Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Fabry Disease
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The incidence of Fabry disease has historically been estimated as 1:50,000 to 1:117,000 births; however, more recent studies suggest the incidence may be as high as 1:1,600 to 1:3,100. This likely reflects a broader phenotypic spectrum identified in the last decade with a ratio of 11:1 of persons with the later-onset:classic phenotypes.
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Clinical Features
(Signs / symptoms)
Fabry disease encompasses a spectrum of phenotypes resulting 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 occurs in males with less than 1% α-Gal A enzyme activity with periodic crises of severe pain in the extremities, appearance of vascular cutaneous lesions, hypohidrosis (diminished sweating response), proteinuria, and corneal and lenticular opacities. Disease progression can lead to cardiac and/or cerebrovascular disease; mitral insufficiency may be present in childhood and adolescence. Progressive decline in renal function leads to end stage renal disease (ESRD). Patients may also have gastrointestinal, auditory, pulmonary, vascular, cranial nerve, and psychological manifestations. Cognitive function can be impaired. While, general intellectual and global cognitive functioning appear unaffected, there is evidence for impairment in executive functioning, information processing speed, and attention. An estimated 15-65% have depression, with pain the most common associated factor.
Heterozygous females typically have milder and more variable symptoms. In addition, males with a greater than 1% α-Gal A activity present later and may have either a cardiac variant phenotype, renal variant phenotype, or cerebrovascular disease presenting as stroke or transient ischemic attack. Males and females with the cardiac variant, present with left ventricular hypertrophy (LVH), mitral insufficiency, cardiomyopathy and arrhythmia, with proteinuria but without ESRD. The renal variant phenotype is typically associated with ESRD without the skin or pain symptoms associated with classic Fabry disease.
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Natural History
(Important subgroups & survival / recovery)
Onset of the classic form is generally in childhood or adolescent years (typically age 4-8 years). Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Heterozygous females typically have a later age of onset than males. Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Patients with Fabry disease overall have a lower quality of life (QoL) compared to the general population. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespln among affected males (50-57 years) and females (70-72) compared to the normal population. The most common cause of death among both sexes is cardiovascular disease with most patients dying of cardiovascular disease having previously received renal replacement therapy. Before the availability of dialysis and transplantation, death from kidney failure occurred early in the first decade in classically affected males. Those patients with late-onset atypical variants of the disease are generally asymptomatic most of their lives. Those with the cardiac variant generally present in the sixth to eighth decade of life; many are diagnosed as the result of having hypertrophic cardiomyopathy. For those with the renal variant, age at onset is typically after 25 years.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Patients should undergo baseline evaluation by a multidisciplinary team. Evaluation should include a complete physical and psychological exam including quality of life, measurement of α-Gal A levels, and examination of the following systems: renal, cardiac, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. (Tier 2)
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Baseline data and all follow up data should be transferred to a central registry. (Tier 2)
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In practice, there is wide variability in the use of ERT even for hemizygotes, with some starting therapy at a young age even without symptoms and others waiting until end organ damage is evident. The decision to initiate ERT should be made according to the clinical judgment of the managing metabolic physician in conjunction with the family of the patient. (Tier 2)
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Limited trial literature has been published regarding the use of ERT for Fabry disease. A systematic review of RCTs of ERT reported on nine studies of 351 patients; however, many of these studies reported only on the effect of ERT on levels of unmetabolized GL-3. Data from 2 trials (n=39) found no statistally significant differences in plasma GL-3 concentration and one trial (n=24) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. However, one trial (n=26) found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (N= 82) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. (Tier 1)
The majority of the literature related to ERT has been data generated registries mandated by regulatory authorities. A systematic review and analysis of pooled proportions included 77 cohort studies comprising 15,305 participants followed over a mean of 3.8 years; however, only data from 39 of these studies could be pooled. Within these cohorts 66% of participants were male and had a mean age of 35 years. For the majority of cohorts the phenotype (classic/non-classic) was not reported. Although the rate of all-cause mortality in the primary analysis was higher in the untreated patients (10.8%), followed by agalsidase alfa (9%), and agalsidase beta (4.4%), there was no significant difference between the groups. Compared with untreated patients, treatment with algalsidase beta resulted in statistically significantly lower proportion of patients with renal complications (6% versus 21%), cardiovascular complications (7% versus 26%), and cerebrovascular complications (3.5% versus 17.8%). The differences between agalsidase alpha and untreated patients were not significantly different. (Tier 1)
A separate systematic review of trial and observation studies was unable to draw any definitive conclusions about the effect of ERT on patient QoL. (Tier 1)
Due to an increased risk of vascular events, other vascular risk factors (hypertension, dyslipidemia, diabetes mellitus, increased weight) should be aggressively managed. (Tier 2)
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Risk of stroke is elevated in patients with Fabry disease. One cohort study found that among 33 Fabry patients, 24% suffered at least one stroke by the age of 29. In order to reduce stroke risk, aspirin may be offered starting at age 30 for males and age 35 for females. Adequate intake of vitamins B12, B6, C, and folate should be promoted. (Tier 2)
Patients should undergo regular surveillance including complete physical and psychological exams and surveillance of the following systems: kidney, cardiac, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. Type and frequency of surveillance vary across systems and with individual patient symptoms. (Tier 2)
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Family Management
No family management recommendations have been provided.
