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for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Fabry disease results from deficient activity of the enzyme α-galactosidase (α-Gal A) and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiovascular and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype.
In contrast, males with greater than 1% α-Gal A activity may have either (1) a cardiac variant phenotype that usually presents in the sixth to eighth decade with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria, but without ESRD, or (2) a rental variant phenotype, associated with ESRD but without the skin lesions or pain.
Diagnosis/testing. In males, the most efficient and reliable method for the diagnosis of Fabry disease is the demonstration of deficient α-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. In females, measurement of α-Gal A enzyme activity is unreliable; although demonstration of decreased α-Gal A enzyme activity is diagnostic of the carrier state, many carrier females have normal α-Gal A enzyme activity. GLA is the only gene known to be assoiciated with Fabry disease. Nearly 100% of affected males have an identifiable GLA mutation. Molecular genetic testing is the most reliable method for the diagnosis of carrier females.
Management. Treatment of manifestations: diphenylhydantoin, carbamazepine, or gabapentin to reduce pain (acroparesthesias); ACE inhibitors to reduce proteinuria; chronic hemodialysis and/or renal transplantation for ESRD. Experts recommend that enzyme replacement therapy (ERT) be initiated as early as possible in all males with Fabry disease, including children and those with ESRD undergoing dialysis and renal transplantation, and in females with significant disease, because all are at high risk for cardiac, cerebrovascular, and neurologic complications. Prevention of secondary complications: prophylaxis of renovascular disease, ischemic heart disease, and cerebrovascular disease as for the general population. Surveillance: annual or more frequent assessment of renal function; annual cardiology and hearing evaluations. Agents/circumstances to avoid: smoking. Testing of relatives at risk: early identification of affected relatives by molecular genetic testing if the disease-causing mutation in the family is known in order to initiate ERT as early as possible in those who are affected.
Genetic counseling. Fabry disease is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate carrier. If only one male in a family is affected, his mother is likely a carrier; rarely, a single affected male in a family may have a de novo mutation. A carrier female has a 50% chance of transmitting the GLA mutation in each pregnancy. An affected male transmits his mutation to all of his daughters. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in a family is known.
Fabry disease should be considered in males and females with the following signs:
Periodic crises of severe pain in the extremities (acroparesthesias)
Vascular cutaneous lesions (angiokeratomas)
Hypohidrosis
Characteristic corneal and lenticular opacities
Stroke
Left ventricular hypertrophy
Renal insufficiency of unknown etiology
Alpha-galactosidase A (α-Gal A) enzyme activity
Males. The most efficient and reliable method for the diagnosis of Fabry disease in affected males is the demonstration of deficientα-galactosidase A ( α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside.
Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathologic mutations (e.g., Asn215Ser) affect intracellular trafficking or packaging/secretion of the enzyme, such that the reduction in enzyme activity in plasma is more marked than the reduction in enzyme activity in leukocytes.
Males with classic Fabry disease have less than 1% α-Gal A enzyme activity.
Males with atypical Fabry disease have residual enzyme activity that is greater than 1% of normal.
Heterozygous females. Measurement of α-Gal A enzyme activity is unreliable for carrier detection. Although demonstration of markedly decreased α-Gal A enzyme activity in a female is diagnostic of the carrier state, some carriers have α-Gal A activity in the normal range.
For laboratories offering biochemical testing see
.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. GLA is the only gene currently known to be associated with Fabry disease.
Clinical testing
Sequence analysis/mutation scanning. Using complete gene sequencing, a mutation in the GLA gene is identified in all affected males with decreased α-Gal A enzyme activity.
Mutation scanning. Mutation scanning with dHPLC (denaturing high performance liquid chromatography) allows rapid detection of mutations by heteroduplex formation between wild-type and mutant DNA. Exon sequencing is required to characterize the mutation [Shabbeer et al 2005].
Deletion testing. Deletion testing is available by a variety of methods to detect exonic and whole-gene deletions in heterozygous females if:
They are the only affected individual in the family available for testing and the disease-causing mutation in the family is unknown and has not been detected by sequence analysis; or
They are at risk of having a family-specific mutation that is known to be an exonic deletion or whole-gene deletion.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability | |
|---|---|---|---|---|
| Affected Males 1 | Carrier Females | |||
| Sequence analysis/mutation scanning | GLA sequence variants | ~100% | Unknown | Clinical
|
| GLA exonic and whole-gene deletions | 0% 2 | |||
| Deletion testing 3 | GLA exonic and whole-gene deletions | Not needed 4 | Unknown | |
1. Males with decreased α-Gal A enzyme activity
2. Sequence analysis/mutation scanning cannot detect exonic and whole-gene deletions on the X chromosome in heterozygous females.
