As a nephrologist, I have treated several Fabry disease patients over the years. Invariably, by the time I see these patients their situation is chronic, and they already have organ damage. This is fairly common because many patients and clinicians don’t recognize the earlier and often less severe symptoms of Fabry disease.
As a result, in many patients, symptoms progress until cardiac hypertrophy develops, and patients experience strokes and transient ischemic attacks, and/or kidney problems (proteinuria and decreased filtration).
When Fabry disease is not diagnosed and treated, complications such as arrhythmias, strokes, and gastrointestinal problems can occur, resulting in patients being referred to different medical specialists. The onset of nephropathy typically results in a referral to a nephrologist. But even at that stage, it can take several weeks or even months for some Fabry patients to receive a confirmed diagnosis. It is essential for nephrologists to be informed about the clinical presentation and pathophysiology of Fabry disease so they can better manage the ailment.
Understanding Fabry disease
Found in approximately 1 out of 117,000 people1, “classical” Fabry disease is an inherited disorder caused by the deficiency of an enzyme called alpha-galactosidase A or alpha-GAL. The gene locus is on the X chromosome, so Fabry disease is a sex-linked disorder. Decreased alpha-GAL activity causes a buildup of a globotriacylceramide known as GL-3 in cells throughout the body, which can affect the heart, kidneys, skin, brain and gastrointestinal system.
Symptoms of Fabry disease usually begin in childhood, especially in males, but early symptoms often lead to an inaccurate diagnosis of rheumatoid or juvenile arthritis, rheumatic fever, erythromelalgia, multiple sclerosis, lupus, neurosis, Raynaud’s syndrome, acute appendicitis, petechiae, or collagen vascular disease.
To ensure that Fabry disease is accurately diagnosed, nephrologists and other clinicians should make note of key signs, including pain (typically in the hands and feet), clusters of small, dark red spots on the skin, decreased ability to sweat, chronic fatigue, heat intolerance, depression, anxiety, corneal whirl (cloudiness of the front part of the eye), gastrointestinal problems, ringing in the ears, and hearing loss.
Genetic testing can confirm a diagnosis of Fabry disease and also determine whether a female who is asymptomatic has a mutation in the alpha-GAL gene. Upon confirmation of Fabry through genetic testing, other members of a patient’s family can then readily be tested. Serum or whole blood alpha-GAL enzyme levels are easily measured but may be in the normal range in female patients who in fact have Fabry disease, emphasizing the importance of genetic testing and confirmation.
If Fabry disease is not diagnosed early, nephropathy can progress and patients can develop significant proteinuria and a progressive loss of kidney function leading to end-stage renal disease. 1 The current experience is that the renal outcome is worse without early diagnosis and intervention.
Although genetic testing is mandatory for a confirmed diagnosis, routine clinical tests may fail to detect early changes in kidney function. In addition, physicians may also ignore “normal” serum creatinine levels or “minimal” proteinuria and fail to assess the severity of kidney involvement.
In the hands of an experienced nephrologist, the renal biopsy can yield important information about the kidney status, even in patients who are already diagnosed with Fabry disease or in those who have minimal proteinuria or “normal” kidney function.
Evidence of scarring (fibrosis and sclerosis) of the glomeruli and/or interstitial tissue and intracellular GL3 deposits are important signs of serious kidney involvement. In addition, my colleagues and I have discovered several new families with Fabry disease after the initial family member underwent a kidney biopsy for proteinuria and decreased filtration rate, and the pathology report revealed that Fabry disease was the cause of the nephropathy. Finally, it may be important to rule out the presence of another, more common kidney disease in patients with Fabry disease.
In contrast to most forms of chronic kidney disease (CKD) that are associated with elevated blood pressure (BP), Fabry disease may well present with “normal” BP measurements. This can be problematic because many Fabry patients do not receive ACE inhibitors or angiotensin receptor blockers (ARBs) to control their proteinuria because their BP is “normal.”
Controlling proteinuria with ACE inhibitors or ARBs is important for patients with Fabry nephropathy, but can be difficult because many patients with Fabry-related nephropathy have relatively low-normal BP. Nephrologists and other clinicians should employ careful dose titration of ACE inhibitors and ARBs to a target of 500 mg/day to control proteinuria without adversely affecting BP. Beta blockers and diuretics are typically poorly tolerated in these patients and can complicate the use of ACE inhibitors or ARBs to control proteinuria.
As a multi-system disease, treatment regimens for Fabry should incorporate ACE inhibitors or ARBs to help stabilize kidney function. Cholesterol control, smoking cessation, and a prudent diet are additional approaches that are commonly used to control all forms of CKD. With these options and strategies available, efforts to expand awareness of Fabry disease in the nephrology community can support more effective treatments that can improve quality of life for many patients affected by the disease.
Nephrologists are well versed in managing patients with complex multi-system diseases like diabetes, so they are especially well positioned to manage the multi-faceted presentations of Fabry disease in males and females. Diagnosis of Fabry disease is straightforward once the possibility is considered. What has to be emphasized is the complex nature of the disease, which requires regular follow up and assessment of the ongoing response to therapy, including repeated measures of serum creatinine, glomerular filtration rate, and urinary protein excretion with ongoing titration of ACE inhibitor or ARB dosing.
David G. Warnock, MD, is the Hilda B. Anderson Endowed Professor in Nephrology at the University of Alabama at Birmingham. 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. Dr. Warnock is a consultant on Fabry disease for Genzyme Corporation, and has received grant support, and travel expenses from Genzyme Corporation.
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