Sindrome di Alport

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Genetics, pathogenesis, and pathology of hereditary nephritis (Alport syndrome)Author

Clifford E Kashtan, MDSection EditorsTej K Mattoo, MD, DCH, FRCPRichard J Glassock, MD, MACP

Deputy EditorMelanie S Kim, MDDisclosures

All topics are updated as new evidence becomes available and ourpeer review processis complete.Literature review current through:May 2013. | This topic last updated:mar 29, 2013.

INTRODUCTIONHereditary nephritis (or Alport syndrome) is an inherited progressive form of glomerular

disease that is often associated with sensorineural hearing loss and ocular abnormalities [1-4]. The

prevalence of the disease is estimated at approximately 1 in 50,000 live births [5]. Alport syndrome

reportedly accounts for 0.3 to 2.3 percent of new cases of end-stage renal disease (ESRD) [6,7].

The pathogenesis, genetics, and renal pathology of Alport syndrome will be reviewed here. The clinical

manifestations and course, diagnosis, and treatment of Alport syndrome are discussed separately.(See"Clinical manifestations, diagnosis and treatment of hereditary nephritis (Alport syndrome)".)

PATHOGENESISElucidation of the pathogenesis of Alport syndrome was facilitated by the chance

observation that the glomerular basement membrane (GBM) of most affected patients did not bind

antibodies from patients with anti-GBM antibody disease (including Goodpasture's syndrome) [3,8-10]. This

finding suggested an abnormality in type IV collagen, the protein target of anti-GBM antibodies. Subsequent

research efforts confirmed that the primary abnormality resides in type IV collagen as discussed in the

following section.

Genetics Alport syndrome is a primary basement membrane disorder arising from mutations in genes

encoding several members of the type IV collagen protein family.

Type IV collagen molecules are composed of three alpha chains that form triple-helical structures through

specific interactions of C-terminal noncollagenous domains [9]. Six distinct IV collagen chains are encoded

by six different genes that are distributed in head-to-head pairs on three chromosomes.

The genes include:

COL4A1 and COL4A2 at 13q34

COL4A3 and COL4A4 at 2q35-37

COL4A5 and COL4A6 on chromosome X.

The six alpha chains of type IV collagen form three triple helical protomers: alpha-1-1-2, alpha-3-4-5, and

alpha-5-5-6. These protomers are further organized into collagen networks by end-to-end connections via C-

terminal and N-terminal interactions.

Genetic analyses of affected families have identified the affected genes for the three different modes of

transmission seen in patients with Alport syndrome as discussed in the following sections. These mutations

disrupt the synthesis of type IV collagen and/or the formation of type IV collagen protomers and networks.

X-linked inheritanceX-linked Alport syndrome accounts for approximately 80 percent of Alport syndrome

cases. It arises from mutations in the COL4A5 gene on the X chromosome, which codes for the alpha-5(IV)

chain of type IV collagen [2,11-17].

Confirmation of the direct pathogenetic role of these mutations was provided by an animal model in which a

specific known human nonsense mutation was introduced into the mouse COL4A5 gene [18]. The primaryclinical and pathologic findings of human X-linked disease were recapitulated in this animal model.

This mode of inheritance leads to important clinical characteristics in affected families:
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Father to son transmission does not occur, since the father passes only the unaffected Y

chromosome to his son.

Women with X-linked Alport syndrome are heterozygous carriers of the disease mutation. Almost all

carriers have some degree of hematuria, and a significant minority develop renal failure [19]. The

variable course in women is probably due to lyonization, by which only one X chromosome is active

per cell. As a result, in most women with X-linked Alport syndrome, roughly one-half of the cells willexpress the mutant X gene and the remaining cells the normal COL4A5 gene, leading to a varied

phenotype that is generally less severe than in affected males. The influence of X-inactivation on

renal outcomes in heterozygotes was recently confirmed in the X-linked Alport syndrome mouse

model [20]. (See"Clinical manifestations, diagnosis and treatment of hereditary nephritis (Alport

syndrome)", section on 'Carriers'.)

Autosomal recessive inheritance Autosomal recessive inheritance accounts for about 15 percent of

patients with Alport syndrome [15]. It arises from genetic defects in either the COL4A3 or COL4A4 genes.

