Are You Confident of the Diagnosis?
What you should be alert for in the history
Fabry disease is an X-linked lysosomal storage disorder resulting from the deficient activity of the enzyme α-galactosidase A (α-Gal A) and the progressive accumulation of its primary glycolipid substrate, globotriaosylceramide (GL-3). Although GL-3 accumulates in most cell types to varying degrees, the fundamental pathology in Fabry disease results from the microvascular endothelial accumulation, leading to ischemia and infarction, and fibrosis of the tissues normally nourished by these vessels.
Affected males with the classic phenotype have little, if any, α-Gal A enzyme activity (<1% of mean normal), whereas males with the later-onset phenotype have residual enzymatic activity, typically greater than 1% of normal. In classically affected males, the microvascular pathology leads to the clinical manifestations, including angiokeratomas, acroparesthesias, hypohidrosis, gastrointestinal abnormalities, and a characteristic corneal opacity early on in childhood or adolescence.
With advancing age, patients show manifestations such as renal insufficiency and failure, cardiac involvement, and cerebrovascular disease. Affected males with the later-onset phenotype present in adulthood, usually lack the classical early manifestations (angiokeratomas, acroparesthesias, hypohidrosis, and corneal opacities), and tend to develop renal and/or cardiac disease in the third to fifth decade of life.
Heterozygous females from classic Fabry families have a wide range of clinical manifestations that vary from asymptomatic to severely affected, while heterozygous females from later-onset families may have symptoms later in life, including cardiac and renal manifestations.
Look for cutaneous lesions (termed angiokeratomas, but actually telangiectasias) in affected males. These present in childhood or adolescence in the “swimsuit” region, especially in the umbilicus and on the scrotum. Heterozygous females from families with the classic phenotype may have sparse angiokeratomas on the breasts and/or groin.
Patients may have decreased or absent ability to sweat, hypohidrosis, or anhidrosis.
In children or adolescents, episodes of burning/tingling pain in the hands and feet (acroparesthesias) are brought on by exercise, fever, stress, or changes in weather conditions. The pain may be chronic but usually presents in episodic crises precipitated by the before-mentioned triggers.
In adults, arrhythmias, left ventricular hypertrophy (LVH), short PR interval, hypertrophic cardiomyopathy, proteinuria, renal insufficiency, transient ischemic attacks (TIAs), and strokes can all be consistent with Fabry disease. You should be especially on alert if there is a family history of any of these symptoms, combined with an X-linked inheritance pattern.
Characteristic findings on physical examination
In affected males during childhood or adolescence, the cutaneous lesions or angiokeratomas appear as small red to black papules with a smooth epidermal surface that occur as isolated lesions or in clusters. They may be flat or slightly raised and they do not blanch with pressure.
In males with the classical phenotype, the lesions are initially located in the umbilicus and groin (swimsuit distribution), but may be elsewhere on the body, including the oral mucosa and conjunctiva. These lesions are an early physical manifestation of the classic phenotype (Figure 1).
As the disease progresses, the lesions become more dense and some may reach 10mm in diameter. They may appear dark-red to black, with a verrucous or keratotic surface, hence the term angiokeratoma. The angiokeratomas are caused by the accumulation of undegraded GL-3 in the endothelium, perithelium and smooth muscle of capillaries, venules, and arterioles. This leads to marked dilatation of these small vessels of the dermal papillae.
A pathognomonic finding of Fabry disease in the eye is a vortex-like corneal dystrophy and lenticular changes observed by slit lamp that do not affect vision (Figure 2). The keratopathy is the most frequent clinical finding in females.
Expected results of diagnostic studies
Although not required for diagnosis, patients have evidence of lysosomal glycosphingolipid deposition when biopsied skin or other tissues are stained with periodic acid-Schiff (PAS), Luxol fast blue (LFB), or other stains for glycolipids. Ultrastructural studies reveal the presence of the characteristic lamellar cytoplasmic inclusions in lysosomes of tissues throughout the body (Figure 3).
Routine blood values and chemistries are typically normal in patients who have not developed renal insufficiency. With advancing age, the renal insufficiency will result in increased serum creatinine and decreased glomerular filtration rate (GFR). Occasionally, the rheumatoid factor, erythrocyte sedimentation rate (ESR), and/or antinuclear antibody (ANA) values may be elevated.
