The packet lists GLA, located on the X chromosome, as the associated gene, with ClinGen gene-disease validity rated DEFINITIVE. The packet does not supply a molecular mechanism field; the definition and GeneReviews describe the condition as a lysosomal storage disease involving deficient alpha-galactosidase A enzyme activity. Inheritance is listed as X-linked. GeneReviews states that hemizygous males are affected and that heterozygous females may be as severely affected as males or may be asymptomatic throughout a normal life span. It describes a 50% chance of transmitting a GLA pathogenic variant in each pregnancy when the mother carries one, notes that the father of a male proband is not expected to carry the variant, and states that an affected male may rarely have a de novo variant or that a mother may have mosaicism.

GeneReviews reports that efforts to establish genotype-phenotype correlations have been limited because most families have a private pathogenic variant, and that significant phenotypic variability exists even among individuals with the same variant. Males with the classic phenotype are described as having a variety of GLA variants, whereas later-onset atypical disease is described as associated with missense or splicing variants that retain residual enzyme activity.

GeneReviews states that Fabry disease typically affects more than one organ system and lists suggestive findings including angiokeratomas, acroparesthesia, sweating abnormalities, cornea verticillata, unexplained left ventricular hypertrophy or arrhythmia, unexplained stroke, gastrointestinal symptoms, and renal insufficiency of unknown cause, together with a family history consistent with X-linked inheritance. Absence of a known family history is noted not to preclude the diagnosis.

In a male proband, GeneReviews describes the diagnosis as established by deficient alpha-galactosidase A enzyme activity in plasma, isolated leukocytes, and/or cultured cells, or by identification of a hemizygous pathogenic or likely pathogenic GLA variant. In a female proband, it is described as established by identification of a heterozygous pathogenic or likely pathogenic GLA variant by molecular genetic testing. GeneReviews notes that enzyme activity measurement is unreliable for identifying heterozygous females, since some heterozygotes have activity in the normal range, and that a GLA variant of uncertain significance neither establishes nor rules out the diagnosis. Molecular testing approaches described include single-gene testing, multigene panels, and comprehensive genomic testing. The packet does not include a separate curated diagnostic methods list.

The packet lists three FDA records with ACTIVE market status: Fabrazyme (agalsidase beta, BLA, approved 2003), Galafold (migalastat hydrochloride, NDA, approved 2018), and Elfabrio (pegunigalsidase alfa, BLA, approved 2023). GeneReviews describes enzyme replacement therapy (ERT) as a targeted therapy, noting that Fabrazyme was approved by the FDA, whereas a second agalsidase product, Replagal, is described as approved in Europe. GeneReviews reports that studies of agalsidase alfa and agalsidase beta describe reduced decline in renal and cardiac function and improvements in pain or gastrointestinal symptoms in some cohorts, and that studies of ERT in females have been reported. The packet does not supply further detail on migalastat or pegunigalsidase alfa beyond the FDA records.

GeneReviews also describes treatment of individual manifestations and surveillance of the cardiac, neurologic, renal, hearing, and psychologic systems at intervals that vary by system and sex, noting these are general guidelines. Orphan designations in the packet, such as those for lucerastat, venglustat, and several AAV vectors, are designations and do not indicate approval. The packet does not include a curated foundational therapies field.

GeneReviews describes Fabry disease as progressive. In its comparison of phenotypes, the classic form has an onset age of 4 to 8 years and an average age of death of 41 years, while late-onset variants have an onset age of about 25 years and an average age of death of 60 years; this is a population-level table entry rather than an individual estimate. For classic disease, GeneReviews states that death occurs from complications of kidney disease, cardiac involvement, and/or cerebrovascular disease. GeneReviews also reports that disease course varies, including variable severity in heterozygous females.

The packet gives a prevalence category of COMMON, corresponding to approximately 1 to 5 per 10,000. GeneReviews reports the incidence of classic Fabry disease at 1 in 50,000 to 1 in 117,000 males and notes that newborn screening studies, including in northern Italy, Taiwan, and several US states, suggest later-onset forms are more common than previously recognized, with figures varying by population.

The packet lists 56 trials on ClinicalTrials.gov for Fabry disease and provides detail for ten records. These include a Phase 3 study of venglustat on pain in participants 16 years and older, sponsored by Sanofi (NCT05206773); a Phase 1 study of AMT-191 in classic Fabry disease sponsored by UniQure Biopharma (NCT06270316, recruiting); a Phase 3 study of migalastat in pediatric subjects with amenable GLA variants sponsored by Amicus Therapeutics (NCT06904261, recruiting); Phase 3 studies of lucerastat sponsored by Idorsia Pharmaceuticals (NCT03737214 and NCT07778667); a Phase 4 study of Replagal in India sponsored by Shire (NCT05067868); an exercise training study sponsored by General University Hospital, Prague (NCT07495410); and a Fabry Disease Registry and Pregnancy Sub-registry sponsored by Genzyme (NCT00196742, recruiting). GeneReviews lists gene therapy, mRNA therapy, PEGylated enzyme, and substrate reduction approaches as under investigation. Patient organizations listed include the Fabry Support & Information Group, and a National Organization for Rare Disorders medical assistance program is listed as accepting.