The COL4A3 and COL4A4 genes encode the alpha-3(IV) chain (which contains the Goodpasture antigen)

and the alpha-4(IV) chain, respectively.

Females are as severely affected as males [12,21,22], and the clinical manifestations in both sexes are

virtually identical to those of classic X-linked hereditary nephritis in males [21,23]. (See"Clinical

manifestations, diagnosis and treatment of hereditary nephritis (Alport syndrome)", section on 'Clinical

manifestations and course'.)

Autosomal dominant inheritance About 5 percent of patients with Alport syndrome have autosomal

dominant disease, which arises from heterozygous mutations in the COL4A3 or COL4A4 genes [24-26]. The

clinical and pathologic features of this form are similar to those of X-linked disease, although deterioration of

renal function tends to occur more slowly [27].

It is unclear why some heterozygous mutations in the COL4A3 or COL4A4 genes cause autosomal dominant

Alport syndrome, a progressive renal disease, while others are associated with thin basement membrane

nephropathy, which typically has a benign outcome [25,26,28]. Some evidence suggests that genetic factors

other than mutations in these genes may affect underlying clinical features [26]. (See"Thin basement

membrane nephropathy (benign familial hematuria)".)

Mechanism of glomerular injuryThe alpha-3, alpha-4, and alpha-5(IV) chains are highly expressed and

co-distributed within the normal GBM [29]. They form a type IV collagen network within the GBM that is

distinct from that formed by alpha-1(IV) and alpha-2(IV) chains [2,30]. Mutations affecting the alpha-3, alpha-

4, and alpha-5(IV) chains impair their deposition into this collagen network, leading to secondary changes in

GBM composition that predispose to the development of glomerulosclerosis.

Several observations support this explanation of the pathophysiologic processes involved in Alport

syndrome:

In most patients with alpha-5(IV) mutations, the alpha-3, alpha-4 chains, and alpha-5(IV) chains are

all absent from the GBM [17]. However, transcription of the alpha-3(IV) and alpha-4(IV) genes is not

turned off in the renal cortex, suggesting that failure of incorporation of these chains is responsible

for the lack of glomerular expression and not failure of synthesis [31]. The GBM is characterized by

the absence of the alpha-3, -4, and -5(IV) chains and by persistence of the fetal distribution of alpha-

1 and alpha-2(IV) chains [32].

In patients with autosomal recessive Alport syndrome, primary mutations in the alpha-3(IV) chain

prevent the expression of the alpha-3, alpha-4, and alpha-5(IV) chains in GBM.

This hypothesis is supported by observations in murine and dog models of hereditary nephritis due

to deletion of the alpha-3(IV) chain or a nonsense mutation of the alpha-5(IV) chain [32-36]. As anexample, in a murine model due to deletion of the alpha-3(IV) chain, abnormalities in the GBM

included absence of alpha-4(IV) and alpha-5(IV) collagen chains, the overexpression of alpha-1(IV)
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and alpha-2(IV) chains and laminin alpha-5, and markedly elevated levels of fibronectin and perlecan

(a heparan sulfate proteoglycan) in the basal laminae [33,35].

Alpha-3, alpha-4, and alpha-5(IV) chain tissue distribution Monoclonal antibody probes have been

used to determine the tissue distribution of the alpha-3, alpha-4, and alpha-5(IV) chains in normal tissues

and tissues of Alport patients.

These chains are normally located in Bowman's capsule and the basement membranes of the

glomerulus, distal and collecting tubules, and several basement membranes of the cochlea and eye

[37,38]. Thus, an abnormality in any of these chains can impair the integrity of basement membranes

in these sites leading to the various clinical findings of Alport syndrome.

In normal individuals the alpha-5(IV) chain is present in the basement membrane underlying the

epidermis, as a component of alpha-5-5-6 networks. The alpha-3 and alpha-4(IV) chains are

normally absent from the basement membrane.