Circumstances to Avoid
Due to the high risk of vascular events patients should be discouraged from smoking. (Tier 2)
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Given the potential effects on cellular levels of α-galactosidase A, amiodarone (an antiarhythmia drug) has been contraindicated in persons with Fabry disease. However, there is little evidence of a detrimental effect and the relative benefit in patients with cardiac arrhythmia should be considered. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Prevalence of Genetic Mutations
Based on 6 studies in newborn screening populations in Europe and Taiwan, the pooled prevalence of newborns with a variant in the GLA gene, which includes variants of undetermined significance, is about 0.04%. (Tier 1)
Relative Risk
(Include any high risk racial or ethnic subgroups)
The incidence of cardiac complications is similar in individuals with the atypical Fabry cardiac variant and individuals with classic Fabry disease. (Tier 3)
The Fabry Registry and Fabry Outcomes Study reported a median age of symptom onset at 11-13 years for males and 19-23 years for females with pain the most frequent presenting symptom (62-76% males, 41-64% females). The following clinical events were reported for individuals in the registries:
Renal dialysis or transplantation:
- Males: 13-17% of males
- Females: 1-2% females
Cardiovascular event (arrhythmia, myocardial infarction, angina pectoris, congestive heart failure, significant cardiac procedure)
- Males: 19%
- Females: 14%
- Males: 7%
- Females: 5%
Cerebrovascular event (stroke, transient ischemic attack, prolonged reversible ischemic neurologic deficit):
- Males: 12-15%
- Females: 11.5-27% (Tier 3)
No information on relative risk was identified.
Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack many of the classical characteristics of the disease (e.g., skin lesion, sweating abnormalities). (Tier 3)
Substaintial intrafamilial and interfamilial variability in age of disease onset and disease progression exists. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Patient management involves non-invasive, multiple organ system medical screening and potentially the use of enzyme replacement therapy (infused bi-weekly). Infusions tend to be reasonably well tolerated, with reported infusion reactions of about 10%, mostly consisting of fever and transient rigors of mild to moderate intensity. Within a pooled analysis of registry data, the rates of reported adverse events was 31% for agalsidase alfa and 34% for agalsidase beta. However, these rates were not significantly different from those reported by untreated patients (37%).
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Misdiagnosis in individuals with Fabry is common in clinical care with some patients having a delay of >50 years before the correct diagnosis, and a delay of >20 years between the onset of symptoms and diagnosis being common. Recent studies have found that nearly half of Fabry patients (46%) experience their first stroke before being diagnosed. (Tier 3)
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Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Cardiovascular disease (males) / Enzyme replacement therapy
Cardiovascular disease (females) / Enzyme replacement therapy
Cerebrovascular events (males) / Enzyme replacement therapy
Cerebrovascular events (females) / Enzyme replacement therapy
End-stage renal disease (males) / Enzyme replacement therapy
End-stage renal disease (females) / Enzyme replacement therapy
Pain crises (males) / Enzyme replacement therapy
Pain crises (females) / Enzyme replacement therapy
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. A Mehta, DA Hughes. Fabry disease. 2002 Aug 05 [Updated 2013 Oct 17]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from:
2. El Dib R, Gomaa H, Carvalho RP, Camargo SE, Bazan R, Barretti P, Barreto FC. Enzyme replacement therapy for anderson-fabry disease. Cochrane Database Syst Rev. (2016) 7:CD006663.
3. Arends M, Hollak CE, Biegstraaten M. Quality of life in patients with fabry disease: a systematic review of the literature. Orphanet J Rare Dis. (2015) 10:77.
4. Biegstraaten M, Arngrimsson R, Barbey F, Boks L, Cecchi F, Deegan PB, Feldt-Rasmussen U, Geberhiwot T, Germain DP, Hendriksz C, Hughes DA, Kantola I, Karabul N, Lavery C, Linthorst GE, Mehta A, van de Mheen E, Oliveira JP, Parini R, Ramaswami U, Rudnicki M, Serra A, Sommer C, Sunder-Plassmann G, Svarstad E, Sweeb A, Terryn W, Tylki-Szymanska A, Tondel C, Vujkovac B, Weidemann F, Wijburg FA, Woolfson P, Hollak CE. Recommendations for initiation and cessation of enzyme replacement therapy in patients with fabry disease: the european fabry working group consensus document. Orphanet J Rare Dis. (2015) 10:36.
5. Bolsover FE, Murphy E, Cipolotti L, Werring DJ, Lachmann RH. Cognitive dysfunction and depression in fabry disease: a systematic review. J Inherit Metab Dis. (2014) 37(2):177-87.
6. Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. (2006) 8(9):539-48.
7. Kes VB, Cesarik M, Zavoreo I, Soldo-Butkovic S, Kes P, Basic-Jukic N, Racki S, Jakic M, Delic-Brkljacic D, Jukic Z, Trkanjec Z, Seric V, Solter VV, Bielen I, Basic S, Demarin V. Guidelines for diagnosis, therapy and follow up of anderson-fabry disease. Acta Clin Croat. (2013) 52(3):395-405.
8. 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. J Genet Couns. (2013) 22(5):555-64.
9. Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, Serra A, Van Biesen W, Vanholder R, Wanner C. Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the european renal best practice. Nephrol Dial Transplant. (2013) 28(3):505-17.
10. Wang RY, Bodamer OA, Watson MS, Wilcox WR. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. (2011) 13(5):457-84.
11. El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A, Barreto F. Enzyme replacement therapy for anderson-fabry disease: a complementary overview of a cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies. PLoS One. (2017) 12(3):e0173358.
12. van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. A systematic review on screening for fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet. (2014) 51(1):1-9.
13. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the fabry outcome survey. Eur J Clin Invest. (2004) 34(3):236-42.
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