Anderson-Fabry Disease: Its Place among Other Genetic Causes of Renal Disease
Jean-Pierre Grünfeld*,
Dominique Chauveau* and
Micheline Lévy
*Service of Nephrology, Hôpital Necker, Paris, France; INSERM U 535, Bâtiment Gregory Pincus, Kremlin-Bicêtre, France.
Correspondance to Dr. Jean-Pierre Grünfeld, Hôpital Necker, Division of Nephrology, INSERM U507, 149 Due de Sevres, Paris Cedex 15, 75743 France. Phone: 33-01-44-49-5306; Fax: 33-01-44-49-5450; E-mail:jean-pierre.grunfeld{at}nck.ap-hop-paris.fr
In the last two decades, decisive advances have been made inthe field of human genetics, including renal genetics. The responsiblegenes have been mapped and then identified in most monogenicrenal disorders by using positional cloning and/or candidategene approaches. These approaches have been extremely efficientsince the number of identified genetic diseases has increasedexponentially over the last 5 years. The data derived from theHuman Genome Project will enable a more rapid identificationof the genes involved in the remaining "orphan" inherited renaldiseases, provided their phenotypes are well characterized.We have entered the post-gene era. What is/are the function(s)of these genes? What are the molecular partners of the geneproduct? What is the disease mechanism, and how is the normalcascade of events disturbed when the gene is altered by a mutation?The main challenge in many renal genetic diseases, includingautosomal dominant polycystic kidney disease (ADPKD), is todesign pharmacologic means to complement/substitute or to bypassdefective steps and thus modify the clinical course of the disease.These steps have been accelerated in a few genetic disorders,such as Anderson-Fabry Disease (AFD), including research ongene therapy.
Two Lysosomal Diseases Involving the Kidney: AFD and Cystinosis
It is interesting to compare the different genetic approachesused in two lysosomal diseases with kidney involvement, AFDand cystinosis. In cystinosis, clinical manifestations occurin early childhood, whereas they appear after 5 years of ageor later in AFD. Both diseases are characterized by intralysosomalaccumulation of a substance, due to either deficient degradation(AFD) or defective egress (cystinosis). AFD, first describedin 1898, is an example in which a classical genetic approachhas been possible, starting from the enzyme and moving to itsgene and, recently, to the production of human -galactosidaseA for enzyme replacement therapy (see Branton et al. in thisissue).
Nephropathic cystinosis, first described in 1903, is an autosomalrecessive disorder characterized by the intra-lysosomal accumulationof cystine. It is caused by a defect in the transport of cystineout of the lysosome, a process mediated by a carrier that remainedunidentified for several decades. However, an important managementstep was devised in 1976, before the biochemical defect wascharacterized in 1982. Indeed cysteamine, an aminothiol, reactswith cystine to form cysteine-cysteamine mixed disulfide thatcan readily exit the cystinotic lysosome. This drug, if usedearly and in high doses, retards the progression of cystinosisin affected subjects by reducing intra-lysosomal cystine concentrations.The gene involved in cystinosis was mapped later in 1995 onchromosome 17p. Three years after that, the gene was identifiedby using positional cloning, and called CTNS. Mutations in CTNSwere detected in affected subjects. CNTS codes for a seven-transmembranedomain protein called cystinosin, which is an integral lysosomalmembrane protein (1). Ctns, the murine homologue of CTNS, hasbeen cloned, opening the possibility to generate knock-out mice,mimicking human cystinosis, and to design new and curative therapeuticapproaches (2).
Epidemiology of AFD among Other Monogenic Kidney Diseases
Data on monogenic disease frequency are often difficult to analyze,not only because of geographic/ethnic differences between populations,but also because of methodologic differences, the classicalparameters used in epidemiology (i.e., disease incidence, diseaseprevalence, and birth prevalence) being frequently confused(3). These difficulties are maximal when diseases are rare.In X-linked diseases, such as AFD, the variability of clinicalfeatures in carrier females presents another obstacle to determiningestimations. In addition, whereas some information on frequencyof classical AFD is available, such information is lacking forboth the "cardiac" and the "renal" variants of AFD, in whichcardiac and renal features respectively predominate. The latterforms have been reported throughout the world, like the classicalform, but there has been a more systematic search for them inJapan. The cardiac variant was diagnosed in 7 (3%) of 230 unrelatedJapanese males, with previously unexplained left ventricularhypertrophy (4,5).
