Fabry Disease

Actionability Adult Summary Report

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

• Mode(s) of Inheritance: X-linked
• Literature Search: 06/24/2015
• Curation Status: Released (1.0.0)

Assertions and Scores

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
End-stage organ disease / ERT (classic males)	2	3E	1A	2	8EA
End-stage organ disease / ERT (late-onset males)	2	3E	1A	2	8EA
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-onset males)	2	2E	0B	3	7EB
Stroke prevention / Aspirin (females)	2	2E	0B	3	7EB

Severity of Outcome

Prevalence of the Genetic Condition

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.

Clinical Features (Signs / symptoms)

Fabry disease results from deficient activity of the enzyme ɑ-galactosidase (ɑ-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% ɑ-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% ɑ-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.

Natural History (Important subgroups & survival / recovery)

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.

Likelihood of Outcome

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

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

>= 40 %

Efforts to establish genotype-phenotype correlations have been limited because most families with Fabry disease are reported to have a private mutation.

Tier 5

Across three major Fabry disease registries the following histories were found at baseline:<p class="paragraph-separator"></p>Males (mean age 35-39)Cardiac hypertrophy: 42-59%<p class="paragraph-separator"></p>Chronic kidney disease >= stage 2: 47-56%<p class="paragraph-separator"></p>Proteinuria: 54-62%<p class="paragraph-separator"></p>Stroke: 7-16%<p class="paragraph-separator"></p>Pain: 79-81%<p class="paragraph-separator"></p>Gastrointestinal symptoms: 55-81%<p class="paragraph-separator"></p>Females (mean age 40-44)Cardiac hypertrophy: 26-35%<p class="paragraph-separator"></p>Chronic kidney disease ≥ stage 2: 54-65%<p class="paragraph-separator"></p>Proteinuria: 24-41%<p class="paragraph-separator"></p>Stroke: 4-16%<p class="paragraph-separator"></p>Pain: 56-65%<p class="paragraph-separator"></p>Gastrointestinal symptoms: 50-70%.

Tier 5

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

Unknown

NA

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).

Intervention Effectiveness

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 ɑ-galactosidase A levels, and examination of the following systems: renal, cardiac, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal.

Tier 2

Baseline data and all follow up data should be transferred to a central registry.

Tier 2

In global practice, there is wide variability in the usage 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.

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 m2 (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

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

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

Circumstances to Avoid

Due to the high risk of vascular events patients should be discouraged from smoking.

Tier 2

Given the potential effects on cellular levels of ɑ-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

Nature of Intervention

Nature of Intervention

Patient management involves non-invasive, multiple organ system medical screening and potentially the use of enzyme replacement therapy.

Context: Adult

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.

Context: Adult

Tier 3

Gene Condition Association

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/

El Dib RP, Nascimento P, Pastores GM. (2013) Enzyme replacement therapy for Anderson-Fabry disease. The Cochrane database of systematic reviews. 2(2):CD006663.

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.

Rombach SM, Smid BE, Linthorst GE, Dijkgraaf MG, Hollak CE. (2014) 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. Journal of inherited metabolic disease. 37(3):341-52.

Salviati A, Burlina AP, Borsini W. (2010) Nervous system and Fabry disease, from symptoms to diagnosis: damage evaluation and follow-up in adult patients, enzyme replacement, and support therapy. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 31(3):299-306.

Sirrs S, Clarke JT, Bichet DG, Casey R, Lemoine K, Flowerdew G, Sinasac DS, West ML. (2010) Baseline characteristics of patients enrolled in the Canadian Fabry Disease Initiative. Molecular genetics and metabolism. 99(4):367-73.

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.