SkinImmunohistochemical studies with a monoclonal antibody directed against the alpha-5(IV) chain

demonstrated complete absence of alpha-5(IV) chain within epidermal basement membranes in most maleswith X-linked Alport syndrome, while female carriers had discontinuous staining (picture 1) [37]. The latter

observation is compatible with lyonization in female carriers, in whom it would be expected that one-half of

their cells would express a normal alpha-5(IV) chain.

However, conventional fluorescence microscopy will detect alpha-5(IV) chain of the skin in about 20 percent

of males with X-linked Alport syndrome and 30 to 40 percent of heterozygous females. Confocal laser

scanning microscopy (CLSM) has demonstrated either a decrease in expression or an abnormal interrupted

distribution of alpha-5(IV) compared to alpha-2(IV) chain staining in some but not all of these patients

[39,40]. Although this technique is currently primarily a research tool, these findings suggest that CLSM may

play a future role in the diagnosis of Alport syndrome, as it appears to be a more sensitive diagnostic

modality than conventional fluorescence microscopy.

All patients with autosomal recessive and autosomal dominant Alport syndrome have normal skin reactivity

for alpha-5(IV) (picture 1). Thus, the presence of epidermal basement membrane staining for the alpha-5(IV)

does not exclude a diagnosis of X-linked or autosomal Alport syndrome. However, the absence of alpha-

5(IV) chain in a skin biopsy is diagnostic of disease.

KidneyImmunostaining of renal biopsy specimens for type IV collagen is useful in the evaluation of

patients with suspected Alport syndrome (figure 1).

X-linked disease As noted previously, males with X-linked Alport syndrome typically show

complete absence of immunostaining for the alpha-3, alpha-4, and alpha-5(IV) chains in their

kidneys, while heterozygous females exhibit patchy loss of staining in GBM and tubular basementmembranes. (See'Mechanism of glomerular injury'above.)

As with skin staining for the alpha-5(IV) chain, approximately 20 percent of males with X-linked

Alport syndrome have normal staining of renal basement membranes for the alpha-3, alpha-4, and

alpha-5(IV) chains. Further quantitative analysis reveals lower amounts of the alpha-3, alpha-

4, and/or alpha-5(IV) chains in these cases compared to normals [41]. Some of these patients have

missense mutations of COL4A5, which may explain the detection of alpha IV chains with

immunostaining, albeit a decrease in intensity [42].

Autosomal recessive disease Patients with autosomal recessive Alport syndrome have

abnormalities of renal type IV collagen expression that differ from those of patients with X-linked

disease. These patients typically exhibit complete absence of staining for the alpha-3 and alpha-4(IV) chains. However, while their GBM show no staining for the alpha-5(IV) chain, there is staining

of Bowman's capsules and tubular basement membranes for the alpha-5(IV) chain. This observation

can be interpreted as failure of the alpha-5(IV) chain to be deposited in the GBM due to the absence
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of the alpha-3 and alpha-4(IV) chains, but the alpha-5(IV) chain, in conjunction with the alpha-6(IV)

chain, is deposited in the basement membranes of the tubule, Bowman's capsules, and epidermis.

LensAnterior lenticonus, which is associated with thinning of the lens capsule, the basement membrane

that surrounds the lens, occurs in 20 to 30 percent of males with X-linked Alport syndrome. If present,

anterior lenticonus is pathognomonic for Alport syndrome. The lens capsule normally contains alpha-3,alpha-4, and alpha-5(IV) chains. In some patients with anterior lenticonus, these chains are absent from the

lens capsule [43].

Cochlea Hearing loss in Alport syndrome may reflect impaired adhesion of the Organ of Corti, which

contains the auditory sensory cells, to the basilar membrane of the inner ear. This impaired adhesion is

thought to be due to the absence of the alpha-3-4-5 type IV collagen network from the Organ of Corti

basement membrane [44].

Other pathologic findings

LeiomyomasLeiomyomas are benign tumors characterized by visceral smooth muscle overgrowth within

the respiratory, gastrointestinal, and female reproductive tracts. Rarely, X-linked Alport syndrome is

associated with leiomyomas. Affected patients carry deletions that involve COL4A5 and extend into the

second intron of the adjacent COL4A6 gene [45]. Of note, defects in the alpha-6 chain gene alone do not

appear to cause Alport syndrome [2].

