jMed Genet 1997;34:326-330 Syndrome of the month Alport's syndrome Frances Flinter Alport's syndrome (AS) is a progressive glomerulonephritis which is associated with high tone sensorineural deafness and charac- teristic eye signs. It accounts for 0.6% of all patients who start renal replacement therapy in Europe, and is most commonly inherited as an X linked disorder with a gene frequency of 1 in 5000. During the last six years several type IV collagen genes have been implicated in the aetiology of AS, and mutation detection studies are enabling genotype/phenotype correlations to be made, as well as facilitating carrier detec- tion and prenatal diagnosis. (J Med Genet 1997;34:326-330) Keywords: Alport's syndrome; glomerulonephritis. History It has been recognised for more than a century that renal disease can be inherited' and the family which Alport described in 19272 had already been reported several times during the previous 25 years.36 By 1927 three generations of this particular pedigree were affected, and Alport was the first author to comment that the occurrence of "nerve" deafness in most of the patients with haematuria probably represented a specific clinical syndrome, rather than being purely coincidental. He also noted that macro- scopic haematuria was the commonest present- ing symptom and that males were affected more severely than females.2 Subsequently many more families were described and the eponym was adopted in 1961.7 The term Alport's syndrome has been used extensively for patients with a variety of clinically heteroge- neous hereditary nephritides, including some without deafness,8 and even benign familial haematuria.9 Only a few authors used strict diagnostic criteria to define a clinically homo- geneous subgroup of families with "classical" AS.10 11 Division of Medical and Molecular Genetics, Guy's Hospital, 7th and 8th Floors, Guy's Tower, St Thomas Street, London SEI 9RT F Flinter Classical (X linked) Alport's syndrome In 1988, a set of four clinical diagnostic criteria was described which enable the identification of families which are affected with the same hereditary nephritis as Alport's original family. " For a diagnosis of AS to be made clinically, any patient (or other affected rela- tives) with unexplained haematuria must fulfil at least three of the four criteria listed below (different features may occur in different subjects within the family): (1) positive family history of macro/microscopic haematuria, chronic renal failure (CRF), or both; (2) electron microscopic evidence of Alport's syn- drome on renal biopsy; (3) characteristic oph- thalmic signs, that is, anterior lenticonus or white macular flecks or both; (4) high tone sensorineural deafness. Thus an affected male with a negative family history may be diagnosed as having AS with confidence only if he has all the typical clinical signs. The clinical criteria are considered in more detail below. (1) POSITIVE FAMILY HISTORY The importance of obtaining detailed medical information about relatives cannot be overem- phasised. In one German study only 20% of patients with some form of familial glomeru- lonephritis were aware of renal disease in their relatives." The same study found that AS accounted for 50% of all familial glomerulo- nephritides. Suspicions may be raised by deaths in early adult life of males in previous generations, as well as by deaths during pregnancy or delivery, and deaths ascribed to "Bright's disease". Formal urine analysis, oph- thalmological examination, and audiograms in first degree relatives are often useful. Adult males who are potentially affected are far more likely to yield useful clinical information than females or children. (2) RENAL BIOPSY Light microscopy contributes little towards a diagnosis of AS. The results are normal in chil- dren under the age of 10, and even in adult life the findings are non-specific. They may include segmental sclerosis and obsolescence, tubular atrophy, interstitial fibrosis, and infiltration by lymphocytes and plasma cells with clusters of foam cells. An experienced pathologist may recognise thickening of the glomerular capil- lary walls by light microscopy.'3 Standard immunofluorescence studies are normally negative, but there may be a reduction or absence of binding to the glomerular basement membrane (GBM) of antibodies to the NC 1 domain of the a3 chain of type IV collagen (obtained from patients with Goodpasture syndrome). It has been suggested that muta- tions within the X linked Alport gene (coding for the a5 chain of type IV collagen) cause the synthesis of an abnormal a5(IV) chain which 326 on June 22, 2020 by guest. Protected by copyright. http://jmg.bmj.com/ J Med Genet: first published as 10.1136/jmg.34.4.326 on 1 April 1997. Downloaded from
Transcript
jMed Genet 1997;34:326-330
Syndrome of the month
Alport's syndrome
Frances Flinter
Alport's syndrome (AS) is a progressiveglomerulonephritis which is associated withhigh tone sensorineural deafness and charac-teristic eye signs. It accounts for 0.6% of allpatients who start renal replacement therapy inEurope, and is most commonly inherited as an
X linked disorder with a gene frequency of 1 in5000. During the last six years several type IVcollagen genes have been implicated in theaetiology ofAS, and mutation detection studiesare enabling genotype/phenotype correlationsto be made, as well as facilitating carrier detec-tion and prenatal diagnosis.(J Med Genet 1997;34:326-330)
Keywords: Alport's syndrome; glomerulonephritis.
