Medical Home Portal - Fabry Disease

Fabry Disease

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Screening
Description
Primary Care Management
Resources

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Anderson-Fabry disease

Angiokeratoma corporis diffusum

Alpha-galactosidase A deficiency

Alpha-galactosidase A pseudodeficiency

GLA deficiency

ICD-10 Coding

E75.21, Fabry (-Anderson) disease

Disorder Category

Lysosomal storage disorder

Screening

Abnormal Finding

α-galactosidase A enzyme assay (only in males)
Newborn screening for Fabry disease is performed in some but not all states.

Tested By

Tandem mass spectrometry (MS/MS)

Description

Fabry disease is an X-linked, progressive, multisystem lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A. This results in an accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids and subsequently progressive impairment of normal cell function in multiple organ systems. [Kaminsky: 2013] [National: 2022] [Chan: 2018] Newborns and babies are asymptomatic.

As an X-linked disorder, males with Fabry disease are typically more severely affected than females. Classically, males will present with signs/symptoms in early childhood. Early signs/symptoms include angiokeratomas, episodic acroparesthesias, sweating abnormalities, and corneal and lenticular opacities. This may progress to adult-onset renal disease/failure, left ventricular hypertrophy, and cerebrovascular disease if untreated. Though much less common, more mild forms of Fabry disease exist in which classic symptoms may start in adulthood, and individual organ systems may be more significantly affected but not others.

Heterozygous females present with significantly more clinical variability ranging from a complete absence of symptoms throughout life to being as severely symptomatic as classical males.

Clinical Characteristics

With treatment, in males with <1% alpha-galactosidase activity, disease progression can be slowed, though some degree of persistent symptoms can be expected despite available treatments. Enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme) is an FDA-approved treatment for Fabry disease in the United States. ERT, given by infusion every 2 weeks for the duration of the patient's life, has been shown to slow the progression of renal and cardiac disease as well as help with pain and other symptoms [Sestito: 2013] [Germain: 2015] [El: 2016].
Without treatment, in males with <1% alpha-galactosidase A activity, the disease will eventually progress with time, and during adolescence/adulthood, patients may experience heart, kidney, and central nervous system problems. [Mehta: 2010] [Sestito: 2013] [Löhle: 2015] Cardiac disease may include mitral insufficiency, conduction abnormalities, left ventricular enlargement, and hypertrophic cardiomyopathy. Renal disease typically starts with proteinuria followed by azotemia and gradual deterioration of renal function in the 3rd to 5th decade of life. In females, symptoms may start in adulthood.

Cerebrovascular disease caused by small vessel involvement may lead to transient ischemic attacks, aneurysms, seizures, and cerebral strokes, resulting in permanent neurological damage. Less common features include chronic gastrointestinal symptoms like diarrhea, nausea/vomiting, abdominal pain, pulmonary disease, hearing loss, tinnitus, and psychological disease, like depression and anxiety, that may be secondary to the chronic nature of the other symptoms. All relevant organ systems need to be assessed, treated, and monitored. [Eng: 2006]

Incidence

Though initially estimated to affect 1:50,000 males [National: 2022], more recent studies involving the newborn screen suggest Fabry disease is far more common, with an incidence as high as 1:3100 to 1:3277. [Spada: 2006] [Hopkins: 2018]

Inheritance

X-linked dominant (with decreased female penetrance)

Primary Care Management

Next Steps After a Positive Screen

Contact the family to inform them of the newborn screening result.
Elicit family history of kidney disease, heart disease, stroke, or paresthesias.
Refer to the ACT Sheet for Fabry Disease (ACMG) ( 237 KB).

Confirming the Diagnosis

To confirm the diagnosis of Fabry disease, work with Newborn Screening Services (see NW providers [1]).
Decreased leukocyte α-galactosidase A enzyme assay in males and elevations in urinary globotriaosylsphingosine (lyso-Gb3) levels are very sensitive biomarkers and can help classify the severity of disease and assist in diagnosis if genetic testing results are unclear. [Niemann: 2014] [Aerts: 2008] [Auray-Blais: 2015]. However, molecular genetic testing for the GLA gene is still necessary to confirm the diagnosis, as decreased leukocyte α-galactosidase A enzymes can present with pseudodeficiency.
A normal leukocyte α-galactosidase A enzyme level is consistent with a false positive.
Females should be evaluated with molecular testing. Measurement of α-Gal A enzyme activity is unreliable.

If the Diagnosis is Confirmed

For evaluation and ongoing collaborative management, consult Medical Genetics (see NW providers [1]).
Refer the family to Genetic Testing and Counseling (see NW providers [6]).
Educate the family regarding signs and symptoms of the condition (see Fabry Disease - Information for Parents (STAR-G)).
Regular monitoring of Fabry disease symptoms alongside their Pediatric Geneticist.
See Care Coordination/Case Management (see NW providers [0]).

Resources

Information & Support

Related Portal Content
Fabry Disease
Assessment and management information for the primary care clinician caring for the child with Fabry disease.
Fabry Disease (FAQ)
Answers to questions families often have about caring for their child with Fabry disease.
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Fabry Disease (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Fabry Disease (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

For Parents and Patients

Fabry Disease (NORD)
Information for families includes synonyms, signs & symptoms, causes, affected populations, related disorders, diagnosis, therapies (both standard and investigational), and support organizations; National Organization of Rare Disorders.