The pathogenetic relationship between deletions of the 5' end of the COL4A6 gene and the formation of

leiomyomas is not understood. One hypothesis suggests that deletions that encompass both the COL4A5

and COL4A6 genes cause misregulation of neighboring genes, which contribute to smooth muscle

overgrowth [45].

RENAL PATHOLOGYHistologic changes in Alport kidneys increase in severity with age. The changes on

light microscopy are nonspecific and include focal increases in glomerular cellularity progressing to

glomerulosclerosis over time, and an interstitial infiltrate containing lipid-laden foam cells of uncertain origin.

The earliest ultrastructural lesion is thinning of the GBM [2,46]. This finding is not pathognomonic since it

also occurs in thin basement membrane nephropathy. However, with time, there is development of

longitudinal splitting of the lamina densa of the GBM producing a laminated appearance that is diagnostic of

Alport syndrome (picture 2A-B). In males with X-linked Alport syndrome, the proportion of GBM showing

splitting increases from about 30 percent by age 10 to more than 90 percent by age 30 [46]. (See"Thin

basement membrane nephropathy (benign familial hematuria)".)

Renal biopsy of affected individuals at a young age may manifest only non-specific light microscopic

changes and no definitive electron microscopic findings. However, results of immunostaining for type IV

collagen alpha chains is frequently diagnostic even in the absence of specific ultrastructural changes. In

prepubertal children, less invasive skin biopsy with appropriate immunohistochemical analysis may be thepreferred diagnostic study. (See"Clinical manifestations, diagnosis and treatment of hereditary nephritis

(Alport syndrome)", section on 'Diagnosis'and'Skin'above.)

SUMMARYHereditary nephritis (or Alport syndrome) is a progressive inherited form of glomerular

disease that is often associated with neural hearing loss and ocular abnormalities. Alport syndrome is a

primary basement membrane disorder arising from mutations in genes encoding several members of the

type IV collagen protein family.

Alport syndrome is a genetically heterogeneous disease with X-linked, autosomal recessive, and autosomal

dominant variants. (See'Genetics'above.)

X-linked variant accounts for approximately 80 percent of affected patients. It arises from mutations

in the COL4A5 gene on the X chromosome, which encodes alpha-5(IV) chains. (See'X-linked

inheritance'above.)
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Autosomal recessive variant accounts for about 15 percent of patients with Alport syndrome. It arises

from genetic defects in either the COL4A3 and COL4A4 genes, which encodes the alpha-3 and

alpha-4(IV) chains, respectively. The clinical manifestations of affected patients regardless of gender

are the same as male patients with X-linked Alport syndrome. (See'Autosomal recessive

inheritance'above and"Clinical manifestations, diagnosis and treatment of hereditary nephritis

(Alport syndrome)".) Autosomal dominant disease accounts for 5 percent of patients with Alport syndrome. It arises from

heterozygous mutations in the COL4A3 or COL4A4 genes. The clinical and pathologic features of

this variant of Alport syndrome are similar to those of X-linked disease, although deterioration of

renal function tends to occur more slowly. (See'Autosomal dominant inheritance'above.)

The alpha-3, alpha-4, and alpha-5(IV) chains are normally located in Bowman's capsule, and the basement

membranes of the glomerulus, distal and collecting tubules, cochlea, and eye. Thus, an abnormality in any of

these chains can impair the integrity of basement membranes in these sites, leading to the various clinical

findings of Alport syndrome. (See"Clinical manifestations, diagnosis and treatment of hereditary nephritis

(Alport syndrome)", section on 'Clinical manifestations and course'and'Mechanism of glomerular

injury'above and'Alpha-3, alpha-4, and alpha-5(IV) chain tissue distribution'above.)

In patients with Alport syndrome, renal histologic changes progress with age. The earliest finding is thinning

of the GBM. This finding is not pathognomonic since it also occurs in thin basement membrane nephropathy.

With increasing age, longitudinal splitting of the lamina densa of the GBM produces a laminated appearance

that is diagnostic of Alport syndrome and is present in 90 percent of male patients by 30 years of age

(picture 2A-B). (See'Renal pathology'above.)

Use of UpToDate is subject to theSubscription and License Agreement.