HistoryIt has been recognised for more than a centurythat renal disease can be inherited' and thefamily which Alport described in 19272 hadalready been reported several times during theprevious 25 years.36 By 1927 three generationsof this particular pedigree were affected, andAlport was the first author to comment that theoccurrence of "nerve" deafness in most of thepatients with haematuria probably representeda specific clinical syndrome, rather than beingpurely coincidental. He also noted that macro-scopic haematuria was the commonest present-ing symptom and that males were affectedmore severely than females.2 Subsequentlymany more families were described and theeponym was adopted in 1961.7 The term
Alport's syndrome has been used extensivelyfor patients with a variety of clinically heteroge-neous hereditary nephritides, including some
without deafness,8 and even benign familialhaematuria.9 Only a few authors used strictdiagnostic criteria to define a clinically homo-geneous subgroup of families with "classical"AS.10 11
Division ofMedicaland MolecularGenetics, Guy'sHospital, 7th and 8thFloors, Guy's Tower, StThomas Street,London SEI 9RTF Flinter
Classical (X linked) Alport's syndromeIn 1988, a set of four clinical diagnostic criteriawas described which enable the identificationof families which are affected with the same
hereditary nephritis as Alport's originalfamily. " For a diagnosis of AS to be madeclinically, any patient (or other affected rela-tives) with unexplained haematuria must fulfilat least three of the four criteria listed below(different features may occur in different
subjects within the family): (1) positive familyhistory of macro/microscopic haematuria,chronic renal failure (CRF), or both; (2)electron microscopic evidence of Alport's syn-drome on renal biopsy; (3) characteristic oph-thalmic signs, that is, anterior lenticonus orwhite macular flecks or both; (4) high tonesensorineural deafness.Thus an affected male with a negative family
history may be diagnosed as having AS withconfidence only if he has all the typical clinicalsigns. The clinical criteria are considered inmore detail below.
(1) POSITIVE FAMILY HISTORYThe importance of obtaining detailed medicalinformation about relatives cannot be overem-phasised. In one German study only 20% ofpatients with some form of familial glomeru-lonephritis were aware of renal disease in theirrelatives." The same study found that ASaccounted for 50% of all familial glomerulo-nephritides. Suspicions may be raised bydeaths in early adult life of males in previousgenerations, as well as by deaths duringpregnancy or delivery, and deaths ascribed to"Bright's disease". Formal urine analysis, oph-thalmological examination, and audiograms infirst degree relatives are often useful. Adultmales who are potentially affected are far morelikely to yield useful clinical information thanfemales or children.
(2) RENAL BIOPSYLight microscopy contributes little towards adiagnosis ofAS. The results are normal in chil-dren under the age of 10, and even in adult lifethe findings are non-specific. They may includesegmental sclerosis and obsolescence, tubularatrophy, interstitial fibrosis, and infiltration bylymphocytes and plasma cells with clusters offoam cells. An experienced pathologist mayrecognise thickening of the glomerular capil-lary walls by light microscopy.'3 Standardimmunofluorescence studies are normallynegative, but there may be a reduction orabsence of binding to the glomerular basementmembrane (GBM) of antibodies to the NC 1domain of the a3 chain of type IV collagen(obtained from patients with Goodpasturesyndrome). It has been suggested that muta-tions within the X linked Alport gene (codingfor the a5 chain of type IV collagen) cause thesynthesis of an abnormal a5(IV) chain which
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Figure 1 Electron micrograph of renal biopsy specimen from patient with Alport'ssyndrome. The black arrow indicates the glomerular basement membrane (GBM), which is
thickened and split.