3. Using a variety of test methods (e.g. MLPA, real time PCR)
4. Sequence analysis can detect exonic and whole-gene deletions on the X chromosome in affected males.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
A number of polymorphisms and rare sequence variants of the GLA gene have been recorded. The most common is Asp313Tyr, originally reported at a frequency of 0.45 % [Yasuda, Shabbeer, Benson et al 2003]; however, the frequency is reported to be tenfold higher by others [Gal et al 2006]. This may explain why Asp313Tyr has been reported in up to 5% of males with a pathogenic mutation.
To establish/confirm the diagnosis in a male
Demonstration of deficient α-Gal A enzyme activity in plasma and/or isolated leukocytes is diagnostic.
Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathologic mutations (e.g., Asn215Ser) affect intracellular trafficking or packaging/secretion of the enzyme, such that the reduction in enzyme activity in plasma is more marked than the reduction in enzyme activity in leukocytes.
Molecular genetic testing that identifies a GLA mutation provides additional confirmation of the diagnosis.
For suspected heterozygous females
Demonstration of markedly decreased α-Gal A enzyme activity in plasma and/or isolated leukocytes confirms the carrier state in a female.
In females with α-Gal A enzyme activity in the normal range, molecular genetic testing is necessary to clarify genetic status.
Note: Carrier testing for at-risk females usually requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
No phenotypes other than classic Fabry disease and its variants have been associated with mutations in GLA.
Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack the characteristic skin lesions and acroparathesias, but have associated end-stage renal disease (ESRD), cardiac manifestations, and risk for neurologic complications such as stroke/transient ischemic attack (TIA).
The classic phenotype is the most common; atypical forms of the disease, which present later in life, may be underdiagnosed [Sachdev et al 2002, Nakao et al 2003].
The Fabry Outcome Survey (FOS) and the Fabry Registry, multicenter international initiatives designed to examine the natural history of Fabry disease and the effects of ERT, are an important source of new data on the disease [Mehta et al 2004, Eng et al 2007].
| Manifestation | Classic | Renal Variant | Cardiac Variant |
|---|---|---|---|
| Age at onset | 4-8 yr | >25 yr | >40 yr |
| Average age of death | 41 yr | >60 yr | >60 yr |
| Angiokeratoma | ++ | – | – |
| Acroparathesias | ++ | –/+ | – |
| Hypohidrosis/anhidrosis | ++ | –/+ | – |
| Corneal/lenticular opacity | + | – | – |
| Heart | LVH/Ischemia 1 | LVH | LVH/myopathy |
| Brain | TIA 2 /stroke | – | – |
| Kidney | ESRD | ESRD | Proteinuria |
| Residual α-Gal A enzyme activity | <1% | >1% | >1% |
+ = Present
– = Absent
1. LVH = Left ventricular hypertrophy
2. TIA = Transient ischemic attack
In males with the classic form of Fabry disease, the major clinical manifestations result from the progressive lysosomal deposition of globotriaosylceramide (GL-3) in the vascular endothelium [Desnick et al 2001].
Onset of symptoms usually occurs in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of renal disease, cardiac involvement, and/or cerebrovascular disease.
Angiokeratomas appear as clusters of individual punctate, dark red to blue-black angiectases in the superficial layers of the skin. The lesions may be flat or slightly raised and do not blanch with pressure. Slight hyperkeratosis is notable in larger lesions. The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. However, a wide variation in the distribution pattern and density of the lesions may occur. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved.
Angiokeratomas are often one of the earliest manifestations of Fabry disease.
The number and size of these cutaneous vascular lesions progressively increase with age. Data from 714 affected individuals (345 males, 369 females) in the Fabry Outcome Survey [Orteu et al 2007] suggest that they are present in 66% of males and 36% of females. The presence of cutaneous vascular lesions correlated with the severity of the systemic manifestations of the disease, as assessed by a modification of the Mainz severity scoring index [Whybra et al 2005].
Persons with the classic phenotype with no or only a few isolated skin lesions have been reported. It should be noted that careful examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions.
Pain (acroparesthesias) occurring as episodic crises of agonizing, burning pain in the distal extremities most often begin in childhood or early adolescence and signal clinical onset of the disease. These crises last from minutes to several days and are usually triggered by exercise, fatigue, emotional stress, or rapid changes in temperature and humidity. Often the pain radiates to the proximal extremities and other parts of the body. Attacks of abdominal or flank pain may simulate appendicitis or renal colic.
The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.
Acroparesthesias presumably result from glycosphingolipid deposition in the small vessels that supply blood to the peripheral nerves. The endothelial glycosphingolipid accumulation narrows the vascular lumen, and vessel spasms or frank infarction cause the excruciating pain.
Anhidrosis, or more commonly hypohidrosis, is an early and almost constant finding. Hyperhydrosis also occurs; in the FOS registry it was seen in 12% of females and 6.4% of males [Lidove et al 2006].
Ocular involvement can include the cornea, lens, conjunctiva, and retina.
