Fabry disease results from pathogenic variants in the GLA gene, located on the X chromosome. The GLA gene encodes alpha-galactosidase A, a lysosomal enzyme responsible for cleaving the terminal galactose from globotriaosylceramide (Gb3) and related glycolipids. When GLA enzyme activity is deficient or absent, Gb3 accumulates progressively within lysosomes of vascular endothelial cells, cardiac cells, renal cells, neurons, and other cell types throughout the body. This glycolipid storage burden drives the multiorgan damage characteristic of Fabry disease. Inheritance is X-linked: hemizygous males carry a single GLA allele and typically exhibit more severe disease, while heterozygous females carry one pathogenic and one functional allele. The degree of clinical expression in heterozygous females is influenced by X-inactivation patterns, which vary among individuals. Genotype-phenotype correlations are limited by substantial intra-familial variability; most families carry a private GLA pathogenic variant unique to that family. Males with the classic phenotype carry a range of variant types including large rearrangements, splicing defects, and missense or nonsense variants, while those with atypical late-onset forms often carry missense variants with residual enzyme activity.

Diagnosis of Fabry disease relies on biochemical and molecular testing. In hemizygous males, measurement of alpha-galactosidase A enzyme activity in plasma or leukocytes demonstrating markedly reduced levels is the primary diagnostic approach. Enzyme activity testing alone is insufficient for diagnosing heterozygous females, in whom activity levels may overlap with the unaffected range; molecular testing—sequencing and deletion/duplication analysis of the GLA gene—is required for diagnosis in females and characterizes the specific variant in males. Fabry disease is typically considered in individuals presenting with characteristic multisystem clinical findings. Features prompting diagnostic evaluation include angiokeratomas, acroparesthesias, cornea verticillata, unexplained left ventricular hypertrophy, unexplained stroke or transient ischemic attack, proteinuria, and renal dysfunction. Diagnostic delay is common; Fabry disease is frequently misdiagnosed as growing pains, idiopathic neuropathy, or cardiomyopathy of unknown cause before the correct diagnosis is established. Newborn screening programs employing enzyme activity assays in dried blood spots followed by molecular confirmation identify cases at birth. Cascade molecular testing of at-risk first-degree relatives is performed following identification of a proband with a confirmed GLA pathogenic variant.

Three FDA-approved therapies address the underlying enzymatic deficiency in Fabry disease. Agalsidase beta (Fabrazyme) is an enzyme replacement therapy consisting of recombinant human alpha-galactosidase A administered by intravenous infusion, replacing the deficient enzyme and reducing glycolipid substrate accumulation across tissues. Pegunigalsidase alfa (Elfabrio) is a PEGylated recombinant human alpha-galactosidase A with an extended circulating half-life, also administered intravenously as enzyme replacement. Migalastat (Galafold) is an oral pharmacological chaperone that stabilizes certain amenable mutant forms of the GLA enzyme, promoting proper protein folding and lysosomal trafficking; it is indicated for patients whose GLA variant has been identified as amenable to this mechanism. Management of Fabry disease additionally encompasses organ-specific care: cardiac management addresses arrhythmias and ventricular hypertrophy; renal care focuses on reducing proteinuria and preserving renal function; and cerebrovascular risk is addressed through established neurological care pathways. Symptomatic management of acroparesthesia and gastrointestinal manifestations forms an additional component of comprehensive care. Multidisciplinary coordination across cardiology, nephrology, neurology, and other specialties reflects the systemic nature of the disease.

The long-term course of Fabry disease is determined primarily by the extent and pace of cardiovascular, renal, and cerebrovascular involvement. In hemizygous males with the classic phenotype, progressive renal failure, cardiac disease, and stroke have historically been major sources of morbidity and reduced longevity. Heterozygous females follow a variable trajectory; a substantial proportion develop clinically significant cardiac, renal, or neurological disease over time, though the course tends to be less severe and later in onset compared with affected males. The natural history is influenced by the specific GLA variant, degree of residual enzyme activity, and organ systems predominantly involved. The availability of enzyme replacement therapy and pharmacological chaperone therapy has altered the disease trajectory for many individuals; outcomes depend on the extent of organ damage present when disease-modifying therapy is initiated. Late-onset Fabry disease—characterized primarily by isolated cardiac or renal involvement—carries a distinct clinical and prognostic profile. Regular assessment of cardiac, renal, and neurological function throughout an individual's lifetime is standard clinical practice given the condition's progressive character.

Fabry disease is an area of active clinical and translational research. Multiple clinical trials across various phases are ongoing, examining enzyme replacement strategies, gene therapy approaches, and pharmacological interventions. Gene therapy using adeno-associated virus vectors of multiple serotypes is under active investigation, aiming to achieve sustained GLA expression following a single administration. Autologous stem cell-based approaches, in which patient-derived cells are engineered to produce functional alpha-galactosidase A enzyme, are in clinical study. Systemic mRNA therapy targeting GLA enzyme reconstitution represents an additional investigational strategy. Substrate reduction therapies and extended-action enzyme formulations are also in clinical evaluation. ClinGen has classified GLA as having DEFINITIVE evidence for its causal role in Fabry disease, anchoring the genetic basis of the condition within the highest tier of evidence. Ongoing research encompasses biomarker development, optimization of treatment initiation thresholds, long-term outcome assessment through international registries, and evaluation of efficacy endpoints across distinct organ systems.