childhood and adolescence (Tondel 2008, 2013; Najafian 2013) in type 1 classic males and females. In type 1 classic males, the decline in typically begins with podocyte involvement and microalbuminuria leading to frank proteinuria, increasing loss of function (decreasing glomerular filtration rate or GFR), all leading 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 or later, but some patients do not develop renal failure (Meehan 2004). 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 failure, if any (Arends 2017).

Cardiac disease. GL-3/Gb3 deposition can be found in all cardiac tissues, including valves, cardiomyocytes, nerves, and coronary arteries (Desnick 1976). Heart disease includes heart enlargement, typically left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM), rhythm abnormalities (arrhythmias), and heart failure (Frustaci 2017). LVH occurs in about 20% of males and females with an average age of diagnosis in the early 20s to 40s among type 1 males and late 30s to 40s among type 1 female heterozygotes. Early heart involvement in type 1 males typically includes arrhythmias and mitral insufficiency in their 20s followed by LVH leading to HCM. Type 2 later-onset males develop similar heart manifestations as type 1 males, but at older ages and may be first diagnosed in cardiac clinics among patients with LVH or HCM (Doheny 2018). Heterozygous females with the type 1 phenotype often have sinus bradycardia as an early finding and may more severely affected heterozygotes can develop LVH progressing to HCM.

Cerebrovascular complications. As a result of the progressive GL-3/Gb3 deposition in the heart leading to atrial fibrillation and 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 (Fellgiebel 2006, Wilcox 2008).

Respiratory abnormalities: Accumulation of glycosphingolipids and consequent fibrosis can cause interstitial lung disease. Pathological changes and tissue remodeling may involve both alveoli and the bronchial tree leading to restrictive lung disease, obstructive airway disease, or a mixture of obstructive and restrictive disease. (Svensson 2015). Respiratory symptoms may occur independent of cardiovascular disease in these patients.

Other pathology: Hearing loss, tinnitus, Dizziness and vertigo potentially due to GL-3/Gb3 deposition in vestibular structures and/or auditory neuropathy are commonly reported in adult patients and while these are not life threatening, contribute to disease burden and negatively affect quality of life. Depression has been reported and a portion of these cases, especially Type I Classic males, were classified as having severe depression. (Cole 2007)

What are the causes for fabry disease?

Genetics Fabry disease is caused by alterations (mutations) 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 the 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 or reduced 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 “Fabry” gene activated, while others will have the X-chromosome with the functioning, normal gene activated. Therefore, in Fabry disease the symptoms and severity of organ involvement are dependent on the percentage of cells in the tissue/organ where the X-chromosome with the GLA gene mutation is active, but with no or markedly decreased function, 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, type 1 classic and type 2 later-onset males with Fabry disease are more uniformly affected, whereas symptoms in females, due to random X-inactivation, may range from asymptomatic or as severely affected as their affected male relatives (Dobrovolny 2005, Echevarria 2016)

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 the accumulating glycolipids (GL-3/Gb3) in the cell’s lysosomes. Fabry disease is caused by mutations in the GLA gene. There are over 965 reported mutations in the GLA gene that are responsible for Fabry disease (Stenson 2017; Human Gene Mutation Database; http://www.hgmd.org), causing the type 1 or 2 phenotypes. Two databases provide phenotype assignments for all reported mutations: dbFGP.org and Fabry-Database.org (Saito 2011). 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 (e.g., Eng 1997, Shabber 2006), while other mutations result in a small amount of residual enzyme activity and the type 2 later-onset subtype (e.g., von Scheidt 1991, Eng 1997, Nakao 2003, Spada 2006). The signs and symptoms of Fabry disease develop due to absent or markedly deficient α-Gal A enzymatic activity. Patients with the type 1 classic phenotype, who have no or very low activity levels (less than 3% 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 (3-15% of mean normal activity, Desnick 2001), 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. There are also mutations in the GLA gene that are benign and do not cause Fabry disease (e.g., Froissart 2003, Doheny 2018)

What are the treatments for fabry disease?

Enzyme replacement may be effective in slowing the progression of the disease. The pain in the hands and feet usually responds to anticonvulsants such as phenytoin (Dilantin) and carbamazepine (Tegretol, Tegretol XR , Equetro, Carbatrol). Gastrointestinal hyperactivity may be treated with metoclopramide (Reglan, Octamide, Maxolon). Some individuals may require dialysis or kidney transplantation.


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