causes the failure of stable incorporation ofa3(IV) chains, so that the antigenicity ofa3(IV) is masked.'4 Some pathologists haveattempted to look at the distribution of the a3,a4, and a5 chains of type IV collagen in theskin, in the hope that these would reflect thefindings on renal biopsy. However, a Japanesepatient has recently been found to have normalbinding of antibodies to all three chains in theskin, but absent binding in the GBM (I Naito,personal communication). Overall, the diag-nostic value of immunofluorescence studies inAS is probably rather limited.Under the electron microscope various defi-
nite ultrastructural lesions of the GBM areseen"5 16 (fig 1). Initially the GBM may appearthin, particularly in children, owing to a reduc-tion in the diameter of the lamina densa.Within the same specimen there may be areas
where the lamina densa becomes thicker andthe GBM appears split. Small electron lucentareas containing dense particles may occurwithin the lamina densa. GBM abnormalitiesmay be patchy, alternating with segments ofnormal thickness, particularly in children andadult females,'7 but serial renal biopsies showthe progressive deteroriation.'" 1 Segmentalareas of GBM splitting are not specific to AS,but the simultaneous occurrence of extensivethickening and splitting together with theinclusion of electron lucent areas containingdense granulations appears to be characteristicof AS, even though EM renal biopsy reportsmay only comment that the findings are "com-patible with a diagnosis of AS".
(3) CHARACTERISTIC OPHTHALMIC SIGNSThe ophthalmic manifestations of AS werefirst reported in 1954,19 and the characteristictriad of signs is well recognised byophthalmologists,20 but only visible using a slitlamp ophthalmoscope. Patients with progres-
sive renal disease and eye abnormalities in theabsence of hearing problems are very rare, 17-2as the deafness usually precedes any eye signs.
Figure 3 Macularflecks.
__~~~~~~~~~~~~~~~~~~~~~~~~--
Figure 4 Peripheral coalescingflecks.
The three characteristic features are: (1) ante-rior lenticonus (fig 2), (2) macular flecks (fig3), and (3) peripheral coalescing flecks (fig 4).
Patients may have one or more of these.Some authors believe that anterior lenticonusis diagnostic of AS,20 22 as all the patients withanterior lenticonus whom they studied hadprogressive renal disease. Anterior lenticonuscauses a slowly progressive axial myopia, andrarely it may progress to anterior capsular cata-ract, for which surgical extraction is required.(Posterior lenticonus is not specific to AS.)Occasionally, lens opacities have been de-scribed in AS, but they are not specific.White perifoveal flecks are also characteristic
of AS. They do not affect the vision andfluorescein angiography of the macula isnormal. Peripheral white flecks are less com-
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mon. In one study,23 72% of affected males and38% of affected females had anterior lenti-conus, macular flecks, or both. The eye signsare rarely detected in childhood and usuallybecome apparent at about the time the kidneysfail. The youngest case in whom the eye signshave been found was 13 years old, and it is notworth routinely screening children under theage of 12 years. The eye signs are much morelikely to be detected in an affected adultrelative.
(4) HIGH TONE SENSORINEURAL DEAFNESSThe detection of sensorineural deafness in apatient with haematuria should always suggesta diagnosis of AS, even in the absence of apositive family history or the diagnostic eyesigns. It is important to perform an audiogramon any patient with unexplained haematuriaeven if the family history is negative, as thehearing loss may be subclinical at first,although it is usually bilateral.The deafness is often progressive during
childhood, particularly in males,23 24 eventuallynecessitating the use of a hearing aid.25 Thehearing loss is usually static in adult life,"7 andeven the most severely affected patients retainsome hearing capacity.26 Occasionally hearingmay improve after a renal transplant,27 but thismay represent a non-specific improvement indeafness attributable to the treatment of21~ ~ turaemia. In males the deafness is present in83% and presents clinically at an average age of11 years,2' causing an average deficit of-66 dB.Fifty-seven percent of females are deaf, with anaverage deficit of -50 dB, but in females thedeafness is often not symptomatic until middleage.The underlying pathology of the hearing
problems is not well delineated, but electronmicroscopic studies have shown a multilayeredbasement membrane in the vas spirale29consistent with the abnormalities found in theGBM and the lens capsule.
