Chapter 48. Fabry Disease

• X-linked recessive lysosomal storage disease.
• Males.
  • –Deficient plasma and/or leukocyte α-galactosidase A (in classic phenotype <1% of normal mean activity; in later-onset variants >1% of normal mean activity).
  • –Certain α-galactosidase A gene mutations provide genotype/phenotype correlations.
  • –Accumulation of globotriaosylceramide (GL-3).
  • –Presence of angiokeratomas, acroparesthesias, hypohidrosis, corneal and lenticular changes, renal failure, cardiac disease, and cerbrovascular disease.
• Females.
  • –Due to random X-chromosome inactivation, commonly females may have plasma and leukocyte α-galactosidase A activity varying from severely deficient to normal.
  • –α-Galactosidase A mutation analysis required for definitive diagnosis.
  • –Females vary in clinical symptoms from asymptomatic to as severe as classically affected males. Symptoms may appear at later ages than in affected males.

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This enzymatic defect results in the progressive accumulation of GL-3 and related glycosphingolipids with terminal α-galactosyl moieties in the lysosomes of endothelial, epithelial, perithelial, and smooth muscle cells throughout the body. In classically affected males who have little, if any, α-Gal A activity, the glycosphingolipid deposition in the vascular endothelium is responsible for the major clinical manifestations of the disease, including angiokeratomas, acroparesthesias, and hypohidrosis. With advancing age, the progressive vascular glycosphingolipid accumulation leads to renal failure, cardiac and cerebrovascular disease, and early death. Based on the United States and European dialysis and transplantation registries, most classically affected males go into renal failure between the ages of 35 and 45 years. Prior to the advent of renal transplantation and dialysis, the average age of death for classically affected males in one series was 41 years. The incidence of classical Fabry disease is estimated to be ˜1 in 40,000–60,000 males.

In addition to the classic Fabry disease phenotype, later-onset variants have been identified that do not include the classic manifestations of Fabry disease, the acroparesthesias, angiokeratoma, hypohidrosis, or corneal and lenticular lesions (Table 48–1). Cardiac variants who present in the fifth to eighth decades of life have left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and mild to moderate proteinuria with normal renal function for age. Residual α-Gal A activity and primarily cardiomyocyte glycosphingolipid deposition are present. Renal variants also lack the classic manifestations of Fabry disease but renal insufficiency develops. Screening of patients with end-stage renal disease (ESRD) of unknown causes has identified mutation-positive patients with Fabry disease. The incidence of the later-onset phenotypes has been estimated at 1 in 4000 males.

Because of random X-chromosome inactivation, heterozygous females may have clinical symptoms of Fabry disease that range from asymptomatic to as severe as in affected males. Heterozygous females are generally less severely affected than males and their symptoms may occur later in life than in affected males.

Enzyme replacement therapy for Fabry disease has recently become available and has been shown to be effective (see Treatment section).

Affected males with the classic and later-onset phenotypes can be reliably diagnosed by the demonstration of deficient α-Gal A activity in plasma, isolated leukocytes, and/or cultured cells. Classically affected males have essentially no α-Gal A activity, while later-onset cardiac and renal variants exhibit residual activity (>1% of normal). Identification of a mutation in the patient's α-Gal A gene confirms the diagnosis of Fabry disease.

Heterozygous females have markedly variable α-Gal A activities because of random X-chromosomal inactivation and, therefore, measurement of plasma and/or leukocyte α-Gal A activity may be misleading. For example, some obligate heterozygotes (daughters of affected males) may have α-Gal A levels ranging from normal to very low activities similar to those of affected males. Many females (˜90%) have the characteristic corneal dystrophy of Fabry disease. Accurate diagnosis of heterozygous females requires demonstration of the specific mutation in the α-Gal A gene. Such testing is recommended for all at-risk females.