A characteristic corneal opacity, termed cornea verticillata and observed only by slit-lamp microscopy, is found in affected males and most heterozygous females. The earliest corneal lesion is a diffuse haziness in the subepithelial layer. With time, the opacities appear as whorled streaks extending from a central vortex to the periphery of the cornea. The whorl-like opacities, typically inferior and cream colored, range from white to golden brown and may be very faint [Nguyen et al 2005]. In the FOS registry cornea verticillata was present in 77% of females and 73% of males undergoing detailed ophthalmic examination [Sodi et al 2007].
Lenticular changes are present in approximately 30% of affected males and include a granular anterior capsular or subcapsular deposit and a unique, possibly pathognomonic, lenticular opacity (the "Fabry cataract"). The cataracts, which are best observed through a dilated pupil by slit-lamp examination using retroillumination, are whitish, spoke-like deposits of fine granular material on or near the posterior lens capsule. These lines usually radiate from the central part of the posterior cortex.
The corneal and lenticular opacities do not interfere with visual acuity.
Aneurysmal dilatation and tortuosity of conjuctival and retinal vessels also occur. Data from FOS indicate that vessel tortuosity is observed more frequently in individuals with a higher disease severity score [Sodi et al 2007].
Cardiovascular and/or cerebrovascular disease is present in most males with the classic phenotype by middle age. The progressive vascular involvement is a major cause of morbidity and mortality, particularly after treatment of ESRD by chronic dialysis or transplantation.
Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement, valvular involvement, and conduction abnormalities are early findings.
Dysrhythmias such as ST segment changes, T-wave inversion, intermittent supraventricular tachycardias, and a short PR interval may be caused by infiltration of the conduction system.
Myocardial deposition may cause left ventricular hypertrophy. Echocardiography demonstrates an increased thickness of the interventricular septum and the left ventricular posterior wall [Pieroni et al 2006]. Left ventricular hypertrophy, often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [Kampmann et al 2005].
Magnetic resonance studies using gadolinium demonstrated late enhancement areas, corresponding to myocardial fibrosis and associated with decreased regional functioning as assessed by strain and strain-rate imaging [Moon et al 2003, Weidemann et al 2005].
Among 714 predominantly adult patients in FOS [Linhart et al 2007], angina, palpitations/arrhythmia, and exertional dyspnea were found in 23%-27% of males and 22%-25% of females. Hypertension, angina pectoris, myocardial ischemia and infarction, congestive heart failure, and severe mitral regurgitation are late signs. Hypertension was found in more than 50% of males and more than 40% of females in the FOS registry [Kleinert et al 2006].
Cerebrovascular manifestations result primarily from multifocal small vessel involvement and may include thrombosis, transient ischemic attacks (TIA), basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, or frank cerebral hemorrhage [Politei & Capizzano 2006]. Data from FOS indicate that stoke or TIA occur in approximately 13% of affected individuals overall (15% males, 11.5% females) [Ginsberg et al 2006]. Cerebrovascular manifestations may be a more frequent presenting feature of Fabry disease than had previously been recognized. Rolfs et al (2005) reported that in Germany a GLA mutation was identified in 21 of 432 males (4.9%) and seven of 289 females (2.4%) age 18-55 years suffering cryptogenic stroke.
Renal involvement. Progressive glycosphingolipid accumulation in the kidney interferes with renal function, resulting in azotemia and renal insufficiency.
During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isothenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.
Gradual deterioration of renal function and the development of azotemia usually occur in the third to fifth decade of life, although end-stage renal disease (ESRD) has been reported in the second decade. Death most often results from ESRD unless chronic hemodialysis or renal transplantation is undertaken. The mean age at death of males not treated for ESRD is 41 years, but occasionally an untreated male with the classic phenotype survives into the seventh decade.
Other clinical features. In addition to the major clinical features described above, males and females with the classic phenotype may have gastrointestinal, auditory, pulmonary, and other manifestations.
Gastrointestinal. Glycosphingolipid deposition in intestinal small vessels and in the autonomic ganglia of the bowel may cause episodic diarrhea, nausea, vomiting, bloating, cramping abdominal pain, and/or intestinal malabsorption [Hoffmann, Schwarz et al 2007]. Achalasia and jejunal diverticulosis, which may lead to perforation of the small bowel, have been described. Radiographic studies may reveal thickened, edematous colonic folds, mild dilatation of the small bowel, a granular-appearing ileum, and the loss of haustral markings throughout the colon.
Pulmonary. Several affected individuals have had pulmonary involvement, manifest clinically as chronic bronchitis, wheezing, or dyspnea. Primary pulmonary involvement has been reported in the absence of cardiac or renal disease. Pulmonary function studies may show an obstructive component [Magage et al 2007].