Patients may show signs of isosthenuria, and red blood cells and casts may be seen in the urine sediment.
Cardiac evaluation may reveal arrhythmias, intermittent supraventricular tachycardias, short PR interval, ST segment changes and T-wave inversion, left-ventricular hypertrophy, and hypertrophic cardiomyopathy.
Confirmation of the clinical diagnosis in males is made by demonstration of deficient α-Gal A activity in plasma and/or leukocytes. Heterozygous females may have low to normal levels of enzymatic activity; this is due to random X inactivation. Suspected heterozygotes require molecular α-Gal A gene analysis to identify the familial mutation.
Many of the symptoms of Fabry disease can be similar to those of other disorders, including rheumatoid or juvenile arthritis, rheumatic fever, erythromelalgia, lupus erythematosus, Raynaud syndrome, fibromyalgia, and multiple sclerosis. In children with acroparesthesias without any other major finding, their complaints are attributed to “growing pains.”
Angiokeratoma of Fordyce, angiokeratoma of Mibelli, and angiokeratoma circumscriptum, are a few diseases that have cutaneous lesions similar to those seen in Fabry disease. None have 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 .
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, are clinically and histologically similar to that of Fordyce, and are not associated with chilblains.
Angiokeratomas, which are similar to or indistinguishable from the clinical appearance and distribution of the cutaneous lesions in Fabry disease, have been described in other lysosomal storage diseases, including: fucosidosis (OMIM #230000), galactosialidosis (OMIM #256540), GM1-gangliosidosis (OMIM #230500), aspartylglucosaminuria, β-mannosidosis (OMIM #248510), and Kanzaki disease (OMIM #609242).
Who is at Risk for Developing this Disease?
The incidence of the classical Fabry disease phenotype is estimated to be about 1 in 40,000 males.
The disease is panethnic. Newborn screening studies conducted in Italy and Taiwan indicate that patients with the later-onset phenotype are more common (1 in 1,500 to 3,500 males) than those with the classical phenotype. The disease is inherited as an X-linked trait, so family members of an affected patient should be tested.
The sons of affected males will not have the disease, while all daughters will be heterozygotes. For heterozygous females, on average 50% of their sons will be affected, and 50% will not inherit the disease. For daughters of heterozygotes, on average 50% will be heterozygotes, and 50% will not inherit the disease gene.
What is the Cause of the Disease?
Fabry disease is caused by mutations in the gene encoding the lysosomal hydrolase, α-Gal A. The galactosidase, alpha (GLA) gene is located on the long arm of the X chromosome (Xq22). To date, more than 600 disease-causing mutations in the GLA gene have been reported. There are no common mutations, and most mutations are family-specific or present in a few families (i.e. private mutations).
The deficient or absent α-Gal A activity results in the accumulation of glycolipids with terminal α-linked galactose molecules. As noted above, the major accumulated glycolipid is globotriaosylceramide (GL-3). In addition, galabiosylceramide (GL-2), the blood group B glycolipid, and lyso-GL-3 accumulate in the lysosomes of various cell types. The progressive GL-3 accumulation, particularly in vascular endothelial lysosomes, leads to ischemia and occlusion of small vessels throughout the body.
The glycosphingolipids also accumulate in perithelial and smooth muscle cells of the cardiovascular-renal system. To a lesser extent, they accumulate in reticuloendothelial, and connective tissue cells; in epithelial cells of the cornea, kidney, and other tissues; and in ganglion and perineural cells of the autonomic nervous system.
GL-3 is synthesized primarily in the liver and secreted into the plasma associated with very low-density lipoprotein (VLDL) particles. GL-3 is taken up by endothelial and other cells by the low-density lipoprotein (LDL) receptor-mediated pathway.
A significant amount of GL-3 is deposited in the lysosomes of the vascular endothelium and other cell types. The vascular involvement is the fundamental pathology that leads to renal insufficiency and failure, cardiac abnormalities, and TIAs and strokes.
Systemic Implications and Complications
In classically affected males who have essentially no α-Gal A activity, clinical manifestations result predominantly from the progressive lysosomal deposition of GL-3 in the vascular endothelium.