The pathogenesis of Fabry disease is directly related to the progressive accumulation of GL-3 and related glycosphingolipids in tissue lysosomes and body fluids. GL-3 is synthesized primarily in the liver and secreted into the plasma associated with low-density lipoprotein (LDL) particles. GL-3 is taken up by endothelial and other cells by the LDL receptor-mediated pathway. A significant amount of GL-3 is deposited in the lysosomes of the vascular endothelium and other cell types. In the kidney, the earliest lesions are due to the accumulation of glycosphingolipids in endothelial and epithelial cells of the glomerulus and of Bowman's space and in the epithelium of the loops of Henle and of distal tubules. In later stages, and to a lesser extent, proximal tubules, interstitial histiocytes, and fibrocytes accumulate the glycosphingolipid. Lipid-laden distal tubular epithelial cells desquamate and may be detected in the urinary sediment. These cells have been shown to account for about 75% of the urinary cells shed by a classically affected hemizygote.

Concurrently, renal blood vessels are involved progressively and often extensively. An early finding is arterial fibrinoid deposits, which may result from the necrosis of severely involved muscular cells. Other histologic changes in the kidney are the sequelae of nonspecific ESRD with evidence of severe arteriolar sclerosis, glomerular atrophy and fibrosis, pseudotubular proliferation of residual glomerular epithelium, tubular atrophy, and diffuse interstitial fibrosis. Kidney size increases during the third decade of life, followed by a decrease in the fourth and fifth decades.

Histologic and ultrastructural studies of kidney tissue from a 75-year-old male with the later-onset cardiac variant of Fabry disease showed that lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells.

Symptoms and Signs

In classically affected males, Fabry disease typically begins in childhood with episodes of pain and discomfort in the hands and feet (acroparesthesias). The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions. In addition, young patients develop a dark red macular papular skin rash, called angiokeratoma, seen most densely from the umbilicus to the knees, a decreased ability to perspire, and characteristic corneal and lenticular changes observed on slitlamp microscopy that do not affect vision. Patients may have gastrointestinal problems including abdominal postprandial pain, diarrhea, vomiting, and nausea. Patients also experience heat or cold intolerance and exercise intolerance. Mild proteinuria, isothenuria, and urinary sediment abnormalities are early evidence of renal involvement.

The disease progresses very slowly and symptoms of kidney, heart, and/or neurologic involvement often do not occur until the ages of 30–45 years. In fact, many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Renal dysfunction leading to uremia with or without hypertension and progressing to ESRD may occur. Cardiovascular dysfunction may include myocardial infarction, cardiac hypertrophy, valvular abnormalities, and arrhythmias while cerebrovascular complications include risk of early stroke, hemiplegia, hemianesthesia, and transient ischemic attacks. Particularly in smokers, there may be pulmonary complications like airflow obstruction and dyspnea.

Patients die from complications of renal disease, cardiac involvement, and/or cerebrovascular disease. Some or all of the symptoms of Fabry disease may occur in heterozygous females but at a later age than in affected males.

Laboratory Findings

Biochemical Testing

Males

The most efficient and reliable method for the diagnosis of affected males is the determination of α-Gal A activity in plasma and/or isolated leukocytes. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-β-d-galactopyranoside. Affected males with classic Fabry disease will have essentially no α-Gal A activity while those with later-onset cardiac and renal variants have some residual activity (>1% of mean normal).

Heterozygous Females

Measurement of plasma and/or leukocyte α-Gal A activity is unreliable for heterozygote detection because of random X-chromosomal inactivation. Some heterozygous females may have normal α-Gal A enzyme levels while other heterozygous females may have very low to intermediate levels of enzymatic activity. α-Gal A mutation analysis is required for the definitive diagnosis of heterozygous females.

Molecular Genetic Testing

Mutation analysis by DNA sequencing of the α-Gal A gene is the most definitive way to confirm the diagnosis of Fabry disease in males and is required for females suspected of being heterozygotes. A mutation in the α-Gal A gene has been identified in >99% of affected males with decreased α-Gal A activity. To date, over 450 α-Gal A mutations have been described; most mutations identified have been private, occurring only in single pedigrees.

Special Tests

Males suspected of having Fabry disease and women suspected of being heterozygotes should have a slitlamp examination by a qualified ophthalmologist to detect the characteristic corneal and lenticular changes present in Fabry disease. The corneal opacities are found in classically affected males and most heterozygous females (˜ 90%), and are typically absent in later-onset variants.

The pain symptoms in Fabry disease are similar to those of other disorders, including rheumatoid arthritis, juvenile arthritis, rheumatic fever, erythromelalgia, lupus, “growing pains,” petechiae, Raynaud's syndrome, fibromyalgia, and multiple sclerosis.

