J Am Soc Nephrol 13: S126–S129, 2002 Anderson-Fabry Disease: Its Place among Other Genetic Causes of Renal Disease JEAN-PIERRE GRU¨ NFELD,* DOMINIQUE CHAUVEAU,* and MICHELINE LE´ VY† *Service of Nephrology, Hoˆpital Necker, Paris, France; †INSERM U 535, Baˆtiment Gregory Pincus, Kremlin- Biceˆtre, France. In the last two decades, decisive advances have been made in Nephropathic cystinosis, first described in 1903, is an auto- the field of human genetics, including renal genetics. The somal recessive disorder characterized by the intra-lysosomal responsible genes have been mapped and then identified in accumulation of cystine. It is caused by a defect in the transport most monogenic renal disorders by using positional cloning of cystine out of the lysosome, a process mediated by a carrier and/or candidate gene approaches. These approaches have that remained unidentified for several decades. However, an been extremely efficient since the number of identified genetic important management step was devised in 1976, before the diseases has increased exponentially over the last 5 years. The biochemical defect was characterized in 1982. Indeed cysteam- data derived from the Human Genome Project will enable a ine, an aminothiol, reacts with cystine to form cysteine-cys- more rapid identification of the genes involved in the remain- teamine mixed disulfide that can readily exit the cystinotic ing “orphan” inherited renal diseases, provided their pheno- lysosome. This drug, if used early and in high doses, retards the types are well characterized. We have entered the post-gene progression of cystinosis in affected subjects by reducing intra- era. What is/are the function(s) of these genes? What are the lysosomal cystine concentrations. The gene involved in cysti- molecular partners of the gene product? What is the disease nosis was mapped later in 1995 on chromosome 17p. Three mechanism, and how is the normal cascade of events disturbed years after that, the gene was identified by using positional when the gene is altered by a mutation? The main challenge in cloning, and called CTNS. Mutations in CTNS were detected in many renal genetic diseases, including autosomal dominant affected subjects. CNTS codes for a seven-transmembrane do- polycystic kidney disease (ADPKD), is to design pharmaco- main protein called cystinosin, which is an integral lysosomal logic means to complement/substitute or to bypass defective membrane protein (1). Ctns, the murine homologue of CTNS, steps and thus modify the clinical course of the disease. These has been cloned, opening the possibility to generate knock-out steps have been accelerated in a few genetic disorders, such as mice, mimicking human cystinosis, and to design new and Anderson-Fabry Disease (AFD), including research on gene curative therapeutic approaches (2). therapy. Epidemiology of AFD among Other Monogenic Two Lysosomal Diseases Involving the Kidney: Kidney Diseases AFD and Cystinosis Data on monogenic disease frequency are often difficult to It is interesting to compare the different genetic approaches analyze, not only because of geographic/ethnic differences used in two lysosomal diseases with kidney involvement, AFD between populations, but also because of methodologic differ- and cystinosis. In cystinosis, clinical manifestations occur in ences, the classical parameters used in epidemiology (i.e., early childhood, whereas they appear after 5 years of age or disease incidence, disease prevalence, and birth prevalence) later in AFD. Both diseases are characterized by intralysoso- being frequently confused (3). These difficulties are maximal mal accumulation of a substance, due to either deficient deg- when diseases are rare. In X-linked diseases, such as AFD, the radation (AFD) or defective egress (cystinosis). AFD, first variability of clinical features in carrier females presents an- described in 1898, is an example in which a classical genetic other obstacle to determining estimations. In addition, whereas approach has been possible, starting from the enzyme and some information on frequency of classical AFD is available, moving to its gene and, recently, to the production of human such information is lacking for both the “cardiac” and the ␣ -galactosidase A for enzyme replacement therapy (see Bran- “renal” variants of AFD, in which cardiac and renal features ton et al. in this issue). respectively predominate. The latter forms have been reported throughout the world, like the classical form, but there has been a more systematic search for them in Japan. The cardiac variant Correspondance to Dr. Jean-Pierre Gru¨nfeld, Hoˆpital Necker, Division of was diagnosed in 7 (3%) of 230 unrelated Japanese males, with Nephrology, INSERM U507, 149 Due de Sevres, Paris