Stage I: Rule-Out Dashboard 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? 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? Family Management Circumstances to Avoid ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? 3. Is the result actionable in an undiagnosed adult with the genetic condition? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1
GENE/GENE PANEL: GLA DISORDER: Fabry disease Topic Narrative Description of Evidence Ref Signif/Burden of Condition 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) 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. 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. 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. 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 α- galactosidase A levels, and examination of the following systems: renal, cardiac, neurologic, Patient ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. (Tier 2) Management Baseline data and all follow up data should be transferred to a central registry. (Tier 2) (1;2) (1-3) (1;3) (3-7) (4;6) In global practice, there is wide variability in the usage of ERT even for hemizygotes, with some (3-8) 2
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) 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 patients with baseline GFR rates greater than 55mL/min/1.73 m 2 (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) (8) (2;9) Surveillance Family Management Circumstances to Avoid 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) 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) 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;6) (3) (3-7) (8) (3;6) (1) 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 3
GENE/GENE PANEL: GLA DISORDER: Fabry disease Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations X-linked 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) (1) Across three major Fabry disease registries the following histories were found at baseline: (11) Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) 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) Expressivity 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). 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. (1) (6) 4
Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score GLA End stage organ disease/ert (classic 2 3E 1A 2 8EA 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. 5
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. 6