In addition to the episodic painful crises, which can last days or weeks, chronic acroparesthesias can occur daily.
Gastrointestinal symptoms are seen in more than 20% of Fabry patients. These include postprandial abdominal cramping, bloating, diarrhea, nausea, and vomiting. Patients usually report alternating between constipation and diarrhea.
Progressive glycosphingolipid deposition in the kidney interferes with renal function. Microvascular involvement of the kidney begins in childhood and progresses to isosthenuria, proteinuria, and tubular dysfunction. Then, with advancing age, this results in progressive renal disease and end-stage renal disease (ESRD), typically by age 35 to 45.
Dialysis or renal transplantation is effective in correcting the renal disease, and renal transplants are not affected by the disease (the disease does not recur in the kidney, because the normal enzyme in the graft prevents accumulation of GL-3). All potential family donors should be evaluated to insure that they are not affected or heterozygotes.
With maturity, most classically affected males experience cardiovascular and/or cerebrovascular disease.
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. Most adult males have sinus bradycardia. AV conduction accelerations (short PR intervals) are more commonly seen in young patients without left ventricular hypertrophy.
In older patients, bundle-branch-blocks and AV abnormalities are more commonly seen. GL-3 accumulation in heart valve tissue with secondary fibrosis and calcification can lead to valvular dysfunction, which is rarely of hemodynamic significance. The progressive vascular involvement is a major cause of morbidity and mortality, particularly after treatment of the renal insufficiency by chronic dialysis or transplantation.
Other manifestations include lower extremity edema in the absence of significant renal disease, hypoalbuminemia, or varices. This lymphedema is due to the accumulation of GL-3 in the lymphatic vessels and nodes.
Progressive high-frequency hearing loss occurs in classically affected males in the third to fifth decades of life. Tinnitus, and/or vertigo, may also appear. The most likely cause of the acute hearing loss is microvascular events. Chronic hearing loss, however, is usually the result of GL-3 accumulation in the audiovestibular ganglia and vessels of the cochlea and is therefore termed sensorineural.
Pulmonary involvement manifests as dyspnea, shortness of breath, or intolerance to exercise and wheezing. Pulmonary function tests may reveal an obstructive pattern. These pulmonary findings are seen especially in smokers. Depression, anxiety, and fatigue are also seen in affected individuals and will negatively impact quality of life.
The first level of treatment for Fabry patients is preventive. The episodes of pain generally have precipitating causes such as physical exertion, fever and illness, changes in temperature, or stress. 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), carbamazepine (Tegretol), or gabapentin (Neurontin). These medications must be taken every day to prevent the onset of pain and/or 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 to monitor general health and, in particular, urinary microalbuminuria and proteinuria, is a vital part of preventive therapy.
Management of Fabry nephropathy should include control of blood pressure, proteinuria, and hyperlipidemia.
The target blood pressure in patients with chronic kidney disease (CKD) is below 130/80mmHg. For kidney health, a low-sodium low-protein diet and pre-symptomatic treatment with angiotensin-receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors should be considered. They are important in the management of the progressive kidney disease, in addition to enzyme replacement therapy (ERT) in patients with proteinuria.
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 recur in the kidney, because the normal enzyme in the graft prevents accumulation of GL-3.
ACE inhibitors and angiotensin II receptor blockers also are mainstay treatment for left ventricular (LV) systolic dysfunction; diuretics can help relieve dyspnea. Pacemakers may be required. Internal cardioverter-defibrillator (ICDs) are used for patients who are considered to be at high risk of sudden cardiac death, although the efficacy in Fabry disease has not been proven.
Prophylaxis with antiplatelet or anticoagulant medication such as aspirin (81mg/day) should be administered, as TIAs and strokes can occur in older patients. Hearing loss can be treated with hearing aids, and noise trauma should be avoided to preserve hearing. Patients should be encouraged not to smoke. Angiokeratomas are usually asymptomatic, although bleeding may occur in rare cases. Cosmetic correction of the affected areas by laser therapy has been reported, but is usually not successful.
Optimal Therapeutic Approach for this Disease
ERT has been available since 2001. Treatment should begin early, as soon as clinical symptoms or signs are observed, particularly in affected males.