Differential diagnosis of the cutaneous lesions must exclude the angiokeratoma of Fordyce, angiokeratoma of Mibelli, and angiokeratoma circumscriptum, none of which has the typical histologic or ultrastructural pathology of the Fabry lesion. The angiokeratoma of Fordyce is similar in appearance to that of Fabry disease, but is limited to the scrotum, and usually appears after age 30 years. The angiokeratoma of Mibelli includes warty lesions on the extensor surfaces of extremities in young adults and is associated with chilblains. Angiokeratoma circumscriptum or naeviformus can occur anywhere on the body, is clinically and histologically similar to that of Fordyce, and is not associated with chilblains.

Angiokeratoma, reportedly similar to or indistinguishable from the clinical appearance and distribution of the cutaneous lesions in Fabry disease, has been described in patients with other lysosomal storage diseases, including fucosidosis, sialidosis (α-neuraminidase deficiency with or without β-galactosidase deficiency), adult-type β-galactosidase deficiency, aspartylglucosaminuria, adult-onset α-galactosidase B deficiency, β-mannosidase deficiency, and a recently reported lysosomal disorder that presents with mental retardation and some features of the mucopolysaccharidoses.

The first level of treatment for Fabry patients is preventive. The episodes of pain generally have precipitating causes such as stress, exposure to the sun or heat, changes in temperature, physical exertion, or fever and illness. Patients should make every effort to avoid these precipitating factors, if possible. Patients with frequent severe pain may benefit from medications such as diphenylhydantoin (Dilantin), carbamazapine (Tegretol), or gabapentin (Neurontin). These medications must be taken every day to prevent the onset of pain and to reduce the frequency and severity of painful attacks. Other preventive measures include avoidance of smoking and in those patients with mitral valve prolapse, taking prophylactic antibiotics when undergoing dental procedures or surgery. Regular visits to a physician who will monitor general health and, in particular, urinary albuminuria and protein is a vital part of preventive therapy. For kidney health, a low sodium low protein diet and presymptomatic treatment with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors should be considered. For those patients with severely compromised kidney function, dialysis and kidney transplantation are available. The success of kidney transplantation offers the ability to restore kidney function in Fabry patients and has improved the overall prognosis for this disease. The disease does not reoccur in the kidney.

Recently, enzyme replacement therapy for Fabry disease has become available in many countries. There are two preparations of recombinant human α-Gal A: Fabrazyme, manufactured by Genzyme Corporation, and Replagal, manufactured by TKT Inc; only Fabrazyme is approved by the Food and Drug Administration for use in the United States. Extensive preclinical, Phase 1/2, 3, and 4 clinical trials of Fabrazyme demonstrated that recombinant human α-Gal A is well tolerated and safe and demonstrated that the patients treated with Fabrazyme (1 mg/kg every 2 weeks) maintained GL-3 clearance from the vascular endothelium in the kidney, heart, and skin, the key sites of pathology in this disease. In addition, histologic examination of other renal, cardiac, and skin cell types revealed complete or partial clearance of accumulated GL-3. Plasma GL-3 was also cleared by Fabrazyme.

Patients on enzyme replacement therapy also reported improved quality of life including decreased pain and gastrointestinal problems, and increased sweating, heat tolerance, and energy. A randomized double-blind placebo-controlled Phase 4 study involving 82 Fabry patients with mild to moderate renal disease (serum creatinine >1.2, but <3.0 mg/dL) demonstrated that the patients who received 1 mg/kg of Fabrazyme every 2 weeks were 61% less likely to experience a clinically significant renal, cardiovascular, or cerebrovascular event after an adjustment for baseline proteinuria between the treated and placebo groups. The most pronounced benefit of Fabrazyme was seen when therapy was started in patients with milder renal disease, emphasizing the importance of early treatment.

A consensus report of physicians expert in Fabry disease recommended that all males with Fabry disease (including those with ESRD) and heterozygous females with substantial disease manifestations should be treated by enzyme replacement therapy as early as possible. Dialysis and transplanted patients with Fabry disease suffer from the nonrenal cardiac and cerebrovascular complications of the disease and, therefore, should be treated with enzyme replacement therapy. Recent studies have shown that Fabrazyme can be administered during hemodialysis as the enzyme is not filtered.