Vascular. Pitting edema of the lower extremities may be present in adulthood in the absence of hypoproteinemia, varices, or other clinically significant vascular disease. Although the pitting edema is initially reversible, progressive glycosphingolipid deposition in the lymphatic vessels and lymph nodes results in irreversible lymphedema requiring treatment with compression hosiery. Varicosities, hemorrhoids, and priapism have also been reported.
Cranial nerve VIII involvement. High-frequency hearing loss, tinnitus, and dizziness have been reported [Hegemann et al 2006].
Psychological. Depression, anxiety, severe fatigue, and other psychosocial manifestations lead to decreased quality of life in many affected individuals.
The clinical manifestations in heterozygous females range from asymptomatic throughout a normal lifespan to as severe as affected males. Variation in clinical manifestations in heterozygous females is attributed to random X-chromosome inactivation.
Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.
Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; pain/tingling in the extremities (acroparethesias) (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; and hypohidrosis. In addition, carriers may have chronic abdominal pain and diarrhea [Gupta et al 2005].
With advancing age, carriers may develop mild to moderate enlargement of the left heart (left ventricular hypertrophy) and valvular disease. More serious manifestations include significant left ventricular hypertrophy, cardiomegaly, myocardial ischemia and infarction, cardiac arrhythmias, transient ischemia attacks, strokes, and ESRD [Shah et al 2005, Deegan et al 2006, Wilcox et al 2008].
The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [MacDermot et al 2001, Whybra et al 2001, Galanos et al 2002].
Renal findings in heterozygotes include isothenuria, the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment, and proteinuria. According to the US and European dialysis and transplantation registries, approximately 10% of carriers develop renal failure requiring dialysis or transplantation.
Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [Sadek et al 2004].
Late-onset Fabry disease with manifestations in the cardiovascular, cerebrovascular, and renal systems may be more common than previously suspected.
Cardiac variant. Males with cardiac disease are asymptomatic during most of their lives and present in the sixth to eighth decade of life with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and mild to moderate proteinuria with normal renal function for age. Many have been diagnosed as a result of having hypertrophic cardiomyopathy.
Magnetic resonance imaging of the heart typically shows late enhancement of the posterior wall with gadolinium reflecting posterior wall fibrosis demonstrated in postmortem specimens [Moon et al 2003].
Their renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop renal failure.
Screening of males with "late-onset" hypertrophic cardiomyopathy (HCM) found that 6.3% who were diagnosed at or before age 40 and 1.4% of males who were diagnosed before age 40 had lowα-Gal A enzyme activity and GLA gene mutations [Sachdev et al 2002]. Cardiac variants may thus be underdiagnosed among affected individuals with cardiomyopathies.
The cardiac variant of Fabry disease can affect women as well as men [Colucci et al 1982, Cantor et al 1998].
Renal variant. Renal variants were identified among Japanese individuals on chronic hemodialysis in whom ESRD had been misdiagnosed as chronic glomerulonephritis [Nakao et al 2003]. Of note, five of the six individuals did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities, but did have moderate to severe left ventricular hypertrophy. These observations indicated that the early symptoms of classic Fabry disease may not occur in individuals with the renal variant who develop renal insufficiency, and that the renal variant may be underdiagnosed. Therefore, it is appropriate to test individuals on renal dialysis and/or undergoing renal transplantation without a primary or biopsy diagnosis for Fabry disease.
Efforts to establish genotype-phenotype correlations have been limited because each family with Fabry disease has a private mutation.
Males with the classic phenotype have a variety of GLA mutations, including large and small gene rearrangements, splicing defects, and missense or nonsense mutations [Desnick et al 2001; Schaefer, Baron et al 2005; Human Gene Mutation Database].
Individuals with later-onset atypical variants (renal, cardiac, or cerebrovascular disease) have missense or splicing mutations that express residualα-Gal A enzyme activity [ Rolfs et al 2005].
Three mutations (Arg112His, Arg301Gln, and Gly328Arg) have been identified in individuals with both the classic phenotype and the cardiac variant phenotype, suggesting that other modifying factors are involved in disease expression [Ashton-Prolla et al 2000].
An analysis of the FOS database showed that disease manifestations in individuals with the Asn215Ser mutation were less severe than those in age-matched individuals with classic Fabry disease [Schaefer, Mehta et al 2005].
The incidence of Fabry disease is estimated to be approximately 1:50,000 males [Desnick et al 2001]; recent population estimates have ranged from 1:80,000 to 1:117,000 [Meikle et al 1999, Desnick et al 2001].
Recent studies suggest that milder forms of the disease that present later in life and primarily affect the cardiovascular, cerebrovascular, or renal system may be more common and may be underdiagnosed.
A newborn screening study from Italy shows an incidence as high as 1:3,100, with an 11:1 ratio of persons with the later-onset:classic phenotypes [Spada et al 2006].
Fabry disease is found among all ethnic, racial, and demographic groups.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The pain of Fabry disease is usually associated with a low-grade fever and an elevated erythrocyte sedimentation rate (ESR); these symptoms have frequently led to the misdiagnosis of rheumatic fever, neurosis, or erythromelalgia.
