Fabry Disease Flashcards
Fabry Disease
Background
Second most prevalent lysosomal storage disease after Gaucher disease
May be seen in all ethnics and races
Fabry Disease
Background
X-linked inborn error with deficiency or defect of lysosomal hydrolase α-galactosidase A (α-Gal A), an enzyme that normally catalyzes the hydrolytic cleavage of the terminal galactose from globotriaosylceramide (Gb3).
Fabry Disease
Background
The enzymatic deficiency/defect leads to lysosomal accumulation of Gb3 in various cells including vascular endothelium and smooth muscle cells, cardiac muscle cells and conduction fibers, kidneys, and nerve root ganglia.
Fabry Disease
Clinical Manifestations
Neurologic: neuropathic pain in extremities, stroke in early age
Dermatologic: telangiectasias, angiokeratomas in groin, hip, periumbilical areas, corneal opacities, thickened lips, bullous nose, hypohidrosis or hyperhidrosis and associated heat/exercise or cold intolerance, respectively
Fabry Disease
Clinical Manifestations
Cardiac: arrhythmias, left ventricular hypertrophy
Gastrointestinal: abdominal pain, diarrhea
Fabry Disease
Clinical Manifestations
Renal: proteinuria (both tubular and glomerular proteinuria possible), progressive CKD, Fanconi syndrome due to proximal tubular injury, polydipsia and polyuria due to distal tubular injury and associated defective urinary concentrating ability, multiple renal sinus, and parapelvic cysts on imaging studies
Fabry Disease
Histopathology
LM:
Vacuolization/foamy appearance of podocytes and rarely distal tubular epithelial cells due to glycolipid accumulation
Nonspecific findings: FSGS or global glomerulosclerosis, tubulointerstitial fibrosis
Fabry Disease
Histopathology
EM:
“myeloid” or “zebra” bodies which are concentric lamellated inclusions often with a striped (zebra) appearance formed by Gb3 deposits within enlarged secondary lysosomes.
Fabry Disease
Histopathology
NOTE: lamellar inclusions may be seen prominently in podocytes associated with chloroquine or plaquenil administration. Less often they occur in gentamicin toxicity, or silicosis, predominantly in proximal, not distal, tubules.
Fabry Disease
Diagnosis
Low α-Gal A activity in leukocytes of plasma in males
Female carriers may have normal to low levels of α-Gal A, thus require genetic analysis for the α-Gal A gene.
Fabry Disease
Diagnosis
Genetic analysis may also be required in males with marginally low α-Gal A activity levels.
Tissue biopsy (skin or kidney) reveals characteristic findings but is typically not necessary.
Fabry Disease
Management
Enzyme (α-Gal A) replacement therapy:
Genetic counseling
Recommended for all males and females with classic presentations
Fabry Disease
Management
Enzyme (α-Gal A) replacement therapy:
Patient-specific consideration in asymptomatic female carriers or males with atypical presentations
Fabry Disease
Management
Enzyme (α-Gal A) replacement therapy:
Enzyme-replacement therapy effectively reduces deposition of Gb3 in most tissues except for podocytes and vascular smooth muscle. Nonetheless replacement therapy may slow kidney function decline in early disease.
Fabry Disease
Management
Enzyme (α-Gal A) replacement therapy:
Replacement options: agalsidase α 0.2 mg/kg or agalsidase β 1.0 mg/kg infusion every 2 weeks. Notable side effects: infusion reactions, development of antibodies against the enzyme
