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Fabry Disease at a Glance
  • Incidence estimated at 1:3,200 to 1:170,000 in all ethnicities.
  • X-linked lysosomal storage disorder.
  • Highly penetrant in males; female heterozygotes have variable expressivity.
  • Partial or complete deficiency of α-galactosidase A with deposition of glycosphingolipids (mostly globotriaosylceramide).
  • Classical variants affect predominantly skin, kidneys, heart, eyes, and brain.
  • Life expectancy shortened by 20 years in males and 15 years in females.
  • Later onset variants: milder, predominantly single organ involvement, for example, renal or cardiac.
  • Dermatologic manifestations: angiokeratomas, telangiectasias, “pseudoacromegalic” facies, hypo- and hyperhidrosis, lymphedema, and Raynaud's phenomenon.
  • Light microscopy: ectatic upper dermal vessels, peripheral epidermal acanthosis, variable hyperkeratosis.
  • Electron microscopy: intracytoplasmic electron dense vacuolar “Zebra bodies.”
  • Treatment: symptomatic, enzyme replacement.

Fabry disease (α-galactosidase A, GLA, deficiency) is generally considered the second most prevalent lysosomal storage disorder, after Gaucher disease1,2 with an estimated incidence ranging between 1:40,000 to 1:170,000 persons. All ethnic groups are affected. Milder variants of the disease are associated with significant residual enzyme activity and may occur with much higher frequency (e.g., 1:3,200), as suggested by a recent survey of neonates in Northern Italy.3 These variants often have predominant involvement of a single organ (e.g., heart or kidney) and have onset in adult life.

Fabry disease (OMIM #301500) is caused by the partial or complete deficiency of a lysosomal enzyme, α-galactosidase A (Fig. 136-1). As a result of this enzyme deficiency, neutral sphingolipids with terminal α-galactosyl residues [predominantly globotriaosylceramide (Gb3)] accumulate in the lysosomes of different tissues and fluids (epithelial cells of glomeruli and tubules of the kidneys; cardiac myocytes; ganglion cells of the autonomic system; cornea; endothelial, perithelial, and smooth muscle cells of blood vessels; and histiocytic and reticular cells of connective tissue). Clinical onset is variable (Fig. 136-2). Although the condition is X linked, heterozygous females are frequently affected and may be as severely affected as hemizygous males.4 Clinical symptoms typically occur a decade or so later in females than in males and organ damage is usually less severe. Variable expression in females is attributed to the Lyon hypothesis, whereby one X chromosome is inactivated on a random basis in the female, while the other provides the genetic information.

Figure 136-1

Metabolic pathway: α-galactosidase A (α-Gal A) metabolizes globotriaosylceramide to galactose (Gal) and lactosylceramide. Cer = ceramide; Glu = glucose.

Figure 136-2

Natural history of Fabry disease: acroparesthesias, angiokeratomas, corneal opacities, and gastrointestinal symptoms are often the first manifestations. Diagnosis is usually delayed and occurs around the second decade. CNS = central nervous system; GI = gastrointestinal.

The GLA gene for α-galactosidase A is located at the Xq22.1 region. More than 400 mutations have been identified in the GLA gene,5,6 including missense, nonsense mutations, and single amino ...

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