Fabry Disease - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology, and Research in Genetics.

GLA Gene (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Discover Fabry (Genzyme)
Diagnosis, management, resources, and support information for families affected by Fabry disease.

Tools

ACT Sheet for Fabry Disease (ACMG) ( PDF Document 237 KB)
Short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for Alpha-galactosidase A (?- gal A) Deficiency (ACMG) ( PDF Document 153 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Fabry: Response to Positive Newborn Screen (Mayo Clinic) ( PDF Document 476 KB)
One-page algorithm for clinicians; Mayo Medical Laboratories.

Fabry Disease: Testing Algorithm (Mayo Clinic) ( PDF Document 496 KB)
Describes appropriate screening and testing based on indications and gender.

Services for Patients & Families Nationwide (NW)

Service Categories	NW		NM	NV	RI
Care Coordination/Case Management		10	58	73	30
Genetic Testing and Counseling	6	6	12	8	11
Medical Genetics	1	2	5	4	7
Newborn Screening Services	1	3	2	2	3

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

Laney DA, Peck DS, Atherton AM, Manwaring LP, Christensen KM, Shankar SP, Grange DK, Wilcox WR, Hopkin RJ.
Fabry disease in infancy and early childhood: a systematic literature review.
Genet Med. 2015;17(5):323-30. PubMed abstract

Thomas AS, Hughes DA.
Fabry disease.
Pediatr Endocrinol Rev. 2014;12 Suppl 1:88-101. PubMed abstract

Authors & Reviewers

Initial publication: July 2022

Current Authors and Reviewers:

Author:	Brian J. Shayota, MD, MPH
Reviewer:	Nancy C. Rose, MD

Page Bibliography

Aerts JM, Groener JE, Kuiper S, Donker-Koopman WE, Strijland A, Ottenhoff R, van Roomen C, Mirzaian M, Wijburg FA, Linthorst GE, Vedder AC, Rombach SM, Cox-Brinkman J, Somerharju P, Boot RG, Hollak CE, Brady RO, Poorthuis BJ.
Elevated globotriaosylsphingosine is a hallmark of Fabry disease.
Proc Natl Acad Sci U S A. 2008;105(8):2812-7. PubMed abstract / Full Text

Auray-Blais C, Blais CM, Ramaswami U, Boutin M, Germain DP, Dyack S, Bodamer O, Pintos-Morell G, Clarke JT, Bichet DG, Warnock DG, Echevarria L, West ML, Lavoie P.
Urinary biomarker investigation in children with Fabry disease using tandem mass spectrometry.
Clin Chim Acta. 2015;438:195-204. PubMed abstract

Chan B, Adam DN.
A Review of Fabry Disease.
Skin Therapy Lett. 2018;23(2):4-6. PubMed abstract / Full Text

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. PubMed abstract / Full Text

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. PubMed abstract
An international panel of physicians with expertise in Fabry disease has proposed guidelines for the recognition, evaluation, and surveillance of disease-associated morbidities, as well as therapeutic strategies.

Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR.
Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.
J Med Genet. 2015;52(5):353-8. PubMed abstract / Full Text

Hopkins PV, Klug T, Vermette L, Raburn-Miller J, Kiesling J, Rogers S.
Incidence of 4 Lysosomal Storage Disorders From 4 Years of Newborn Screening.
JAMA Pediatr. 2018;172(7):696-697. PubMed abstract / Full Text

Kaminsky P, Noel E, Jaussaud R, Leguy-Seguin V, Hachulla E, Zenone T, Lavigne C, Marie I, Maillot F, Masseau A, Serratrice C, Lidove O.
Multidimensional analysis of clinical symptoms in patients with Fabry's disease.
Int J Clin Pract. 2013;67(2):120-7. PubMed abstract

Löhle M, Hughes D, Milligan A, Richfield L, Reichmann H, Mehta A, Schapira AH.
Clinical prodromes of neurodegeneration in Anderson-Fabry disease.
Neurology. 2015;84(14):1454-64. PubMed abstract / Full Text

Mehta A, Beck M, Eyskens F, Feliciani C, Kantola I, Ramaswami U, Rolfs A, Rivera A, Waldek S, Germain DP.
Fabry disease: a review of current management strategies.
QJM. 2010;103(9):641-59. PubMed abstract / Full Text

National Library of Medicine.
Fabry Disease.
MedlinePlus Genetics; (2022) https://medlineplus.gov/genetics/condition/fabry-disease/#frequency. Accessed on July 2022.

Niemann M, Rolfs A, Störk S, Bijnens B, Breunig F, Beer M, Ertl G, Wanner C, Weidemann F.
Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease.
Circ Cardiovasc Genet. 2014;7(1):8-16. PubMed abstract

Sestito S, Ceravolo F, Concolino D.
Anderson-Fabry disease in children.
Curr Pharm Des. 2013;19(33):6037-45. PubMed abstract

Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ.
High incidence of later-onset Fabry disease revealed by newborn screening.
Am J Hum Genet. 2006;79(1):31-40. PubMed abstract / Full Text