Symptoms in individuals with Fabry disease are similar to those of other disorders including rheumatoid arthritis, juvenile arthritis, rheumatic fever, systemic lupus erythematosus (SLE), "growing pains," petechiae, Raynaud syndrome, early-onset stroke [Cabrera-Salazar et al 2005, Rolfs et al 2005] and multiple sclerosis [Callegaro & Kaimen-Maciel 2006].
Males with Fabry disease may be unrecognized in cardiac clinics, where they are diagnosed with hypertrophic cardiomyopathy, and in nephrology clinics, where they are diagnosed with ESRD [Bekri et al 2005, Ichinose et al 2005, Tanaka et al 2005].
Differential diagnosis of the cutaneous lesions must exclude the angiokeratoma of Fordyce spots, angiokeratoma of Mibelli, and angiokeratoma circumscriptum, none of which has the typical histologic or ultrastructural lysosomal storage pathology of the Fabry lesion.
The angiokeratoma of Fordyce spots are similar in appearance to those of Fabry disease but are limited to the scrotum and usually appear after age 30 years.
The angiokeratoma of Mibelli are warty lesions on the extensor surfaces of extremities in young adults and are associated with erythematosus subcutaneous swellings.
Angiokeratoma circumscriptum or naeviformus can occur anywhere on the body, are clinically and histologically similar to those of Fordyce, and are not associated with chilblains (erythematous subcutaneous swellings).
Angiokeratoma, in clinical appearance and distribution reportedly similar to or indistinguishable from the cutaneous lesions seen in individuals with Fabry disease, have been described in individuals 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 lysosomal disorder with mental retardation and some features of the mucopolysaccharidoses [Desnick et al 2001].
To establish the extent of disease in an individual diagnosed with Fabry disease, the following evaluations are recommended:
Careful history for evidence of acroparesthesias and hypohidrosis or other manifestations of the disorder
Renal function studies
Cardiac evaluation, including echocardiography
Examination of the skin for angiokeratomas
Formal audiologic assessment
Ophthalmologic evaluation
Acroparesthesias
Diphenylhydantoin. The severe pain of such episodes in affected males and carriers often responds to low-maintenance doses of diphenylhydantoin by reducing the frequency and severity of the periodic crises of excruciating pain and constant discomfort.
Carbamazepine has similar effects. The combination of the two drugs may also significantly reduce the frequency and severity of the pain. Potential side effects are gingival hypertrophy with diphenylhydantoin and dose-related autonomic complications with carbamazepine, including urinary retention, nausea, vomiting, and ileus.
Gabapentin has been demonstrated to improve pain [Ries et al 2003].
Renal disease. Renal insufficiency is the most frequent and serious late complication in males with the classic phenotype; therefore, ACE inhibitors should be used in those with evidence of renal involvement, especially to reduce proteinuria.
Chronic hemodialysis and/or renal transplantation have become lifesaving procedures. The engrafted kidney remains histologically free of glycosphingolipid deposition because the normal α-Gal A enzyme activity in the allograft catabolizes endogenous renal glycosphingolipid substrates. Therefore, successful renal transplantation corrects renal function.
Reviews of the registries of the European Renal Association-European Dialysis and Transplantation Association and the United States Renal Data System support excellent outcomes for renal transplantation in individuals with Fabry disease. For example, during the ten-year period from 1988 to 1998, 93 individuals who underwent renal transplantation were reported to the US registry. Compared to a matched control group, recipients with Fabry disease had equivalent five-year life survival (82% vs 83%) and graft survival (67% vs 75%), respectively.
Note: (1) Immune function in males with Fabry disease is similar to that in other individuals with uremia, obviating any immunologic contraindication to transplantation in this disease. Autoimmune conditions have, however, been reported to occur at an increased frequency in Fabry disease [Martinez et al 2007]. (2) Transplantation of kidneys from carriers for Fabry disease should be avoided, as the organs may already contain significant substrate deposition; all related potential donors must be evaluated to exclude affected males and carrier females.
Enzyme replacement therapy (ERT). The two ERTS using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme® (algalsidase beta; Genzyme Corp) and ReplagalTM (algalsidase alpha; Shire Genetic Therapies, UK). Both were approved in 2001 by the European Agency for Evaluation of Medical Products; only Fabrazyme® was approved by the FDA for use in the US.
The following is a summary of some of the clinical trials for each drug:
In a single-center, double-blind, placebo-controlled Phase II trial of ReplagalTM, 26 males selected for the presence of pain received either 0.2 mg/kg of enzyme or placebo every two weeks for a total of 12 doses. The primary efficacy end point was reduction of pain. Severity of neuropathic pain improved in the 14 treated with enzyme and changed little in the 12 who received the placebo, a statistically significant effect of treatment of pain [Schiffmann et al 2001]. The individuals treated with enzyme had an approximately 50% reduction in plasma GL-3 concentration, a significant improvement in cardiac conduction, a significant increase in body weight, and some improvement in certain tests of renal function. In a European study of 15 severely affected female heterozygotes treated for up to 55 weeks, ERT was safe and well tolerated [Baehner et al 2003].
