Fabry Disease

Actionability Adult Summary Report

Gene:
Mode(s) of Inheritance:X-linked
Literature Search: 06/24/2015
Curation Status: Released (2.1.0)
Release History

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
No assertions found.

Actionability Assertion Rationale

  • This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Cardiovascular disease (males) / Enzyme replacement therapy 2 2C 2A 2 8CA
Cardiovascular disease (females) / Enzyme replacement therapy 2 2C 2A 2 8CA
Cerebrovascular events (males) / Enzyme replacement therapy 2 2C 2A 2 8CA
Cerebrovascular events (females) / Enzyme replacement therapy 2 2C 2A 2 8CA
End-stage renal disease (males) / Enzyme replacement therapy 2 2C 2A 2 8CA
End-stage renal disease (females) / Enzyme replacement therapy 2 1C 2A 2 7CA
Pain crises (males) / Enzyme replacement therapy 1 3C 2A 2 8CA
Pain crises (females) / Enzyme replacement therapy 1 3C 2A 2 8CA
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

Prevalence of the Genetic Condition

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.
View Citations

A Mehta, et al. (2002) NCBI: NBK1292, El Dib R, et al. (2016) PMID: 27454104

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.
View Citations

A Mehta, et al. (2002) NCBI: NBK1292, Arends M, et al. (2015) PMID: 26076709, Biegstraaten M, et al. (2015) PMID: 25885911, Bolsover FE, et al. (2014) PMID: 23949010, El Dib R, et al. (2016) PMID: 27454104, Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776, Laney DA, et al. (2013) PMID: 23860966, Terryn W, et al. (2013) PMID: 23234755, Wang RY, et al. (2011) PMID: 21502868

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.
View Citations

A Mehta, et al. (2002) NCBI: NBK1292, Arends M, et al. (2015) PMID: 26076709, El Dib R, et al. (2016) PMID: 27454104, Eng CM, et al. (2006) PMID: 16980809

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.

Mode of Inheritance

X-linked

Prevalence of Genetic Variants

1-2 in 5000
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 View Citations

van der Tol L, et al. (2014) PMID: 23922385

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown
The incidence of cardiac complications is similar in individuals with the atypical Fabry cardiac variant and individuals with classic Fabry disease.
Tier 3 View Citations

A Mehta, et al. (2002) NCBI: NBK1292

>= 40 %
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% Stroke

- Males: 7%

- Females: 5% Cerebrovascular event (stroke, transient ischemic attack, prolonged reversible ischemic neurologic deficit):

- Males: 12-15%

- Females: 11.5-27%

Tier 3 View Citations

A Mehta, et al. (2002) NCBI: NBK1292

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown
No information on relative risk was identified.

Expressivity

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 View Citations

A Mehta, et al. (2002) NCBI: NBK1292

Substaintial intrafamilial and interfamilial variability in age of disease onset and disease progression exists.
Tier 3 View Citations

Biegstraaten M, et al. (2015) PMID: 25885911

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.

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 View Citations

Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776, Laney DA, et al. (2013) PMID: 23860966, Terryn W, et al. (2013) PMID: 23234755

Baseline data and all follow up data should be transferred to a central registry.
Tier 2 View Citations

Kes VB, et al. (2013) PMID: 24558776, Terryn W, et al. (2013) PMID: 23234755

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 View Citations

Biegstraaten M, et al. (2015) PMID: 25885911, Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776, Laney DA, et al. (2013) PMID: 23860966, Terryn W, et al. (2013) PMID: 23234755, Wang RY, et al. (2011) PMID: 21502868

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 View Citations

El Dib R, et al. (2016) PMID: 27454104

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 View Citations

El Dib R, et al. (2017) PMID: 28296917

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 View Citations

Arends M, et al. (2015) PMID: 26076709

Due to an increased risk of vascular events, other vascular risk factors (hypertension, dyslipidemia, diabetes mellitus, increased weight) should be aggressively managed.
Tier 2 View Citations

Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776

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 View Citations

Eng CM, et al. (2006) PMID: 16980809

Surveillance

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 View Citations

Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776, Laney DA, et al. (2013) PMID: 23860966, Terryn W, et al. (2013) PMID: 23234755

Circumstances to Avoid

Due to the high risk of vascular events patients should be discouraged from smoking.
Tier 2 View Citations

Eng CM, et al. (2006) PMID: 16980809, Kes VB, et al. (2013) PMID: 24558776

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 View Citations

A Mehta, et al. (2002) NCBI: NBK1292

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.

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%).
Context: Adult
View Citations

El Dib R, et al. (2016) PMID: 27454104, El Dib R, et al. (2017) PMID: 28296917

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.
Context: Adult
Tier 3 View Citations

Kes VB, et al. (2013) PMID: 24558776, Mehta A, et al. (2004) PMID: 15025684

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.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers

References List

A Mehta, DA Hughes. Fabry Disease. (2002) [Updated Oct 17 2013]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1292/

Arends M, Hollak CE, Biegstraaten M. (2015) Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet journal of rare diseases. 10(1750-1172):77.

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. (2015) Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet journal of rare diseases. 10(1750-1172):36.

Bolsover FE, Murphy E, Cipolotti L, Werring DJ, Lachmann RH. (2014) Cognitive dysfunction and depression in Fabry disease: a systematic review. Journal of inherited metabolic disease. 37(2):177-87.

El Dib R, Gomaa H, Carvalho RP, Camargo SE, Bazan R, Barretti P, Barreto FC. (2016) Enzyme replacement therapy for Anderson-Fabry disease. The Cochrane database of systematic reviews. 7(1469-493X):CD006663.

El Dib R, Gomaa H, Ortiz A, Politei J, Kapoor A, Barreto F. (2017) 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. 12(3):e0173358.

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. (2006) Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genetics in medicine : official journal of the American College of Medical Genetics. 8(9):539-48.

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. (2013) Guidelines for diagnosis, therapy and follow up of Anderson-Fabry disease. Acta clinica Croatica. 52(3):395-405.

Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. (2013) Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. Journal of genetic counseling. 22(5):555-64.

Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. (2004) Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. European journal of clinical investigation. 34(3):236-42.

Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, Serra A, Van Biesen W, Vanholder R, Wanner C. (2013) Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 28(3):505-17.

van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. (2014) A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. Journal of medical genetics. 51(1):1-9.

Wang RY, Bodamer OA, Watson MS, Wilcox WR. (2011) Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genetics in medicine : official journal of the American College of Medical Genetics. 13(5):457-84.

Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is it actionable in an undiagnosed adult with the condition?
  4. Is this condition an important health problem?
  5. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?