Two preparations of the enzyme are available: agalsidase-alpha (Replagal, Shire Pharmaceuticals) and agalsidase-beta (Fabrazyme, Genzyme Corp). Only agalsidase-beta is FDA-approved and commercially available in the United States.
Agalsidase-beta, delivered intravenously at 1mg/kg every 2 weeks, has been shown in randomized double-blind placebo-controlled clinical trials to clear the accumulated GL-3 from interstitial capillary endothelial cells of the kidney, and to stabilize the estimated glomerular filtration rate (eGFR). ERT with agalsidase-beta also clears GL-3 from the vascular endothelial cells in the heart and skin.
A phase IV randomized double-blind placebo-controlled study in older Fabry patients with mild to moderate renal insufficiency demonstrated that agalsidase-beta slowed the progression of renal dysfunction. Subsequent studies have shown that the addition of ACE-inhibitors or angiotensin II receptor blockers may augment the renal protective effects of enzyme replacement. In addition, experimental approaches are being evaluated for the treatment of Fabry disease.
Chaperone therapy uses small molecules that bind to the misfolded enzyme to stabilize it in the endoplasmic reticulum (ER). The binding of the chaperone molecule helps the mutant enzyme fold into its correct shape. This allows the enzyme to be properly trafficked from the ER and targeted to the cellular lysosomes in various organs, thereby increasing enzyme activity and cellular function and reducing substrate and stress on cells.
The advantage of chaperone therapy is that it can be given orally and that it can reach a variety of tissues and cell types.
Gene therapy is still in its early stages; some studies in mice have been promising. However, there have been no trials in humans.
Patient management options are summarized in Table I.
|General||General status, complete physical examination, genetic counseling, pedigree||Baseline (at first visit), then annually|
|Kidney||Serum electrolytes, creatinine, BUN; 24-hour or spot urine for total protein/creatinine, albumin/creatinine, sodium, creatinine||Baseline, then annually. Frequency of renal monitoring increases as renal function decreases.|
|Cardiac||Symptoms inquiry: palpitations, angina||Baseline, then annually|
|Blood pressure, rhythm||Annually|
|ECG, echocardiography 2-D with Doppler||Baseline, then annually|
|Holter monitoring, 30-day event monitoring||If an arrhythmia is suspected or palpitations are present|
|MRI, strain rate imaging||Optional|
|Coronary angiography||If clinical signs of angina|
|Neurologic||Symptoms inquiry: acroparesthesias, fatigue, fever, sweating, heat/ cold tolerance, joint pains, stroke-related symptoms, TIA||Baseline, then annually|
|Neurologic exam||Baseline, then annually|
|Brain MRI without contrast||Baseline at age of diagnosis or at 35 years of age to document CNS involvement. Every 3 to 5 years, re-evaluation to observe progression. At time of a TIA or stroke|
|Magnetic resonance angiography||If cerebral vasculopathy should be excluded|
|Cold/heat intolerance, pain, vibratory thresholds, sweat output, post-ganglionic sudomotor function, superficial skin blood flow||Annually|
|Comorbid stroke risk factors: Cholesterol (total, LDL, HDL), triglycerides||Baseline, then annually|
|Comorbid stroke risk factors: Lipoprotein A, total plasma homocysteine, factor V Leiden (G1691A), Protein C, Protein S, prothrombin G20210A, antithrombin III, anticardiolipin antibody, lupus anticoagulant||Baseline. If hyperlipidemia, appropriate treatment.|
|Symptoms inquiry: tinnitus, hearing loss, vertigo, dizziness||Baseline, then annually|
|Audiometry, tympanometry, otoacoustic emissions||Baseline, every 2 years or more frequently for clinical indications|
|Ophthalmologic||General ophthalmologic exam (slit-lamp, direct ophthalmoscopy, best corrected visual acuity, visual fields)||Baseline, annually if vision is impaired|
|Pulmonology||Symptoms inquiry: cough, exertional dyspnea, wheezing, exercise intolerance||Baseline, then annually|
|Spirometry, including response to bronchodilators, treadmill exercise testing, oximetry, chest x-ray||Baseline, every 2 years or more frequently for clinical indications|
|Gastrointestinal||Symptoms inquiry: postprandial abdominal pain, bloating, diarrhea, nausea, vomiting, early satiety, difficulty gaining weight||Baseline, then annually|
BUN- blood urea nitrogen
CNS- central nervous system
LDL- low-density lipoprotein
HDL- high-density lipoprotein
MRI- magnetic resonance imaging
Unusual Clinical Scenarios to Consider in Patient Management
Many patients with Fabry disease, particularly those with the later-onset phenotype, are not diagnosed or are misdiagnosed. Screening males on hemodialysis and in cardiac and stroke clinics for plasma α-Gal A deficiency has proven an effective approach to identify these patients.