A Phase III clinical trial of Fabrazyme®, a multinational, double-blind, randomized, placebo-controlled study, demonstrated that individuals who received Fabrazyme® (1 mg/kg every two weeks for a total of 11 doses) cleared GL-3 from the endothelial cells of the kidney, heart, and skin, whereas those treated with placebo did not [Eng et al 2001, Thurberg et al 2002]. In the double-blind study, the primary efficacy end point was the clearance of GL-3 from the interstitial capillary endothelial cells of the kidney. At the end of the double-blind study, 20 of the 29 (69%) individuals in the Fabrazyme®-treated group were free of microvascular endothelial deposits of GL-3 as compared with none of the 29 individuals in the placebo group (P<0.001). Individuals in the Fabrazyme®-treated group also had decreased microvascular endothelial deposits of GL-3 in the skin (P<0.001) and heart (P<0.001) compared with those receiving the placebo. In individuals treated with enzyme, plasma levels of GL-3 decreased into normal range.
In conjunction with the accelerated approval process for Fabrazyme®, the FDA required a Phase IV study to evaluate the direct clinical benefit of the drug after marketing approval. This double-blind, placebo-controlled trial involving 76 individuals with Fabry disease with mild to moderate renal insufficiency began in early 2001. The risk of major clinical events (a combination of death, myocardial infarction, stroke, development of ESRD, or a 33% increase in serum creatinine concentration) was reduced 53% by agalsidase beta after adjustment for baseline proteinuria (P=0.06) [Banikazemi et al 2007].
Experience with Fabrazyme® in Europe indicated that it stabilized deteriorating renal function [De Schoenmakere et al 2003] and improved cardiac function [Waldek 2003, Weidemann et al 2003]. Improvement in the function of C-, Aδ-, and Aβ-nerve fibers in the neuropathy of Fabry disease also improved [Hilz et al 2004]. A retrospective survey of 17 individuals showed decreased pain severity and occurrence and improved heat tolerance and psychological well-being [Guffon & Fouilhoux 2004]. A study of three individuals with Fabry disease with kidney transplantation showed decreased plasma GL-3 concentrations, decreased extremity pain, and improved cardiac function, indicating that ERT is safe and effective against extrarenal manifestations of Fabry disease [Mignani et al 2004]. Also, ERT can be carried out during hemodialysis because the enzyme is not lost in the dialysate.
Treatment with agalsidase alfa appears capable of stabilizing hearing loss [Hajioff et al 2003, Hajioff et al 2006]. Peripheral nerve function and sweating improved [Schiffmann et al 2003].
ERT with agalsidase alfa significantly improved quality of life in females [Deegan et al 2006] and in both males and females [Hoffmann et al 2005]. Data from FOS suggest that agalsidase alfa may slow deterioration of renal and cardiac disease, reduce pain, and improve quality of life [Beck et al 2004; Schwarting et al 2005; Hoffmann, Beck et al 2007]. The enzyme is safe in children [Ramaswami et al 2006]. In persons with advanced renal disease, weekly administration of 0.2 mg/kg agalsidase alfa may be associated with a slower decline in renal function [Schiffmann et al 2007]. The addition of ACE inhibitors and ARB blockade, in association with agalsidase beta, helps slow decline of renal function [Tahir et al 2007].
A small comparative study of agalsidase alfa or beta at a dose of 0.2 mg/kg showed no difference in reduction of left ventricular mass or other disease parameters after 12 or 24 months of treatment [Vedder et al 2007]. Antibody formation has been reported with both agalsidase alfa and beta in males, but not females [Linthorst et al 2005]; however, the impact of this on the overall efficacy of treatment is currently unknown.
A panel of physician experts have recommended that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESRD undergoing dialysis and renal transplantation, and in female carriers with significant disease [Desnick et al 2003, Eng et al 2006] because all are at high risk for cardiac, cerebrovascular, and neurologic complications, such as transient ischemic attacks and strokes.
Prophylaxis. The prophylaxis of renovascular disease, ischemic heart disease, and cerebrovascular disease in persons with Fabry disease is the same as for the general population.
Proteinuria/albuminemia should be minimized with ACE/ARB [Tahir et al 2007]; blood pressure control optimized; and cholesterol normalized.
Aspirin and other anti-platelet agents such as clopidogrel may be recommended for the prophylaxis of stroke.
Use of aspirin and lipid-lowering agents and optimal blood pressure control are recommended in persons with symptoms of cardiac ischemia [Eng et al 2006].
