For some patients experiencing poor kidney function, there may be an underlying genetic cause—Fabry disease. Understanding Fabry disease may be especially important for patients who experience impaired kidney function and for clinicians who treat them, because it is often misdiagnosed. If left untreated, Fabry disease can lead to kidney failure and other serious health problems.
What is Fabry disease?
Fabry disease is a rare, genetic disease found in approximately 1 out of 117,000 people. It is caused by a deficiency of the enzyme alpha galactosidase A, also known as alpha GAL, which breaks down a fatty substance called GL-3 in the body. The deficiency causes a build-up of GL-3 in cells throughout the body, eventually affecting the kidneys, heart, skin, brain and gastrointestinal system. In the kidneys, the build-up of GL-3 impairs their ability to filter waste and chemicals in the body. Left untreated, this can gradually lead to end stage renal disease, where dialysis or kidney transplantation may be the only viable treatment options.
In Fabry patients, disease progression is often unpredictable and symptoms can range from mild to severe. While the signs of the disease typically appear in childhood, the disease is often not diagnosed because many symptoms mimic other diseases such as rheumatoid or juvenile arthritis. However, there have been some instances where people do not experience any symptoms until well into adulthood. In addition to impaired kidney function, symptoms of Fabry disease include:
- pain, typically in the hands and feet
- clusters of small, dark red spots on the skin
- decreased ability to sweat
- chronic fatigue
- heat intolerance
- cloudiness of the front part of the eye
- gastrointestinal system problems
- ringing in the ears
- hearing loss
A genetic or “family” disease, Fabry disease is passed down from a parent to his or her children. The defective gene associated with Fabry is inherited through the mother and is located on the X chromosome. If a person has the Fabry gene, he or she can pass the gene on to their children. There is a difference in the way males and females pass the gene on to their children. Males with Fabry disease pass the gene on to all of their daughters, but not sons, while females with Fabry disease can pass the gene on to both their daughters and sons.
Genetic testing can be used to confirm a diagnosis of Fabry. Due to the progressive nature of the disease, early diagnosis and intervention is important. Nephrologists and others clinicians work with patients who experience poor kidney function and are often on the front lines in helping patients to identify and take action to address the symptoms of Fabry disease.
The importance of genetic testing has to be re-emphasized. A genetic diagnosis makes a definitive diagnosis of Fabry disease, and mutations "run true" in a single family group. Therefore, once a mutation is found it is easy to screen the rest of the family. Serum enzyme assays, also used for diagnosis, are more readily available in local labs than genetic testing. However, there are too many false negatives, especially in females. This is why genetic testing can be viewed as mandatory.
Nephropathy, or damage to the kidneys, is one of the major complications of Fabry for both men and women. While genetic testing is often crucial in diagnosing the disease, these tests often do not detect changes in kidney function. This can be especially problematic because many Fabry patients do not receive angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), which help maintain kidney function. Nephrologists and other kidney specialists are often positioned to help patients initiate these important therapies.
Proteinuria, a condition where protein in the blood passes through the kidneys into the urine, is also common in Fabry patients. Controlling proteinuria with ACEIs or ARBs can be challenging because many patients with Fabry nephropathy have “normal” blood pressure. As a result, careful dose titration is needed to control proteinuria. A target of 500 mg/day of urine protein excretion without adversely affecting the blood pressure is recommended. Beta blockers and diuretics are generally poorly tolerated in these patients, and only complicate the use of ACEIs or ARBs to control proteinuria.
Patients with Fabry nephropathy who are treated with ACEIs or ARBS need to be followed on a regular basis, with regular monitoring of serum creatinine, urine creatinine, protein and albumin and ideally, 24 hour sodium excretion rate. Without regular monitoring, it is very difficult to know that urine protein excretion is being controlled to less than 500 mg/day.
Lymphedema, also a complication of Fabry disease, occurs when lymphatic fluid accumulates in the interstitial tissue, which causes swelling in the arm and legs, and occasionally in other parts of the body. It is often asymmetric, more common in males, and does not respond well to diuretic therapy. Compression stockings and restricting salt intake to 2.4 grams per day are helpful.
David G. Warnock, MD is the Hilda B. Anderson Endowed Professor in Nephrology at the University of Alabama at Birmingham and a leading nephrologist. Dr. Warnock’s work focuses on genetic and environmental factors that contribute to hypertension and chronic kidney disease. He also focuses on inherited disorders of renal function, with an emphasis on the renal manifestations of Fabry disease. He has published research in many peer-reviewed journals, including the Journal of the American Society of Nephrology, Current Opinion in Nephrology & Hypertension, and the Clinical Journal of the American Society of Nephrology. He is a member of the American Society for Clinical Investigation, American Association of Physicians, American Physiologic Society, ASN, NFK and ISN, and has served as the President of the National Kidney Foundation. Dr Warnock is a consultant on Fabry disease for Genzyme Corporation, and has received grant support, and travel expenses from Genzyme Corporation.
This article was originally printed in the March 2013 issue of aakpRENALIFE magazine.