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Fabry Disease

Synonyms: Anderson-Fabry Disease, Alpha-Galactosidase A Deficiency

, MA, MD, FRCP, FRCPath and , MA, DPhil, FRCP, FRCPath.

Author Information
, MA, MD, FRCP, FRCPath
Director, Lysosomal Storage Disorders Unit
Consultant Haematologist, Royal Free Hospital
University College London School of Medicine
London, United Kingdom
, MA, DPhil, FRCP, FRCPath
Senior Lecturer Haematology, Lysosomal Storage Disorders Unit
Department of Haematology
Royal Free Hospital
University College London
London, United Kingdom

Initial Posting: ; Last Update: October 17, 2013.

Summary

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), sweating abnormalities (anhydrosis, hypohydosis, and rarely hyperhidrosis), 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 cardiac 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 renal variant phenotype, associated with ESRD but without the skin lesions or pain.

Diagnosis/testing. In males, the most efficient and reliable method of diagnosing 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 in which mutations are known to cause Fabry disease. Nearly 100% of affected males have an identifiable GLA mutation. Molecular genetic testing is the most reliable method of diagnosing carrier females.

Management. Treatment of manifestations: Diphenylhydantoin, carbamazepine, or gabapentin to reduce pain (acroparesthesias); ACE inhibitors or angiotensin receptor blockers to reduce proteinuria; chronic hemodialysis and/or renal transplantation for ESRD. The role of ERT in the long-term prophylaxis of renal, cardiac, and CNS manifestations is unproven; however, 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; biennial brain MRI/MRA.

Agents/circumstances to avoid: Smoking.

Evaluation 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.

GeneReview Scope

Fabry Disease: Included Disorders
  • Classic Fabry disease
  • Atypical and late-onset variants of Fabry disease

Diagnosis

Clinical Diagnosis

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)
  • Sweating abnormalities (anhydrosis, hypohydosis, and rarely hyperhidrosis)
  • Characteristic corneal and lenticular opacities
  • Unexplained stroke
  • Unexplained left ventricular hypertrophy
  • Renal insufficiency of unknown etiology

Testing

A diagnostic algorithm is provided in Gal et al [2011] (see full text).

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 deficient α-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 pathogenic mutations (e.g., p.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.

Molecular Genetic Testing

Gene. GLA is the only gene in which mutations are known to cause Fabry disease.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Fabry Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Affected Males Carrier Females
GLASequence analysis 4Sequence variants 5~100% 6, 7<100% 8
Targeted mutation analysisc.427G>C 9100% for the targeted variant
Duplication/deletion analysis 10Partial- and whole-gene deletionsSee footnote 11

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. For issues to consider in interpretation of sequence analysis results, click here.

5. A common normal variant, p.Asp313Tyr (see Molecular Genetics, Benign allelic variants), originally reported at a frequency of 0.45% [Yasuda et al 2003a], has been reported to be tenfold higher by others [Gal et al 2006]. This may explain why this variant has been reported in up to 5% of males with an additional pathogenic mutation.

6. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

7. Includes the mutation detection frequency using deletion/duplication analysis.

8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

9. Targeted analysis for the c.427G>C mutation may be appropriate where the prevalence of that mutation is high.

10. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

11. Deletion/duplication analysis can be used (a) to confirm a putative exonic/whole-gene deletion in males after failure to amplify by PCR in sequence analysis and (b) to identify partial- and whole-gene deletions in females.

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Gal et al 2012 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • For males
    • 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 pathogenic mutations (e.g., p.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: (1) Carrier testing for at-risk females usually requires prior identification of the disease-causing mutation in the family. (2) Although carriers are heterozygotes for this X-linked disorder, they may develop significant clinical findings related to the disorder. (3) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. At-risk males may be diagnosed by deficient α-Gal A enzyme activity

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack the characteristic skin lesions, acroparathesias, and sweating abnormalities 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 probably the most common, although 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].