Cedex 15, 75743 previously unexplained left ventricular hypertrophy (4,5). France. Phone: 33-01-44-49-5306; Fax: 33-01-44-49-5450; E-mail: [email protected] 1046-6673/1300-0126 AFD among Lysosomal Storage Diseases Journal of the American Society of Nephrology The frequency of AFD among lysosomal storage diseases Copyright © 2002 by the American Society of Nephrology can be estimated from the reports of reference laboratories for DOI: 10.1097/01.ASN.0000015235.57104.A1 the diagnosis of such diseases throughout the world. It ranges J Am Soc Nephrol 13: S126–S129, 2002 AFD and Other Causes of Renal Disease S127 from 2.8 to 7.7% (5–7). The number of cases of AFD related for low levels of serum cholesterol ester, a simple and reliable to demographic data (i.e., the number of live births during the marker for diagnosis. Recurrence in renal allografts has been study period) enabled the authors to estimate birth prevalence. observed. Early systemic atherosclerotic changes may develop. It should be noted, however, that identifying cases through a The clinical presentation of lipoprotein glomerulopathy first screening laboratory leads to an underestimation, because as- described in 1989 by Saito et al. (9) is different. Lipoprotein certainment is probably far from complete. An approximate deposition occurs within glomerular capillary lumina, forming AFD birth prevalence was estimated to 0.09 per 10,000 live voluminous thrombi consisting of lipid droplets, but it spares births in Australia (5), 0.02 in the Netherlands (6), and 0.03 in glomerular cells; there is type III hyperlipoproteinemia with British Columbia, Canada (7). These three populations are apolipoprotein E abnormality; the renal disease is progressive mainly Caucasian. and recurs in transplanted kidneys (10). The molecular mech- Table 1 summarizes data on birth prevalence evaluated anism of lipoprotein glomerulopathy has not been completely through newborn-population surveys in cystinosis, nephron- clarified. ophthisis, and Alport syndrome. In ADPKD, there is obviously no study on birth prevalence. However, risk on the one hand When to Consider a Genetic Cause of Renal and heterozygote frequency on the other hand may be consid- Disease in Adults ered equivalents of ADPKD birth prevalence (3). Epidemio- Progress in molecular genetics has deeply modified the logic data on renal replacement therapy among patients with classification of many genetic entities such as Alport syndrome AFD are presented in the article by Obrador et al. in this issue. and nephronophthisis-medullary cystic kidney disease com- AFD among Lipidoses plex. Whereas nephropediatricians are well aware of genetic diseases, adult nephrologists are often less attentive to them. AFD also belongs to the group of renal lipidoses, of which Investigation of family history should not be omitted in the it is the most prevalent disease (8). Renal involvement is very examination of every renal patient. The possibility of a genetic rare in Gaucher disease, another lysosomal disease, in which it disease is schematically raised in two clinical situations. occurs mostly after splenectomy. This group includes lecithin- cholesterol acyltransferase (LCAT) deficiency, lipoprotein glo- merulopathy, and various extremely rare inherited diseases. Positive Family History Familial LCAT deficiency is an autosomal recessive disorder Positive family history is easily demonstrated in autosomal- characterized by corneal opacities producing a “pseudo-arcus,” dominant diseases with high penetrance such as ADPKD. mild hemolytic anemia, and progressive renal involvement. However, in X-linked and autosomal-recessive diseases, the Enzyme deficiency causes high levels of LDL, leading to number of affected subjects may be very limited, and some- glomerular foam cells, which predominate in endothelial and times the proband is the first and only symptomatic member of mesangial cells. In addition, LCAT deficiency is responsible the kindred. In X-linked diseases, female heterozygous carriers Table 1. Comparison of data on birth prevalence (adapted from reference (3)) Birth Prevalence Disease Country (Years of Study) per 10,000 Comments on Sources of Data Livebirths Fabry disease Australia (1980 to 1996) 0.09 Reference laboratory data The Netherlands (1970 to 1996) 0.02 Reference laboratory data British Columbia, Canada (1972 to 1996) 0.03 Reference laboratory data Cystinosis France, including Overseas Territories 0.06 Newborn population-based survey (1972 to 1994) West Germany (1960 to 1979) 0.06 Newborn population-based survey Denmark (1962 to 1971) 0.09 Newborn population-based survey Australia (1980 to 1996) 0.04 (0.05a) Reference laboratory data British Columbia, Canada (1972 to 1996) 0.07 (0.08a) Reference laboratory data