REFERENCESClinical manifestations, diagnosis and treatment of hereditary nephritis (Alport syndrome)Author

Clifford E Kashtan, MDSection Editors

Tej K Mattoo, MD, DCH, FRCPRichard J Glassock, MD, MACPDeputy EditorMelanie S Kim, MDDisclosures

All topics are updated as new evidence becomes available and ourpeer review processis complete.Literature review current through:May 2013. | This topic last updated:apr 12, 2013.

INTRODUCTIONHereditary nephritis (or Alport syndrome) is an inherited progressive form of glomerular

disease that is often associated with sensorineural hearing loss and ocular abnormalities [1-4]. Alport

syndrome is a primary basement membrane disorder arising from mutations in genes encoding severalmembers of the type IV collagen protein family.

The clinical manifestations, diagnosis, and treatment of Alport syndrome will be reviewed here. The

pathogenesis, genetics, and pathology of Alport syndrome are discussed separately. (See"Genetics,

pathogenesis, and pathology of hereditary nephritis (Alport syndrome)".)

GENETICSAlport syndrome is a genetically heterogeneous disease that results from mutations in genes

encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen. These alpha IV collagen chains are

normally located in various basement membranes of the kidney, cochlea, and eye. Abnormalities in these

chains result in defective basement membranes at these sites, leading to the clinical features of this disorder

(ie, progressive glomerular disease, sensorineural hearing loss, and ocular abnormalities). (See"Genetics,

pathogenesis, and pathology of hereditary nephritis (Alport syndrome)", section on 'Genetics'and'Clinicalmanifestations and course'below.)
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Transmission of Alport syndrome can be X-linked, autosomal recessive, or autosomal dominant.

(See"Genetics, pathogenesis, and pathology of hereditary nephritis (Alport syndrome)", section on

'Genetics'.)

X-linked transmission accounts for approximately 80 percent of affected patients and arises from

mutations in the COL4A5 gene on the X chromosome. Autosomal recessive variant accounts for about 15 percent of patients with Alport syndrome and

arises from genetic defects in either the COL4A3 or COL4A4 genes.

Autosomal dominant disease accounts for 5 percent of patients with Alport syndrome and arises

from heterozygous mutations in the COL4A3 or COL4A4 genes.

INCIDENCE Alport syndrome has been reported in hundreds of unrelated kindreds that represent all

geographic and ethnic groups. Although the overall incidence in the general population is unknown, data

from the United States demonstrates Alport syndrome accounts for 3 percent of children with end-stage

renal disease (ESRD) and 0.2 percent of adults with ESRD [1].

Case series of patients undergoing kidney biopsies demonstrate that the difficulty in determining the

incidence as the diagnosis of Alport syndrome varies from 1 to 11 percent depending upon the indications for

biopsy [1,5-7].

The gene frequency of Alport syndrome in the United States has been estimated at 1:5000 to 10,000,

suggesting there are approximately 30,000 to 60,000 affected individuals in the US [8].

CLINICAL MANIFESTATIONS AND COURSEThe classical presentation of Alport syndrome is based

upon clinical manifestations of affected males with X-linked disease. These features include glomerular

disease that progresses to end-stage renal disease (ESRD), ocular abnormalities (eg, anterior lenticonus),

sensorineural hearing loss, and a family history of hematuria associated with renal failure and deafness.

Clinical presentation and course in patients with autosomal recessive disease are similar to those with X-

linked disease. Patients with autosomal dominant disease generally exhibit more gradual loss of renalfunction [9,10]. (See'Genetics'above.)

Renal manifestationsThe initial renal manifestation of Alport syndrome is asymptomatic persistent

microscopic hematuria, which is present in early childhood in affected patients. Since screening urinalysis is

seldom performed in routine pediatric primary care, microscopic hematuria may not be detected unless the

patient is screened because of an affected family member. Recurrent episodes of gross hematuria are not

uncommon especially during childhood. Gross hematuria may be the initial presenting finding and often

occurs after an upper respiratory infection [11]. Boys without hematuria by the age of 10 years are unlikely to

have Alport syndrome [1].