Table 2. Major Manifestations in Classic and Atypical Fabry Disease

ManifestationClassicRenal VariantCardiac Variant
Age at onset4-8 yrs>25 yrs>40 yrs
Average age of death41 yrs>60 yrs >60 yrs
Angiokeratoma++
Acroparathesias++–/+
Hypohidrosis/anhidrosis++–/+
Corneal/lenticular opacity+
HeartLVH/ ischemiaLVHLVH/cardiomyopathy
BrainTIA / stroke
KidneyESRDESRDProteinuria
Residual α-Gal A enzyme activity<1%>1% >1%

+ = present

– = absent

LVH = left ventricular hypertrophy

TIA = transient ischemic attack

Classic Fabry Disease

Affected Males

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 (FOS) [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 disease manifestations [Zampetti et al 2012].

Persons with the classic phenotype with no or only a few isolated skin lesions have been reported. It should be noted that examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions. Female heterozygotes and persons with atypical and late onset variants may have isolated angiokeratoma; cherry angiomas have also been described.

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 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 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; while not specific for Fabry disease, vessel tortuosity is observed more frequently in individuals with a higher disease severity score [Sodi et al 2007, Allen et al 2010].

Cardiac and/or cerebrovascular disease is present in most males with the classic phenotype by middle age. Cardiac disease is the major cause of morbidity and mortality in those who have undergone dialysis or transplantation for treatment of ESRD.

Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement, valvular involvement, and conduction abnormalities are early findings.

ECG changes including ST segment changes, T-wave inversion, and dysrhythmias such as a short PR interval and intermittent supraventricular tachycardias 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]. T1 mapping illustrates intramural fat deposition and posterior wall fibrosis [Sado et al 2013].

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 [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]. FOS data indicate that stroke or TIA occur in approximately 13% of affected individuals overall (15% males, 11.5% females) [Ginsberg et al 2006]. The Fabry Registry has reported that cerebrovascular manifestations are often a presenting feature of Fabry disease and may be more frequent than previously recognized [Sims et al 2009]. 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. However, other studies have not confirmed such a high prevalence [Brouns et al 2010, Wozniak et al 2010, Rolfs et al 2013].

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 et al 2007b]. 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 [Cole et al 2007].

Heterozygous (Carrier) Females

The clinical manifestations in heterozygous females range from asymptomatic throughout a normal life span to as severe as affected males. Variation in clinical manifestations in heterozygous females is attributed to random X-chromosome inactivation [Deegan et al 2006].

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].

Life expectancy and cause of death. Based on data from the Fabry Registry, 75 of 1422 males and 12 of 1426 females were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry. The life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease [Waldek et al 2009]. Most patients (57%) who died of cardiovascular disease had previously received renal replacement therapy. In the Fabry Outcome Survey (FOS) the principal causes of death among 181 affected relatives (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%) [Mehta et al 2009]. In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients.

Atypical Variants of Fabry Disease

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, cardiomyopathy, conduction disturbances and arrhythmias. . Many have been diagnosed as a result of having hypertrophic cardiomyopathy. They exhibit mild to moderate proteinuria with normal renal function for age.

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].

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 low α-Gal A enzyme activity and GLA mutations [Sachdev et al 2002]. Cardiac variants may thus be underdiagnosed among affected individuals with cardiomyopathies.

Newborn screening in Taiwan has revealed a high prevalence (~1:1600 males) of individuals with the IVS4+919G>A mutation where older family members with late onset cardiac features have been found [Lin et al 2009].

Clinical manifestations of the cardiac variant of Fabry disease are found in 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.

Genotype-Phenotype Correlations

Efforts to establish genotype-phenotype correlations have been limited because each family with Fabry disease has a private mutation.

Prevalence

The incidence of Fabry disease is estimated at 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].

In a study of the Taiwan Chinese population an unexpected high prevalence of the cardiac-variant Fabry-causing mutation IVS4+919G>A was found among newborns (~1:1600 males) as well as patients with idiopathic hypertrophic cardiomyopathy [Lin et al 2009].

Fabry disease is found among all ethnic, racial, and demographic groups.

Differential Diagnosis

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].

Two recent studies have indicated that several patients with familial Mediterranean fever, which can also cause pain and renal involvement, have been misdiagnosed as having Fabry disease [Lidove et al 2012, Zizzo et al 2013].

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.