The frequency of AFD among lysosomal storage diseases can beestimated from the reports of reference laboratories for thediagnosis of such diseases throughout the world. It ranges from2.8 to 7.7% (5–7). The number of cases of AFD relatedto demographic data (i.e., the number of live births duringthe study period) enabled the authors to estimate birth prevalence.It should be noted, however, that identifying cases througha screening laboratory leads to an underestimation, becauseascertainment is probably far from complete. An approximateAFD birth prevalence was estimated to 0.09 per 10,000 live birthsin Australia (5), 0.02 in the Netherlands (6), and 0.03 in BritishColumbia, Canada (7). These three populations are mainly Caucasian.
Table 1 summarizes data on birth prevalence evaluated throughnewborn-population surveys in cystinosis, nephronophthisis,and Alport syndrome. In ADPKD, there is obviously no study onbirth prevalence. However, risk on the one hand and heterozygotefrequency on the other hand may be considered equivalents ofADPKD birth prevalence (3). Epidemiologic data on renal replacementtherapy among patients with AFD are presented in the articleby Obrador et al. in this issue.
AFD also belongs to the group of renal lipidoses, of which itis the most prevalent disease (8). Renal involvement is veryrare in Gaucher disease, another lysosomal disease, in whichit occurs mostly after splenectomy. This group includes lecithin-cholesterolacyltransferase (LCAT) deficiency, lipoprotein glomerulopathy,and various extremely rare inherited diseases. Familial LCATdeficiency is an autosomal recessive disorder characterizedby corneal opacities producing a "pseudo-arcus," mild hemolyticanemia, and progressive renal involvement. Enzyme deficiencycauses high levels of LDL, leading to glomerular foam cells,which predominate in endothelial and mesangial cells. In addition,LCAT deficiency is responsible for low levels of serum cholesterolester, a simple and reliable marker for diagnosis. Recurrencein renal allografts has been observed. Early systemic atheroscleroticchanges may develop. The clinical presentation of lipoproteinglomerulopathy first described in 1989 by Saito et al. (9) isdifferent. Lipoprotein deposition occurs within glomerular capillarylumina, forming voluminous thrombi consisting of lipid droplets,but it spares glomerular cells; there is type III hyperlipoproteinemiawith apolipoprotein E abnormality; the renal disease is progressiveand recurs in transplanted kidneys (10). The molecular mechanismof lipoprotein glomerulopathy has not been completely clarified.
When to Consider a Genetic Cause of Renal Disease in Adults
Progress in molecular genetics has deeply modified the classificationof many genetic entities such as Alport syndrome and nephronophthisis-medullarycystic kidney disease complex. Whereas nephropediatricians arewell aware of genetic diseases, adult nephrologists are oftenless attentive to them. Investigation of family history shouldnot be omitted in the examination of every renal patient. Thepossibility of a genetic disease is schematically raised intwo clinical situations.
Positive Family History
Positive family history is easily demonstrated in autosomal-dominantdiseases with high penetrance such as ADPKD. However, in X-linkedand autosomal-recessive diseases, the number of affected subjectsmay be very limited, and sometimes the proband is the firstand only symptomatic member of the kindred. In X-linked diseases,female heterozygous carriers can be asymptomatic or have limitedabnormalities that can be missed or appear late in life. Inthe case of AFD, women can be severely affected (see Obradoret al. in this issue). In autosomal recessive diseases, heterozygotesare often asymptomatic. The consanguineous marriages, suggestiveof recessive diseases, are rare in many countries. Most affectedsubjects with recessive conditions whose parents are unrelatedare compound heterozygotes, with two different mutations ofthe same gene. A pattern simulating recessive inheritance, i.e.,two or more siblings affected with no disorder in the parent,may occur in case of gonadal (germline) mosaicism. Mitochondrialdisorders with renal involvement have emerged recently. Theycan originate from nuclear gene mutations or mitochondrial genemutations. The first are inherited as other mendelian characters,whereas the second show unusual inheritance features; the conditioncan affect both sexes, but is passed only by affected mothers.