Typical clinical course of an affected malewith X linked ASSixty seven percent of males present with mac-roscopic haematuria during an intercurrentinfection at an average age of 3'/2 years. Theauthor has never known an at risk male withdocumented normal urine analysis at the age of5 years to develop AS subsequently. Allaffected males subsequently develop protein-uria (never the other way round). Typically,deafness becomes clinically apparent at about10 years, and the blood pressure begins to risein the mid-teens. Renal function is usuallydeteriorating by 20 years, and 94% of maleshave abnormal renal function by 25 years. Theaverage age of end stage CRF is 21 years, andit is unusual for males to retain normal renalfunction beyond the age of 30 years.30
Typical clinical course in females with Xlinked ASThe clinical course in females is extremelyvariable. A few are as severely affected as males(presumably because of non-random X inacti-vation), but the majority are clinically asympto-
matic throughout a normal lifespan. Thirty sixpercent present with macroscopic haematuriaat an average age of 9 years, and a further 40%are detected when they are found to havemicroscopic haematuria on routine urineanalysis. Earlier reports have suggested a genepenetrance in adult females of 85%, implyingthat 15% do not even have microscopichaematuria,3' but other authors have foundthat all obligate carriers have microscopic hae-maturia (at least) by the age of 20 years.30 32One third become hypertensive (usually inmiddle age) and the risk ofCRF may be as highas 15%,23 although this figure may be artifi-cially inflated by ascertainment bias.
Recent EDTA (European Dialysis andTransplant Association) data have suggestedthat for patients aged 15 to 29 years at the startof renal replacement therapy, males andfemales with Alport's syndrome have a superiorsurvival to those with standard primary renaldisease (S Rigden, personal communication).
Autosomal recessive ASAutosomal recessive AS is much rarer than theX linked form, and heterozygotes often havemicroscopic haematuria. (It has been sug-gested that autosomal dominant benign famil-ial haematuria is seen in manifesting heterozy-gote carriers of autosomal recessive Alport'ssyndrome (Lemmink et al, submitted forpublication). Affected (homozygous) childrendevelop chronic renal failure at a young age(often between 5 and 15 years of age), andusually have sensorineural deafness, but theireyes are often normal.33-35
Autosomal dominant ASThere are over 30 published pedigrees showingmale to male transmission of a hereditarynephritis which has been called AS,8 but nonewould fulfil the criteria listed above.'0 12 Deaf-ness is very unusual in these families, and noneof the affected subjects has any of thecharacteristic eye signs, although a variety ofnon-specific eye abnormalities is described.36 37The histological evidence is also weak, withnon-specific abnormalities of the GBM pre-dominating in most cases.Autosomal dominant hereditary nephritis is
much rarer than classical X linked AS, andmales and females are affected with equalseverity. Macroscopic haematuria is rare andrenal disease is usually diagnosed in adult lifefollowing the detection of microscopic haema-turia, proteinuria, or hypertension. Chronicrenal failure usually develops in middle age.384
Extrarenal abnormalitiesApart from deafness and ocular signs, severalother extrarenal abnormalities have been re-ported in association with AS. The mostimportant is oesophageal, tracheobronchial,and genital leiomyomatosis.42 Most casereports are French, and the phenotype is asso-ciated with a contiguous deletion involvingCOL4A5 (the Alport gene) and part ofCOL4A6, which is adjacent.44
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Macrothrombocytopenia (thrombocytope-nia (TCP) and giant cell platelets) occurring inpatients with AS has been reported,45 46 but inat least three of the reported families the TCPand renal disease segregate independently, andthe association may be purely coincidental.Chance association probably also explainscases of AS with antithyroid antibodies47 andAS with hyperprolinaemia/hyperamino-aciduria. 25
The type IV collagen genesType IV collagen, the main structural compo-nent of glomerular basement membranes, wasisolated in 1971. The two major polypeptidechains which associate to form a triple helicalheterotrimeric molecule are a (IV) anda2 (IV), and they are present in a 2:1 ratio. Thegenes for these two chains (COL4A1 andCOL4A2) lie adjacent to each other onchromosome 13. The rarer a3 and a4 chainsare coded for by a similar pair of genes onchromosome 2 and mutations here are associ-ated with autosomal recessive AS.Linkage studies during the 1980s suggested
a gene localisation for X linked AS onXq22.495' In 1990 two groups described anovel type IV collagen chain, a5(IV), and thegene, which mapped to Xq22.2, was clonedand called COL4A5.52 5 The COL4A5 genecontains 51 exons, covering 240-310 kb ofgenomic DNA which produces a 6.5 kbtranscript, making it one ofthe longest collagengenes described to date. Several mutationswere reported in unrelated pedigrees, whichcosegregated with the disease, 5456 and sincethen several hundred mutations have beendetected. Most are unique to the individualpedigree, and the few shared mutations may beexplained by a common ancestry.57About 10-15% of patients have a large dele-
tion which is detectable on Southern blotting.The largest deletion identified so far involvesthe loss of 450 kb ofDNA, only about 10 kb ofwhich lies within the gene, the rest of the dele-tion extending beyond the 3' end.55 58 Anotherpatient is deleted for 50 out of 51 exons, havingonly exon 1 (E Boye, unpublished data). A fur-ther 25-30% of patients have smaller muta-tions, including nonsense, missense, and splicesite alterations, and the mutations reported arescattered across the gene with no particularmutational hotspot.
