Biochemical and Molecular Genetic Basis of Fabry Disease GREGORY M. PASTORES,* YEONG-HAU H. LIEN † *Neurogenetics Program, Department of Neurology and Pediatrics, New York University School of Medicine, New York, New York; and † Department of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona. Anderson-Fabry disease (AFD) is an inborn error of glyco- sphingolipid metabolism that is due to a deficiency of the lysosomal hydrolase -galactosidase A (-Gal A) (1). It is an X-linked lysosomal storage disorder (LSD) associated with multisystemic involvement resulting from the accumulation of neutral glycosphingolipids (mostly ceramide trihexoside [CTH]) in various organs (2). The disease manifests primarily in affected hemizygous males and to some extent in heterozy- gous (carrier) females. After a brief overview of the clinical features, this section of the supplement focuses on the bio- chemical and genetic basis of AFD. Overview of Clinical Manifestations The clinical features of AFD include corneal and lenticular opacities (Figure 1), acroparesthesias, angiokeratomas (Fig- ure 2), hypohidrosis, and major end organ disease (with in- volvement of the kidneys, heart, and brain) (3,4). Acropares- thesia constitutes the earliest major source of morbidity during the first two decades of life and often remains undiagnosed unless other manifestations or a positive family history provide diagnostic clues. Most affected males have proteinuria and ultimately develop renal failure. Details on the renal aspects of AFD follow in subsequent sections. The clinical course can also be complicated by cardiac and cerebrovascular disease, which combined with renal failure, lead to early mortality. The clinical course in heterozygous (carrier) women with AFD indicates a later onset of symptoms and milder progression, although some women may have presentations not unlike that seen in the classically affected male. The median survival is 50 yr (interquartile range, 40 to 56) for affected males and 70 yr (57 to 78) for carrier females (3,4). Fabry disease is a rare pan-ethnic disorder with an estimated frequency of 1 in 117,000 male births (5). However, recent studies suggest that the incidence may be underestimated, as certain patients with residual enzyme activity (5 to 35% of normal levels) have disease characterized predominantly by cardiac involvement. Indeed, in one study that involved screen- ing of patients with left ventricular hypertrophy, 3% were found to have an underlying -Gal A deficiency (6). In addi- tion to ventricular hypertrophy, arrhythmias and valvular in- volvement were also noted (see Kampmann et al. in this issue). Although there was no indication of chronic renal insuffi- ciency, several of the patients were found to have proteinuria. The diagnosis of AFD among patients without a positive family history has been a challenge to nephrologists and an even greater dilemma for other physicians who may see these patients before the onset of renal failure. Indeed, there is often significant delay in the diagnosis of AFD, with mean age at diagnosis for males of 21.9 yr (3). The renal manifestations usually occur during adolescence or adulthood. Most renal related symptoms and signs are nonspecific. Polyuria due to concentration defects may be the earliest renal symptom, but it is often ignored by patients or physicians. Proteinuria, usually in the non-nephrotic range, and chronic renal insufficiency are the most common reasons for a referral to nephrologists. Bi- refringent oval fat body with a Maltese cross pattern can be seen in the urine sediment under polarized light, but this finding is not specific to AFD. Renal biopsy is frequently not considered because of the lack of active urine sediment or nephrotic syndrome. Thus, the clues for AFD are derived mainly from recognition of the associated extrarenal manifes- tations, which include recurrent burning pain in the hands and feet (acroparesthesia), heat intolerance, lack of sweating, and characteristic skin lesions—individual punctate, dark red spots or angiokeratomas in a “bathing suit” distribution (Figure 2). Incidental findings of corneal opacity from slit-lamp micro- scopic examinations by ophthalmologists or optometrists can be another sign (Figure 1). In adults, unexplained left ventric- ular hypertrophy, arrhythmia, and stroke-like symptoms such as hemiparesis, vertigo, diplopia, and others should also raise the index of suspicion for AFD. The Metabolic Defect Glycosphingolipids (GSLs) are components of the plasma membrane that are degraded in the lysosome after internaliza- tion through the endocytic pathway. Their sequential catabo- lism requires the concerted action of several hydrolyzing en- zyme and various cofactors (e.g., sphingolipid activator proteins). Deficiency of these enzymes or their relevant cofac- tors lead to distinct clinical entities (e.g., Tay-Sachs, Sandhoff, G M1 gangliosidosis, Fabry, Gaucher), associated with charac- teristic manifestations that reflect the tissue-specific sites of storage of the incompletely degraded substrates (7). Correspondence to Dr. Gregory M. Pastores, Neurogenetics Program, Department of Neurology and Pediatrics, New York University School of Medicine, New York, NY 10016. Phone: 212-263-8344; Fax: 212-263-8310; E-mail: gregory.pastores@med.nyu.edu Gregory Pastores has received research grants from Genzyme. Yeong-Han H. Lien has received a research grant from Transkaryotic Therapies, Inc. 1046-6673/1300-0130 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000015236.70757.C4 J Am Soc Nephrol 13: S130–S133, 2002