  • Angiokeratoma of Fordyce is characterized by spots similar in appearance to those of Fabry disease but limited to the scrotum and usually appearing after age 30 years.
  • Angiokeratoma of Mibelli is characterized by warty lesions on the extensor surfaces of extremities in young adults and associated with erythematous subcutaneous swellings (chilblains).
  • Angiokeratoma circumscriptum or naeviformus can occur anywhere on the body, is clinically and histologically similar to angiokeratoma of Fordyce, and is not associated with chilblains.

Angiokeratomas, 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 intellectual disability and some features of the mucopolysaccharidoses [Desnick et al 2001].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Fabry disease, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Fabry disease, the following evaluations are recommended:

  • Careful history for evidence of acroparesthesias and sweating abnormalities (i.e., hypohidrosis) or other manifestations of the disorder
  • Renal function studies, including BUN, creatinine, and urinalysis
  • Cardiac evaluation, including echocardiography
  • Examination of the skin for angiokeratomas
  • Formal audiologic assessment
  • Ophthalmologic evaluation
  • Neurologic assessment
  • Medical genetics consultation

Treatment of Manifestations

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. ACE inhibitors or angiotensin receptor blockers 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.

Prevention of Primary Manifestations

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 Replagal™ (algalsidase alpha; Shire Human 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 Replagal™, 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 randomized single center study in 15 males with Fabry disease and left ventricular hypertrophy showed significant reduction in left ventricular mass after six months of treatment with agalsidase alpha compared to placebo [Hughes et al 2008].
  • 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 2006, Hoffmann et al 2007a]. 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.
  • During 2009-2012 a shortage of agalsidase beta resulted in the substitution of agalsidase alfa for agalsidase beta in several cohorts of affected individuals. Reports thus far have not indicated any significant difference in clinical parameters as a result of this transition [Smid et al 2011, Tsuboi & Yamamoto 2012, Pisani et al 2013].

There is an emerging consensus that ERT has, at best, a limited impact on the long-term outcome of Fabry disease. Long-term results from registry studies (e.g., FOS [Mehta et al 2004]) have been encouraging; but studies of consecutive affected persons from individual centers [Rombach et al 2013, Weidemann et al 2013] suggest that cardiac, renal, and cerebrovascular outcomes are comparable among treated and untreated cohorts. A recent Cochrane review has also highlighted the generally poor quality of evidence in favor of ERT for Fabry.

Despite these emerging data, 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 including transient ischemic attacks and strokes.

Prevention of Secondary Complications

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.
  • Although evidence as to the effect on long term outcomes is lacking, 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].

Surveillance

The following are appropriate:

  • Annual or more frequent renal function studies
  • Annual cardiology evaluation
  • Annual hearing evaluation
  • Biennial brain MRI/MRA

Agents/Circumstances to Avoid

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.

Evaluation of Relatives at Risk

Given the 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.

Pregnancy Management

An increased incidence of pregnancy-related complications or fetal anomalies has not been described in females with Fabry disease. The diagnosis of Fabry disease in females has been made during the investigations of proteinuria persisting post partum.

Therapies Under Investigation

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]. A trial of gene therapy via autologous stem cell transplantation is currently in progress in Canada.

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 III trials are now in progress in males and females with Fabry disease with a pharmacologic chaperone (1-deoxygalactonorijimycin; DGJ; Amigal™; 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.

Other

Substrate reduction therapy for Fabry disease has a biochemical rationale. Clinical trials of substrate reduction therapy will be commencing soon.

Genetic Counseling

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. —ED.

Mode of Inheritance

Fabry disease is inherited in an X-linked manner.

Risk to Family Members

Parents of an affected male proband

  • The father of an affected male is not affected.
  • 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 [Dobrovolný 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

Offspring of a (symptomatic or asymptomatic) 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.

Carrier Detection

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 possible if the disease-causing mutation has been identified in the family. 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 molecular genetic testing.

Related Genetic Counseling Issues

Fabry disease practice guidelines are available. See Laney et al [2013] (full text).