In spite of enormous efforts, using a varietyof techniques, to define the remaining 55% ofmutations, these remain elusive.59 It is possiblethat mutations in non-coding segments ofCOL4A5 account for a significant proportionof X linked cases. Linkage studies have notsuggested a second locus for X linked families,and if another gene is involved it must lienearby.The COL4A6 gene lies upstream of
COL4A5 in a head to head arrangement,60 61but only a few patients have mutations here,and always in association with a deletion inCOL4A5. These contiguous deletions extendfrom the 5' end of COL4A5 and include justthe first two exons of COL4A6 in patients withAS and leiomyomatosis, and extend further
into COL4A6 in patients with AS andcongenital cataracts without leiomyomatosis(C Antignac, E Boye, personal communica-tion). No patient with AS has been found tohave an isolated mutation just affectingCOL4A6.Mutations in the autosomal collagen genes
COL4A3 and COL4A4 on chromosome 2have been described in a few cases ofautosomal recessive Alport's syndrome.60Once a mutation has been detected in a fam-
ily, accurate carrier detection and prenataldiagnosis become possible. Molecular testshave shown that clinical screening, includingurine analysis, ophthalmological examination,and audiograms, are very useful in at risk rela-tives, as females with no clinical signs areunlikely to carry the mutation (residual riskafter negative clinical screen about 2%).Several prenatal tests have been performed andlinkage studies using intragenic markers areavailable if no mutation has been detected.
Genotype/phenotype correlationsAbout 3-5% of AS patients who receive acadaver renal transplant develop anti-GBMantibody nephritis, and 40-50% of thesepatients have a big deletion in COL4A5 (com-pared with 15% of AS patients overall). Thegrafts are lost rapidly, despite intervention, andrecurrence of the problem in subsequent graftsis common. Two point mutations have alsobeen associated with post-transplant anti-GBM nephritis, however, so other factors mustalso be relevant.6' Deletions within COL4A5may also be associated with a more severe phe-notype generally, including a younger age ofCRF, early deafness, and the presence of eyesigns. Missense mutations and splicing errorsare less likely to be associated with eye lesions,juvenile renal failure, and anti-GBM antibodynephritis61 (EC Concerted Action, unpub-lished data).
Gene therapyAS has a significant morbidity and mortality,and research into the possibility of genetherapy is under way in spite of the complexi-ties involved with a disease caused by muta-tions in a big gene affecting an inaccessible tar-get organ.The whole COL4A5 cDNA will need to be
transferred, together with appropriate regula-tory gene elements, into renal glomeruli. Thiswill require knowledge about gene regulation(promoters, tissue specific enhancers), and alsoappropriate transfer systems which can targetthe glomeruli. New animal models are neededurgently as the only mammal with an X linkednephritis is the Samoyed dog, and its nephritisis atypical, with proteinuria preceding haema-turia. The affected dogs also have normal eyesand normal hearing. However, in vivo experi-ments in rabbits and pigs have resulted in noexpression of a virus (carrying the Lac Zreporter gene) after direct injection into therenal artery initially, but very high expression inthe glomeruli when the experiment wasrepeated after the use of vasodilators. The
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