++
AT-A-GLANCE
Incidence estimated at 1:3200 to 1:170,000 population 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 are milder and predominantly involve a single organ (eg, renal or cardiac).
Dermatologic manifestations include angiokeratoma, telangiectases, “pseudoacromegalic” facies, hypohidrosis and hyperhidrosis, lymphoedema, and Raynaud phenomenon.
Light microscopy shows ectatic upper dermal vessels, peripheral epidermal acanthosis, and variable hyperkeratosis.
Electron microscopy shows intracytoplasmic, electron-dense, vacuolar “Zebra bodies.”
Treatment is symptomatic, enzyme replacement; chaperone therapy (for amenable mutations).
++
Fabry disease (α-galactosidase A deficiency) is generally considered the second most prevalent lysosomal storage disorder, after Gaucher disease,1,2 with an estimated incidence ranging between 1:40,000 and 1:170,000 persons. All ethnic groups are affected. Neonatal screening studies reveal a higher incidence of mutations in the GLA gene and some of the affected individuals suffer from milder variants of the disease, which are associated with significant residual enzyme activity. These may occur with much higher frequency (eg, 1:3200) as suggested by a recent survey of neonates in Northern Italy.3 A study of more than 7000 neonates in Japan suggests an incidence of pathogenic mutations of approximately 1:70004 and a similar incidence has been reported from Europe.5 These variants often have predominant involvement of a single organ (eg, heart or kidney) and have onset in adult life. A study of the Taiwan Chinese population revealed an unexpectedly high prevalence of the cardiac-variant Fabry-causing mutation IVS4+919G>A among newborns (approximately 1:1600 males), as well as patients with idiopathic hypertrophic cardiomyopathy.6
+++
ETIOLOGY AND PATHOGENESIS
++
Fabry disease (Online Mendelian Inheritance in Man #301500) is a rare X-linked metabolic disorder caused by the partial or complete deficiency of a lysosomal enzyme, α-galactosidase A (Fig. 127-1). 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). Elevated levels of globotriaosylsphingosine, which is the deacylated derivative of Gb3, correlate with disease severity in males and females. Globotriaosylsphingosine inhibits the activity of α-galactosidase A and it has been suggested that elevated levels in females could be of pathogenic significance.7 Clinical onset is variable (Fig. 127-2). Although the condition is X linked, heterozygous females are frequently affected and may be as severely affected as hemizygous males.8 Clinical symptoms typically occur a decade or so later in females than in males and organ damage ...