See Management, Evaluation of Relatives at Risk for information on evaluating 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 [Dobrovolný 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, are carriers, or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

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 to 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Fabry Support and Information Group (FSIG)
    108 NE 2nd Street
    Suite C
    PO Box 510
    Concordia MO 64020
    Phone: 660-463-1355
    Fax: 660-463-1356
    Email: info@fabry.org
  • National Fabry Disease Foundation (NFDF)
    4301 Connecticut Avenue Northwest
    Suite 404
    Washington DC 20008-2369
    Phone: 800-651-9131 (toll-free)
    Fax: 800-651-9135 (toll-free)
    Email: info@fabrydisease.org
  • National Library of Medicine Genetics Home Reference
  • Canadian MPS Society
    RPO Parkgate
    PO Box 30034
    North Vancouver British Columbia V7H 2Y8
    Canada
    Phone: 800-667-1846; 604-924-5130
    Fax: 604-924-5131
    Email: info@mpssociety.ca
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
    Email: info@ntsad.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: +44 0845 389 9901
    Email: mps@mpssociety.co.uk
  • Fabry Registry
    Genzyme Corporation
    500 Kendall Street
    Cambridge MA 02142
    Phone: 800-745-4447 ext 15500 (toll-free); 617-591-5500
    Fax: 617-374-7339
    Email: fabryregistry@genzyme.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Fabry Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Fabry Disease (View All in OMIM)

300644GALACTOSIDASE, ALPHA; GLA
301500FABRY DISEASE

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The variant p.Asp313Tyr, a common 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 p.Asp313Tyr in COS-7 cells resulted in approximately 60% of wild-type enzymatic activity and showed normal lysosomal localization [Froissart et al 2003, Yasuda et al 2003b]. Thus, p.Asp313Tyr is a variant that does not cause Fabry disease.

Pathogenic allelic variants. In classic Fabry disease, affected males have a variety of pathogenic variants, including missense and nonsense mutations, large and small gene rearrangements, and splicing defects. More than 500 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, Schäfer 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 p.Ile91Thr, p.Arg112His, p.Phe113Leu, p.Asn215Ser, p.Met296Ile, p.Arg301Gln, and p.Gly328Arg. (Of note, the p.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 (p.Arg112His, p.Arg301Gln, and p.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 Table A.)

Table 3. Selected GLA Allelic Variants

Type of VariantDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Benignc.937G>Tp.Asp313TyrNM_000169​.2
NP_000160​.1
Pathogenicc.272T>Cp.Ile91Thr
c.335G>Ap.Arg112His 1
c.337T>Cp.Phe113Leu
c.427G>C p.Ala143Pro
c.644A>Gp.Asn215Ser
c.888G>Ap.Met296Ile
c.902G>Ap.Arg301Gln 1
c.982G>Ap.Gly328Arg 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Genotype/Phenotype Correlations.

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.

References

Published Guidelines/Consensus Statements

  1. Bennett RL, Hart KA, O Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (pdf). Available online. 2002. Accessed 5-6-14. [PubMed: 12735292]
  2. Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available online. 2013. Accessed 5-6-14.

Literature Cited

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Suggested Reading

  1. Brady RO. Enzyme replacement for lysosomal diseases. Annu Rev Med. 2006;57:283–96. [PubMed: 16409150]
  2. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 150. Available online. 2013. Accessed 5-6-14.
  3. Meschia JF, Brott TG, Brown RD. Genetics of cerebrovascular disorders. Mayo Clin Proc. 2005;80:122–32. [PubMed: 15667040]
  4. Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, Rosing DR, Robinson C, Schaefer E, Gal A, Dambrosia JM, Garman SC, Brady RO, Schiffmann R. Pediatric Fabry disease. Pediatrics. 2005;115:e344–55. [PubMed: 15713906]

Chapter Notes

Author History

Kenneth H Astrin, PhD; Mount Sinai School of Medicine (2001-2008)
Robert J Desnick, PhD, MD; Mount Sinai School of Medicine (2001-2008)
Derralynn A Hughes, MA, DPhil, FRCP, FRCPath (2008-present)
Atul Mehta, MA, MD, FRCP, FRCPath (2008-present)

Revision History

  • 17 October 2013 (me) Comprehensive update posted live
  • 10 March 2011 (me) Comprehensive update posted live
  • 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
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