Genetic: Fabry's Disease

Does this patient have Fabry disease?

Fabry disease is a genetic lysosomal storage disorder caused by defects in the GLA gene on the X chromosome, leading to a deficiency in alpha-galactosidase A. This leads to an accumulation of glycosphingolipids in multiple tissues and cell types, with subsequent organ dysfunction related to direct deposition of the glycosphingolipids as well as inflammation and/or fibrosis related to these deposits. Symptoms in early childhood include severe “burning” pain in hands and feet, growth retardation, nausea and abdominal pain, post prandial diarrhoea and hypohidrosis. Unfortunately, due to the non specific nature of the symptoms in childhood, the diagnosis is often missed and many of these patients are diagnosed with the disease in adulthood.

Hyperfiltration, microalbuminuria and proteinuria, sometimes nephrotic range, can be seen in the second or third decade of life, often progressing to renal failure by the fifth decade of life. Severe burning pain in hands and feet, which radiates proximally, and gets worse with stress, heat, illness and exercise is a hallmark of the disease; there are no physical findings of erythema or tenderness associated with the pain of Fabry disease, and often management of pain in such patients is a challenge. Cardiac involvement manifests as left ventricular hypertrophy, arrhythmias, as well as premature coronary artery disease, and is one of the most common causes of mortality in patients with Fabry disease. Central nervous system (CNS) involvement is also very common, and includes autonomic dysfunction, strokes and transient ischemic attacks (TIAs), often at an early age.

Angiokeratomas of the skin are one of the classic findings of Fabry disease, and often help in making the diagnosis. These are reddish purple macular skin lesions often found in a distribution around the umbilicus (abdomen, hips, buttocks, thighs, genitalia), and have a predisposition to bleed. Other dermatologic manifestations include subungal hemorrhages, oral and conjunctival telangiectasias and palmar erythema. Corneal opacities are often seen on a slit lamp exam in patients with Fabry disease, though these are asymptomatic in nature and hence often recognized after the diagnosis of Fabry has been made. Gastrointestinal symptoms of nausea, abdominal pain and diarrhoea may persist into adulthood.

What tests to perform?

If there is a strong clinical suspicion for Fabry disease based on clinical signs and symptoms, a detailed work up is warranted. In male patients, alpha-galactosidase A activity can be checked in leukocytes or plasma, and most hemizygotes have minimal enzyme activity. In female patients, genetic testing is essential to make the diagnosis as they are heterozygotes with variable X chromosome inactivation. The genetic test can also be performed on the amniotic fluid for a prenatal diagnosis.

Echocardiography may reveal hypertrophic cardiomyopathy, and a hypoechogenic line on the echo, described as subendocardial binary appearance, which is relatively specific for patients with Fabry disease.

A renal biopsy in the setting of undefined proteinuria may lead to the diagnosis of Fabry disease.

In untreated patients, life expectancy is decreased by 15-20 years, with a steep decline after age 35 years.

Prenatal screening has not been universally recommended, especially because of the lack of studies demonstrating a benefit of enzyme replacement therapy (ERT) in infancy or early childhood. Screening is recommended for (1) Male relatives of Fabry patients; (2) male and female patients with symptoms suggestive of Fabry disease; and (3) Female relatives of Fabry patients.

How should patients with Fabry disease be managed?

Enzyme replacement therapy for Fabry disease became commercially available in Europe in 2001 and in the US in 2003, and the preparation available in US is agalsidase beta. ERT therapy for Fabry may reduce renal, cardiac, and cerebrovascular events as well as death in patients with Fabry disease.

Treatment should be instituted in all male adult patients at the time of diagnosis. In pediatric male patients, ERT should be instituted at the time of development of symptoms, or if they remain asymptomatic, can be considered at 10-13 yrs of age. Females of all ages with Fabry disease can be monitored, and ERT instituted if significant symptoms develop, or if there is evidence of progressive end organ damage.

ACE inhibitors and angiotensin receptor blockers (ARBs) play a major role in decreasing proteinuria and preventing progression of renal disease, and should be used in conjunction with ERT. The goal of treatment with these agents is to reduce proteinuria independent of BP targets. In addition, continued therapy with statins for dyslipidemia, and aspirin for stroke prevention has been shown to have beneficial cardiovascular effects. Beta blockers can worsen bradycardia, which is an inherent feature of cardiac involvement in Fabry disease, and should be used carefully. Symptomatic measures like use of metoclopramide for nausea, and H2 blockers for dyspepsia may help the GI symptoms.

Pain control is a challenge, and often patients need referrals to pain management clinics. Often good results are seen with medications like carbamezepine, phenytoin, gabapentin and topiramate. Laser treatment has been used for the treatment of problematic angiokeratomas with a good response rate. Patients who develop end stage renal disease secondary to Fabry disease are good candidates for renal transplantation, without recurrence in the near term.

What happens to patients with Fabry Disease?

The inheritance pattern of Fabry disease is X linked, and symptoms often appear in early childhood, though may not be recognized till early adulthood in some patients. The incidence has been described to be ~1 in 100,000, with a higher incidence in men as expected. Symptoms often present in early childhood, and pain and gastrointestinal (GI) symptoms are often disabling in nature leading to school absences, growth retardation in children, and loss of work days in adults. Renal manifestations present in the second decade of life as proteinuria and progress to end stage renal disease typically by the fifth decade of life.

Cardiac events, including arrhythmias as well as hypertrophic cardiomyopathy and coronary artery disease, are extremely common and the most common cause of death in female patients with Fabry disease. Cerebrovascular events, including premature strokes and TIAs, are also very common, and a major cause of morbidity and mortality.

Physiologic and/or pathophysiologic implications

Pharmacologic considerations.

  • ERT is a primary management of Fabry disease

  • ACE inhibitors and ARBs have been shown to have a beneficial effect in renal prognosis when used as antiproteinuric agents

  • Aspirin and or clopidogrel should be used as stroke prophylaxis

  • ACE inhibitors and ARBs should be used in patients with hypertrophic cardiomyopathy

  • β blockers should be used with caution in patients with coronary artery disease (CAD) due to predisposition of these patients to bradycardia

  • Statins should be used for the management of dyslipidemia

How to utilize team care?


The infusion of the enzyme replacement therapy is occasionally associated with rigors and infusion reactions, which can be minimised with premedication. Home therapy with enzyme replacement has been done in Europe with good results, and this raises hope of increasing patient autonomy and reducing clinic visits, with adequate help from home health care staff and pharmacists.

Therapists (physical, occupational, speech, other)

Pain clinic and psychologists often play a big role in the management of patients with Fabry disease, both in dealing with the pain related to the disease as well as the psychological implications of the lifelong disease.

Are there clinical practice guidelines to inform decision making?

Guidelines for the evaluation and management of patients with Fabry disease have been published. Annual clinician visits, with a detailed physical exam, as well as blood work including blood counts and chemistries, with measurement of urine protein and creatinine clearance may be beneficial. Cardiac evaluation with an echocardiogram and electrocardiogram every 2 years is also recommended. Frequent assessment of pain and quality of life, with involvement of a multidisciplinary team consisting of physicians, psychologists, pharmacists and pain specialists is also highly desirable.