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Stage I: Rule-Out Dashboard
Incidental Findings in Adults
GENE/GENE PANEL: GLA
DISORDER: Fabry disease
HGNC ID: 4296
OMIM ID: 301500
ACTIONABILITY
PENETRANCE
1. Is there a qualifying resource, such as a practice guideline or
systematic review, for the genetic condition?
YES
NO
2. Does the practice guideline or systematic review indicate that
the result is actionable in one or more of the following ways?
Yes
No
NO
SIGNIFICANCE/BURDEN OF DISEASE
YES
Surveillance or Screening
Family Management
NO
NEXT STEPS
Circumstances to Avoid
6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5)
all “YES”?
NO
3. Is the result actionable in an undiagnosed adult with the genetic
condition?
YES
YES
5. Is this condition an important health problem?
Patient Management
YES (≥ 1 of above)
4. Is there at least one known pathogenic variant with at least
moderate penetrance (≥40%) or moderate relative risk (≥2) in
any population?
NO
YES (Proceed to Stage II)
NO (Consult Actionability Working Group)
Exception granted, proceed to Stage II
Exception not granted, STOP
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Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
GENE/GENE PANEL: GLA
Topic
Narrative Description of Evidence
DISORDER: Fabry disease
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Signif/Burden of Condition
Prevalence of the
genetic disorder
Clinical Features
(Signs/symptoms)
The incidence of Fabry disease is estimated at 1:50,000 males; for both sexes, the population
incidence estimates have ranged from 1:80,000 to 1:117,000. 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.
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 occurs in males with less than 1% α-Gal A enzyme activity and usually has onset in
childhood or adolescent years (generally ages 4-8 years). The onset of symptoms in the classic form
occurs in childhood or adolescence with periodic crises of severe pain in the extremities,
appearance of vascular cutaneous lesions, hypohidrosis (diminished sweating response), and
corneal and lenticular opacities. Cardiac and/or cerebrovascular disease (e.g., LV-hypertrophy,
heart failure, stenosis, atherosclerotic plaques, coronary vasospasm, thrombotic and
thromboembolic complications) is present in most males by middle age; mitral insufficiency may be
present in childhood and adolescence. Progressive decline in renal function leads to end stage
renal disease (ESRD) usually during the third to fifth decade. Patients also have gastrointestinal,
auditory, pulmonary, vascular, cranial nerve, and psychological manifestations.
(1;2)
(1-3)
Heterozygous females typically have milder symptoms and 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.
Natural History
(Important
subgroups &
survival/recovery)
Males with a greater than 1% α-Gal A activity present later and may have either a cardiac variant
phenotype or renal variant phenotype. For those with the cardiac variant, age of presentation is
generally in the sixth to eight decade of life with left ventricular hypertrophy (LVH), mitral
insufficiency and/or cardiomyopathy with proteinuria but without ESRD. Clinical manifestations of
the cardiac variant may be found in women as well as men. The renal variant phenotype is typically
associated with ESRD without the skin or pain symptoms associated with classic Fabry disease.
Based on registry data, the life expectancy for patients was 58.2 years in males and 75.4 years for
females. The most common cause of death among both sexes was 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.
(1;3)
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.
2. How effective are interventions for preventing the harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patients should undergo baseline evaluation by a multidisciplinary team. Evaluation should include
a complete physical and psychological exam including quality of life, measurement of αgalactosidase A levels, and examination of the following systems: renal, cardiac, neurologic,
Patient
ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. (Tier 2)
Management
(3-7)
Baseline data and all follow up data should be transferred to a central registry. (Tier 2)
(4;6)
In global practice, there is wide variability in the usage of ERT even for hemizygotes, with some
(3-8)
2
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
starting therapy at a young age even without symptoms and others waiting until end organ damage
is evident. (Tier 2)
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)
(8)
Treatment with enzyme replacement therapy (using agalsidase alfa or beta) may reduce the rate of
end-organ complications (stroke, cardiac and renal events, death) compared to untreated patients.
Evidence for this effect is mixed and weak, and includes patients with advanced-stage disease as
well as studies of small size. One RCT (n=82; mean age 46, 12% female) of patients with Fabry with
mild-moderate kidney disease showed that treatment with agalsidase beta delayed time to first
clinical event (HR: 0.47 (95% CI, 0.21 to 1.03) p = 0.06) with the most significant effect found in
2
patients with baseline GFR rates greater than 55mL/min/1.73 m (HR: 0.19 (95% CI: 0.05 to 0.82) p=
0.025). One prospective study (57 treated patients with agalsidase alfa or beta; mean age 58; 50%
female) composed mainly of patients with classic Fabry with chronic kidney disease, LVH, or white
matter lesions found no difference in time to first (p=0.69) or second complication (p=0.72)
between treated patients and registry control data; however, the odds for developing a
complication declined with longer treatment duration for both first (0.81 [0.68-0.96] per year of
ERT) and second complications (0.52 [0.31-0.88] per year of ERT) regardless of sex. One cohort
study of 289 patients with Fabry disease (mean age 44; 58% female) found no difference between
treatment status and the probability of having a stroke/TIA (HR = 2.08 (95% CI 0.42 to 10.20) p =
0.36 ). A prospective cohort of 40 patients with genetically proven Fabry diseae (mean age 40; 22%
female) found no difference in the rate of a end-organ complications between the ERT treated
patients and a historical cohort (sex adjusted HR 1.48 (95% CI 0.72–3.06) p= 0.284.(Tier 1)
(2;9)
Due to an increased risk of vascular events, management of other vascular risk factors
(hypertension, dyslipidemia, diabetes mellitus, increased weight) should be aggressive. (Tier 2)
Surveillance
Family Management
Circumstances to
Avoid
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)
A detailed family history should be taken in order to determine at-risk family members and testing
offered, because most mutations are familial. Affected family members identified as a result of
screening should undergo the same baseline diagnostic and surveillance recommendations
detailed above. (Tier 2)
Due to the high risk of vascular events patients should be discouraged from smoking. (Tier 2)
(3;6)
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)
(1)
(3)
(3-7)
(8)
(3;6)
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
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Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