Of course, a negative family history does not exclude a geneticdisease. Several factors may account for this. Family investigationmay sometimes be complicated by the reluctance of some familymembers to cooperate, namely to provide information on parents,siblings, or offspring. False paternity is misleading (it canbe recognized by DNA fingerprinting). De novo mutation may occurand explain the appearance of the disease in an individual whohas no previous family history of the condition. The rate ofde novo mutations differs from one genetic disease to another:low in ADPKD, high up to 60% of the cases in tuberous sclerosis.In X-linked Alport syndrome, it has been claimed to be approximately15%.
The phenotypic expression of a genetic disease may be quiteheterogeneous among various affected members of a given familycarrying the same inherited mutation. Extensive study may benecessary to identify the carrier parent of tuberous sclerosis,with only very localized skin changes and/or asymptomatic intracranialcalcifications. Such a variable expression from one family toanother or even within a given family is found in dominant ratherthan recessive diseases and may be explained by environmentalfactors and modifier genes. Another explanation for this variabilityis somatic mosaicism. The mutation, not present in the germline, appears later in the development of the zygote in somebut not all cells. Consequently, the disease develops in somebut not all tissues. This phenomenon has been demonstrated intuberous sclerosis, von Hippel-Lindau disease, Lowe syndrome,and Alport syndrome [see references in reference 11]. In casesof germline mosaicism, apparently normal individuals may havemultiple offspring with severe symptoms.
No Positive Family History, but the Disease Occurs in a Young Adult and Cannot Be Classified at First Glance
Nephrologists are often oriented by renal or extrarenal features.Obviously, the diagnosis of ADPKD cannot be missed by ultrasonography,but microcysts due to the glomerulocystic disease (another dominantdisease) may be difficult to identify. The diagnosis of AFDmay be first established on typical renal biopsy findings ina young adult, a not uncommon presentation. The presence ofdeafness suggests Alport syndrome, although hearing loss maybe associated with renal disease in many other inherited disorders,such as AFD, branchio-oto-renal syndrome, Alström syndrome,hypoparathyroidism, mitochondrial cytopathies, etc (12). Similarly,the occurrence of eye abnormalities detected by a systematicexamination may orient toward a genetic disease: macular flecksto Alport syndrome, corneal opacities to LCAT deficiency, corneaverticillata to AFD. In addition, skin, nail or bone, etc. examinationmay reveal tuberous sclerosis, nail-patella syndrome, etc. Regardingrare diseases, consulting databases, such as ORPHANET (http://orphanet.infobiogen.fr)and Online Mendelian Inheritance in Man (OMIM: http://www.ncbi.nlm.nih.gov/omim/searchomim.htlm)or computer-assisted diagnosis can be rewarding.
One of the most important lessons for adult nephrologists isthat rare inherited diseases, believed to be restricted to pediatricnephrology, may first reveal and be diagnosed in adults. Autosomal-recessivepolycystic kidney disease or rare diseases, such as Alagillesyndrome (cholestasis due to paucity of intrahepatic bile ducts,butterfly vertebrae, congenital heart disease, and renal abnormalitiesin 20 to 30% of the cases) may progress to end-stage renal diseaselate in life (13,14). Renal involvement due to mitochondrialDNA mutations may first manifest in adults, in association withdeafness, diabetes mellitus, maculopathy, and/or cardiomyopathy,mimicking therefore many other renal diseases. In an Australianreport (5), the median age at diagnosis of AFD was 28.6 yr,ranging from 0.0 to 55.7 yr. In a heterozygous female, the diagnosisof AFD with heart and kidney involvement was first establishedat 74 yr of age (15). Indeed, renal disease has not been describedin children with AFD; hence this disease will characteristicallypresent first to the adult nephrologist.
Finally, it should be remembered that "well-classified" renaldiseases, such as reflux nephropathy, are often familial, eventhough the genes involved are unidentified today, and that primaryglomerular diseases, such as focal segmental glomerulosclerosisor IgA nephropathy, are often sporadic but may be familial,opening new avenues in research concerning the mechanisms ofthese diseases. In summary, nephrologists should consider geneticdiseases that lead to end-stage renal failure, especially forgenetic counseling in the families and for specific therapyif available.
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Introduction
Two Lysosomal Diseases Involving...
-galactosidase A for enzyme replacement therapy (see Branton et al. in this issue). 