The role of ERT in the long-term prophylaxis of renal, cardiac, and CNS manifestations is unproven; however, on the basis of stabilization of organ function in persons with more advanced disease, some have suggested the initiation of ERT in early disease stages: at first sign of disease manifestations in boys; at age 12-13 years in asymptomatic boys; and at the time of diagnosis in adult males [Eng et al 2006].
Annual or more frequent renal function studies
Annual cardiology evaluation
Annual hearing evaluation
The obstructive lung disease, which has been documented in older hemizygous males and heterozygous females, is more severe in smokers; therefore, affected individuals should be discouraged from smoking.
Amiodarone has been reported to induce cellular and biochemical changes resulting in a phenocopy in particular of the keratopathy of Fabry disease [Whitley et al 1983]. Given potential effects on cellular levels of alpha galactosidase A enzyme activity, it has been contraindicated in persons with Fabry disease. However, little evidence of a detrimental effect in this specific group exists and the relative benefit in patients with cardiac arrhythmia should be considered.
Given availability of ERT, early identification of affected relatives is warranted by molecular genetic testing if the disease-causing mutation has been identified in the family.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Gene replacement therapy has been investigated in the mouse model of Fabry disease [Ziegler et al 1999, Ziegler et al 2002, Ziegler et al 2004]; no human trials have been undertaken to date.
Chaperone therapy, a novel approach, uses small molecules designed to enhance the residual enzyme activity by protecting the mutant enzyme from misfolding and degradation in the cell [Desnick & Schuchman 2002]. A report of chaperone therapy in a male with the cardiac variant demonstrated the "proof of concept" for this therapeutic strategy for Fabry disease [Frustaci et al 2001].
Phase I trials have demonstrated elevation of plasma alpha galactosidase levels in healthy volunteers [Fan et al 1999, Ishii et al 2004]. Phase II trials are now in progress in males and females with Fabry disease with a pharmacologic chaperone (1-deoxygalactonorijimycin; DGJ; AmigalTM; Amicus Therapeutics, NJ, USA). DGJ has been demonstrated to enhance trafficking of mutant alpha-galactosidase A to lysosomes of fibroblasts derived from persons with Fabry disease and increase enzyme activity while reducing GL-3 substrate in tissues of a transgenic/knockout animal model of Fabry disease.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Despite biochemical rationale for the potential use of substrate reduction therapy in Fabry disease, this approach has not thus far proven to have clinical merit.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Fabry disease is inherited in an X-linked manner.
Parents of an affected male proband
In a family with more than one affected individual, the mother of an affected male individual is an obligate carrier.
If only one individual in the family is affected, the mother of the affected male is likely a carrier. Rarely, the affected male may have a de novo gene mutation.
Sibs of an affected male proband
The risk to sibs depends on the carrier status of the mother.
If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.
Female carriers may be symptomatic.
If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Although maternal germline mosaicism has not been demonstrated in this condition, it remains a possibility.
Sibs of a (symptomatic or asymptomatic) carrier female
If the mutation was inherited from her affected father, all of her sisters will be carriers and none of her brothers will be affected.
If the mutation was inherited from her mother, there is a 50% chance of transmitting the GLA mutation in each pregnancy. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.
Paternal germline mosaicism has been demonstrated in this condition [Dobrovolny et al 2005]. Thus, even if the disease-causing mutation has not been identified in paternal DNA, female sibs of a female carrier may still be at increased risk of inheriting the disease-causing mutation.
Offspring of an affected male
All daughters of an affected male are obligate carriers and may be symptomatic.
All sons of an affected male are unaffected.
Offspring of an affected male
All daughters of an affected male are obligate carriers.
All sons of an affected male are unaffected.
Offspring of a (symptomatic or unsymptomatic) carrier female. The risk of transmitting the GLA mutation in each pregnancy is 50%. Male offspring who inherit the mutation will be affected; female offspring who inherit the mutation will be carriers and may be affected.
Female carriers
Measurement of α-Gal A enzyme activity is unreliable for carrier detection. Although demonstration of decreased α-Gal A activity in a female is diagnostic of the carrier state, some carriers have α-Gal A activity in the normal range.
Carrier testing of at-risk female relatives is available by molecular genetic testing when the GLA mutation in the family is known. Identification of a mutation in one GLA allele provides accurate determination of carrier status.
Ophthalmologic examination for the characteristic whorl-like corneal opacities by slit-lamp microscopy can be considered if enzyme analysis is uninformative and the specific mutation in the family has not been identified by molecular genetic testing. However, only 80%-90% of carrier females have the corneal lesions.
Rarely, the carrier female may have a de novo gene mutation.
Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their gender, may be at risk of being carriers and/or of being affected. At-risk females should be offered clinical examination, genetic counseling, and biochemical and/or molecular genetic testing.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
De novo mutations. Very few de novo mutations have been detected; however, data are not available on the frequency of germline mosaicism in females. Germline mosaicism in a male has been reported [Dobrovolny et al 2005].