Banikazemi, M, Bultas, J, Waldek, S, Wilcox, WR, Whitley, CB, McDonald, M. “Agalsidase-beta therapy for advanced Fabry disease: a randomized trial”. Ann Intern Med. vol. 146. 2007. pp. 77-86. (A randomized, double-blind, placebo-controlled phase IV clinical trial demonstrated that enzyme replacement at 1mg/kg every 2 weeks slowed disease progression in patients with advanced disease)
Desnick, RJ, Brady, R, Barranger, J, Collins, AJ, Germain, DP, Goldman, M. “Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy”. Ann Intern Med. vol. 138. 2003. pp. 338-46. (Recommendations for diagnosis and treatment.)
Eng, CM, Germain, DP, Banikazemi, M, Warnock, DG, Wanner, C, Hopkin, RJ. “Fabry disease: guidelines for the evaluation and management of multi-organ system involvement”. Genet Med. vol. 8. 2006. pp. 539-48. (More recent recommendations for diagnosis and treatment.)
Eng, CM, Guffon, N, Wilcox, WR, Germain, DP, Lee, P, Waldek, S. “Safety and efficacy of recombinant human alpha-galactosidase A–replacement therapy in Fabry's disease”. N Engl J Med. vol. 345. 2001. pp. 9-16. (A randomized, double-blind, placebo-controlled phase pivotal phase III clinical trial of enzyme replacement therapy that demonstrated the safety and effectiveness of 1mg/kg every 2 weeks in treating Fabry disease)
Eng, CM, Yannis, IA, Eng, CM, Scriver, C.R., Beaudet, A.L., Sly, W.S.. “a-Galactosidase A deficiency: Fabry disease”. The metabolic and molecular basis of inherited disease. 2001. pp. 3733-74. (A general comprehensive review.)
Nakao, S, Kodama, C, Takenaka, T, Tanaka, A, Yasumoto, Y, Yoshida, A. “Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype”. Kidney Int. vol. 64. 2003. pp. 801-7. (Targeted screening of male hemodialysis patients by plasmaα-Gal A enzyme levels identified unrecognized patients with Fabry disease)
Nakao, S, Takenaka, T, Maeda, M, Kodama, C, Tanaka, A, Tahara, M. “An atypical variant of Fabry's disease in men with left ventricular hypertrophy”. N Engl J Med. vol. 333. 1995. pp. 288-93. (Plasmaα-Gal A screening of patients with left ventricular hypertrophy identified unrecognized patients with Fabry disease.)
Spada, M, Pagliardini, S, Yasuda, M, Tukel, T, Thiagarajan, G, Desnick, R. “High incidence of later-onset Fabry disease revealed by newborn screening”. Am J Hum Genet. vol. 79. 2006. pp. 31-40. (Newborn screening of more than 37,000 babies by plasmaα-Gal A activity identified infants with classic and later-onset Fabry disease.)
Thurberg, BL, Randolph Byers, H, Granter, SR, Phelps, RG, Gordon, RE, O’Callaghan, M. “Monitoring the 3-year efficacy of enzyme replacement therapy in Fabry disease by repeated skin biopsies”. J Invest Dermatol. vol. 122. 2004. pp. 900-8. (Dermatologic findings from phase III clinical trial of enzyme replacement therapy at 1mg/kg every 2 weeks.)
Thurberg, BL, Rennke, H, Colvin, RB, Dikman, S, Gordon, RE, Collins, AB. “Globotriaosylceramide accumulation in the Fabrykidneyis cleared from multiple cell types after enzyme replacement therapy”. Kidney Int. vol. 62. 2002. pp. 1933-46. (Renal clearance of GL-3 from various renal cell types in a phase III clinical trial of enzyme replacement therapy at 1mg/kg every 2 weeks.)
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