Overview

Fabry disease is an X-linked, multi-systemic, genetic disorder of glycosphingolipid metabolism. Clinical manifestations are due to absence/deficiency of lysosomal α-galactosidase (α-GAL) activity, the result of pathogenic variants in GLA.1

Fabry disease patients are typically classified as “classic” or “non-classic,” often referred to as “late-onset”: 

  • Classic males primarily present in childhood or adolescence with neuropathic pain, angiokeratomas, corneal opacities, hypohidrosis, and gastrointestinal disturbances. In adulthood, patients with classic disease are at risk for kidney failure, cardiomyopathy, cardiovascular disease, arrhythmias, and stroke/transient ischemic attack2
  • Organ damage often begins without overt symptoms, particularly in females, and may become irreversible and potentially life-threatening3,4
  • Non-classic patients present with variable age of onset and manifestations, most commonly seen in the fourth to seventh decades and may be initially limited to single-organ involvement2
  • Phenotypic heterogeneity and overlap with more common conditions can make predicting genotype:phenotype correlations challenging2

Female Fabry patients have a wide spectrum of disease manifestations from asymptomatic to a severe phenotype similar to classic males.1

  • In a Registry survey of 1077 females heterozygous for GLA mutations, 69.4% had signs and symptoms of Fabry disease5

To review publications on Fabry disease, click here.

Clinical Snapshot

  • Classic males primarily present in childhood or adolescence2
  • Non-classic patients present with variable age of onset and frequently limited to cardiac manifestation2
  • Organ damage often begins without overt symptoms, particularily in females3,4
  • α-GLA enzyme assay in plasma and leukocytes is considered diagnostic in males; diagnosis in females requires a genetic test2

Inheritance

As an X-linked disease, the pathogenic variant that causes Fabry disease can be transmitted by both males and females6-7

  • Sons with a pathogenic GLA variant are affected
  • Daughters with a pathogenic GLA variant can have variable clinical severity, ranging from asymptomatic to severe disease due to non-random X-inactivation

    Overview
    Signs and Symptoms
    Diagnosis
    Publications
    Additional Materials

Segregation of X-Linked Trait

References: 
1. Germain DP. Orphanet J Rare Dis. 2010;5:30. 2. Ortiz A, et al. Mol Genet Metab. 2018;123(4):416–427. 3. Moura LA, et al. ASN Kidney Week 2017; Abstract SA-PO628. 4. Niemann M, et al. JACC Cardiovasc Imaging. 2011; 4(6):592–601. 5. Wilcox WR, et al. Mol Genet Metab. 2008;93(2):112–128. 6. Desnick RJ, et al. α-Galactosidase A Deficiency: Fabry Disease. In: Valle D, et al; eds. New York, NY. McGraw Hill, 2001. 7. Echeverria L, et al. Clin Genet. 2016;89(1):44–54.

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