Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.
Eyes front and ears open. Class is now in session.
The disease that we will be learning about today is:
What is Fabry Disease?
- Fabry disease is an X-linked disease caused by mutations in the GLA gene, which encodes the alpha-Gal A enzyme. These mutations can cause alpha-Gal A, to be either absent or deficient.
- When alpha-Gal A is absent or deficient the substrate, GL-3 and lyso-Gb 3 accumulate, leading to damage of cells within affected parts of the individual’s body and causing the various pathologies seen in Fabry disease.
- Fabry disease leads to progressive, irreversible organ damage, typically involving the nervous, cardiac, and renal systems, as well as multiple other tissues.
- The symptoms can be severe, differ from patient to patient, and begin at an early age, resulting in significant clinical, humanistic, and healthcare costs.
- Fabry disease requires lifelong medical intervention to manage the complications of this devastating disease across multiple organ systems.
- Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylceramide) in blood vessel walls throughout the body. The primary defect which allows this to occur is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide.
How Do You Get It?
- Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father.
- A female with Fabry receives one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.
- All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.
What Are The Symptoms?
- In Women
- The most common symptom of Fabry disease seen in heterozygous females is corneal dystrophy, which occurs in around 70% of females.
- Females may show a wide range of clinical manifestations. Some individuals remain completely asymptomatic and have normal levels of a-GAL a while some are as severely affected as hemizygous males.
- This variability is most likely to be caused by random inactivation of one copy of the X-chromosome in each cell. Symptoms such as tinnitus and vertigo, cardiovascular abnormalities, cerebrovascular abnormalities, fatigue.
- Women may often be misdiagnosed as having lupus or other conditions.
- Other symptoms that have been reported in females with Fabry disease include angiokeratomas, acroparesthesias, anhidrosis, gastrointestinal disturbances, vascular lesions in the conjunctiva and retina, kidney disease, autonomic and other neurological complication
- In Men
- Painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather
- Many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function.
- Other symptoms may include varying degrees of abdominal discomfort, frequent bowel movements shortly after eating, joint pain, back pain primarily in the kidney region or ringing of the ears (tinnitus).
- This disease is slowly progressive and symptoms of kidney, heart and/or neurologic involvement usually occur between the ages of 30 to 45.
- A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
- In Children
- The earliest symptoms of Fabry disease in children are usually pain and angiokeratomas
- Pain and burning sensations in the hands and feet.
- Although the signs and symptoms of Fabry disease generally appear during childhood, the diagnosis may often be missed. The pain may, however, be dismissed as ‘growing pains’, while angiokeratomas (a spotted, dark red skin rash, seen most densely from the umbilicus to the knees) may be overlooked during a routine clinical examination, particularly if they are confined to locations such as the backs of the ears.
- Cardiac and renal involvement can also begin in childhood, thus early diagnosis and careful monitoring are necessary. Other symptoms include hypohidrosis (inability to sweat), GI symptoms that mimic chronic inflammatory bowel disease, recurrent nausea and vomiting, vertigo, tinnitus, headaches, fevers.
How Is It Treated?
- Pain associated with Fabry disease can be difficult to treat but usually responds to medications such as Tegretol (carbamazepine), Dilantin, or Neurotin. Metoclopramide, Lipisorb (a nutritional supplement), Pancrelipase may be beneficial in treating Gastrointestinal hyperactivity. Food and Drug Administration (FDA) approved treatment for Fabry has demonstrated positive results. Enzyme Replacement Therapy (ERT) was approved in 2003.
- Migalastat hydrochloride (Galafold) is a pharmacological chaperone. It is formulated as capsule for oral route of administration. Galafold is indicated for long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (alpha-galactosidase A deficiency) and who have an amenable mutation.
- Many individuals with Fabry disease make some alpha-Gal A enzyme that is capable of degrading substrate. However, because of a genetic mutation, the endogenously produced alpha-Gal A is not effectively delivered to lysosomes to reduce GL-3.