GENE/GENE PANEL: GLA
Topic
Narrative Description of Evidence
DISORDER: Fabry disease
Ref
3. What is the chance that this threat will materialize?
Mode of Inheritance X-linked
Prevalence of
Genetic Mutations
Penetrance
OR
Relative Risk
(include high risk racial
or ethnic subgroups)
Expressivity
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)
Efforts to establish genotype-phenotype correlations have been limited because most families
with Fabry disease are reported to have a private mutation.
(10)
Across three major Fabry disease registries the following histories were found at baseline:
(11)
(1)
Males (mean age 35-39)
Cardiac hypertrophy: 42-59%
Chronic kidney disease ≥ stage 2: 47-56%
Proteinuria: 54-62%
Stroke: 7-16%
Pain: 79-81%
Gastrointestinal symptoms: 55-81%
Females (mean age 40-44)
Cardiac hypertrophy: 26-35%
Chronic kidney disease ≥ stage 2: 54-65%
Proteinuria: 24-41%
Stroke: 4-16%
Pain: 56-65%
Gastrointestinal symptoms: 50-70% (Tier 5)
NA
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).
(1)
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.
5. Would the underlying risk or condition escape detection prior to harm in the
setting of recommended care?
Chance to Escape
Clinical Detection
It is unlikely that those with the classic form of Fabry disease would be missed in clinical care;
however, for female patients and those with late-onset variants, renal and cardiac
manifestations, may present with stroke or ESRD as their initial manifestation. Recent studies
have found that nearly half of Fabry patients (46%) experience their first stroke before being
diagnosed.
(6)
4
Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
Final Consensus Scores
Gene(s)
Outcome/intervention pair
Severity
Likelihood
Effectiveness
GLA
Nature of the
Intervention
2
Total
Score
8EA
End stage organ disease/ERT (classic
2
3E
1A
males)
End stage organ disease/ERT (late on-set
2
3E
1A
2
8EA
males)
End stage organ disease/ERT (females)
2
3E
1A
2
8EA
Stroke prevention/aspirin (Classic males)
2
2E
0B
3
7EB
Stroke prevention/aspirin (late on-set
2
2E
0B
3
7EB
males)
Stroke prevention/aspirin (females)
2
2E
0B
3
7EB
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionabilityevidence-based-summaries/.
Date of Search (06.24.2015):
Reference List
1. Mehta A, Hughes DA. Fabry Disease. GeneReviews. University of Washington; 2013.
2. El Dib RP, Nascimento P, Pastores GM. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane
Database Syst Rev 2013;2:CD006663.
3. Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, et al. Fabry disease: guidelines for the
evaluation and management of multi-organ system involvement. Genet Med 2006 Sep;8(9):539-48.
4. Terryn W, Cochat P, Froissart R, Ortiz A, Pirson Y, Poppe B, et al. Fabry nephropathy: indications for screening and
guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant 2013
Mar;28(3):505-17.
5. Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, et al. Fabry disease practice guidelines:
recommendations of the National Society of Genetic Counselors. J Genet Couns 2013 Oct;22(5):555-64.
6. Kes VB, Cesarik M, Zavoreo I, Soldo-Butkovic S, Kes P, Basic-Jukic N, et al. Guidelines for diagnosis, therapy and
follow up of Anderson-Fabry disease. Acta Clin Croat 2013 Sep;52(3):395-405.
7. Salviati A, Burlina AP, Borsini W. Nervous system and Fabry disease, from symptoms to diagnosis: damage
evaluation and follow-up in adult patients, enzyme replacement, and support therapy. Neurol Sci 2010
Jun;31(3):299-306.
8. Wang RY, Bodamer OA, Watson MS, Wilcox WR. Lysosomal storage diseases: diagnostic confirmation and
management of presymptomatic individuals. Genet Med 2011 May;13(5):457-84.
9. Rombach SM, Smid BE, Linthorst GE, Dijkgraaf MG, Hollak CE. Natural course of Fabry disease and the
effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in
different disease stages. J Inherit Metab Dis 2014 May;37(3):341-52.
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Stage II: Summary Report
Incidental Findings in Adults
Non-diagnostic, excludes newborn screening & prenatal testing/screening
10. van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, et al. A systematic review on
screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet
2014 Jan;51(1):1-9.
11. Sirrs S, Clarke JT, Bichet DG, Casey R, Lemoine K, Flowerdew G, et al. Baseline characteristics of patients enrolled in
the Canadian Fabry Disease Initiative. Mol Genet Metab 2010 Apr;99(4):367-73.
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