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, carriers, or at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal testing is possible for pregnancies of women who are carriers. The usual procedure is to determine fetal sex by performing chromosome analysis or specialized studies on fetal cells obtained by chorionic villus sampling (CVS) usually performed at approximately ten to 12 weeks' gestation or amniocentesis at approximately 15-18 weeks' gestation. If the karyotype is 46,XY,α-Gal A enzyme activity is measured in fetal cells. If the GLA mutation in the family is known, the diagnosis may be confirmed by molecular genetic testing of fetal DNA.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| GLA | Xq22 | Alpha-galactosidase A |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| GLA | 2717 (MIM No. 300644) | GLA |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Normal allelic variants: GLA spans approximately 13 kb of gDNA and contains seven exons; the cDNA is 1290 bases and encodes a polypeptide of 429 amino acids including a 31-amino acid signal peptide. Asp313Tyr, a rare exon 6 variant with decreased activity in vitro and reduced activity at neutral pH resulting in low plasma α-Gal A activity, has been identified in 0.45% of normal individuals (n = 800 alleles). Expression of Asp313Tyr in COS-7 cells resulted in approximately 60% of wild-type enzymatic activity and showed normal lysosomal localization [Froissart et al 2003; Yasuda, Shabbeer, Osawa et al 2003]. Thus, Asp313Tyr is a variant that does not cause Fabry disease.
Pathologic allelic variants: In classic Fabry disease, affected males have a variety of mutations, including missense and nonsense mutations, large and small gene rearrangements, and splicing defects. More than 300 mutations have been identified and most are family specific, occurring only in single pedigrees [Desnick et al 2001; Germain et al 2002; Shabbeer et al 2002; Rodriguez-Mari et al 2003; Stenson et al 2003; Schaefer, Baron et al 2005]. However, mutations at CpG dinucleotides have been found in unrelated families of different ethnic or geographic backgrounds. Haplotype analysis of mutant alleles that occurred in two or more families reveals that those with rare alleles are probably related, whereas those with mutations involving CpG dinucleotide "hot spots" are not [Ashton-Prolla et al 2000]. Very few de novo mutations have been detected; however, data are not available on the frequency of germline mosaicism. In the cardiac variant of Fabry disease, all individuals to date have missense or splicing mutations that expressed residual α-Gal A activity, including Ile91Thr, Arg112His, Phe113Leu, Asn215Ser, Met296Ile, Arg301Gln, and Gly328Arg. (Of note, the Asn215Ser mutation was found in several unrelated individuals with the cardiac variant.) All renal variants identified to date have been associated with missense mutations [Nakao et al 2003]. Three mutations (Arg112His, Arg301Gln, and Gly328Arg) have been identified in individuals with the classic phenotype and the cardiac variant phenotype, suggesting that other modifying factors are involved in disease expression [Ashton-Prolla et al 2000]. (For more information, see Genomic Databases table.)
Normal gene product: Alpha-galactosidase A (a/pha-Gal A) is a lysosomal exoglycohydrolase. The mature α-Gal A enzyme polypeptide is 398 amino acids and contains three functional N-glycosylation sites. The active enzyme is a homodimer of approximately 101 kd.
Abnormal gene product: GLA mutations result in mRNA instability and/or severely truncated α-Gal A or an enzyme with markedly decreased activity.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Fabry Support and Information Group
108 NE 2nd Street Suite C
PO Box 510
Concordia MO 64020
Phone: 660-463-1355
Fax: 660-463-1356
Email: Jack@Fabry.org
www.Fabry.org
National Library of Medicine Genetics Home Reference
Fabry disease
Canadian MPS Society
PO Box 30034
RPO Parkgate
North Vancouver V7H 2Y8
Canada
Phone: 800-667-1846; 604-924-5130
www.mpssociety.ca
National Tay-Sachs and Allied Diseases Association, Inc
2001 Beacon Street Suite 204
Brighton MA 02135
Phone: 800-906-8723; 617-277-4463
Fax: 617-277-0134
Email: info@ntsad.org
www.ntsad.org
Fabry Registry
Email: help@fabryregistry.com
Fabry Registry
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Kenneth H Astrin, PhD; Mount Sinai School of Medicine, New York (2001-2008)
Robert J Desnick, PhD, MD; Mount Sinai School of Medicine, New York (2001-2008)
Derralynn A Hughes, MA, DPhil, MRCP, MRCPath (2008-present)
Atul Mehta, MA, MD, FRCP, FRCPath (2008-present)
26 February 2008 (me) Comprehensive update posted to live Web site
27 August 2004 (me) Comprehensive update posted to live Web site
2 January 2004 (rd) Revision: Management - ERT
5 August 2002 (me) Review posted to live Web site
17 September 2001 (rd) Original submission