In early childhood, the serum creatinine and blood pressure are normal. Over time, proteinuria, hypertension,

and progressive renal insufficiency develop. ESRD usually occurs between the ages of 16 and 35 years in

patients with X-linked or autosomal recessive disease. In some families, the course is more indolent with

renal failure being delayed until age 45 to 60, especially in those with autosomal dominant Alport syndrome.

In females with X-linked Alport syndrome, recurrent episodes of gross hematuria, proteinuria, hearing loss,

and diffuse glomerular basement membrane (GBM) thickening are associated with more severe renal

dysfunction and ESRD at an earlier age [12].

Phenotype-genotype correlationThe tempo of progressive renal dysfunction depends, at least in part,

upon the underlying mutation. Patients with large deletions and nonsense mutations have more severe

disease (both renal and extrarenal) than those with missense mutations [1-4,13].

This was illustrated in the following reviews of families with X-linked Alport syndrome that demonstrated thecorrelation between ESRD and types of mutation in the COL4A5(IV) gene.
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In the first study of 195 European families, the risk of ESRD by 30 years of age for patients with

missense mutations, splice site mutations, and large deletion, nonsense, or frameshift mutations was

50, 70, and 90 percent, respectively [13]. Large rearrangements of the COL4A5 gene or any

mutations that shift the reading frame of the gene were also associated with early onset of hearing

loss and a higher incidence of anterior lenticonus [13].

In the second study of 175 families from the United States, the average age of onset for ESRD for

patients with missense mutations, splice site mutations, and truncating mutations was 37, 28, and 25

years of age, respectively [14]. Mutations located closer to the 5' end of the gene were associated

with a younger onset of ESRD, and an increased risk of ocular changes and hearing loss than those

located closer to the 3' end. Patients with splice or truncating mutations were also more likely to

have ocular abnormalities and hearing loss.

Hearing lossBilateral sensorineural hearing loss is a common feature in patients with Alport syndrome

[15]. Hearing loss begins in the high frequency range and progresses over time to frequencies in the range

of conversational speech. One study of families with X-linked disease reported that audiologic testing

detected hearing loss in 85 percent of affected boys and 18 percent of female carriers by 15 years of age

[11]. In general, the rate of hearing loss is similar to the progression of renal insufficiency.

Ocular manifestationsSeveral ocular defects involving the lens, retina, and cornea have been reported

in patients with Alport syndrome [16,17].

Lens Anterior lenticonus is a regular conical protrusion on the anterior aspect of the lens due to

thinning of the lens capsule. It occurs in 20 to 30 percent of males with X-linked Alport syndrome and

is pathognomonic of the disease. Lenticonus can be complicated by the presence of subcapsular

cataracts, which may lead to loss of visual acuity. (See"Cataract in children".)

Retina Retinal changes are asymptomatic, and when there is anterior lenticonus, they are always

present [18]. The changes consist of bilateral white or yellow granulations that are superficially

located in the retina surrounding the foveal area [19]. These findings are also specific for Alport

syndrome.

Cornea Corneal changes are nonspecific findings in patients with Alport syndrome and include

posterior polymorphous dystrophy and recurrent corneal erosion, which can cause severe ocular

pain.

CarriersWomen with X-linked Alport syndrome are heterozygous carriers of the disease mutation. They

have a range of clinical findings due to lyonization, by which only one X chromosome is active per cell. As a

result, approximately one-half of their cells will express the mutant COL4A5 gene and the remaining cells the

normal COL4A5 gene, leading to a variable phenotype that is generally less severe than in affected males.

This was shown in a study of the natural history of female carriers with proven COL4A5 mutations [20].

Among female carriers followed in 195 affected families, the incidence of ESRD before age 40 was only 12percent, compared with 90 percent in affected males [13]. With increasing age, there was an increased risk

of progressive renal disease with a 30 percent probability of developing ESRD by age 60 in these female

carriers. However, this may be an overestimate, since approximately one-third of the women, most likely less

severely affected, were lost to follow-up. There was variation in phenotypes among family members with the

same genotype, most likely due to the variability of gene expression due to lyonization.

Risk factors for chronic renal insufficiency in female carriers include episodic gross hematuria in childhood,

sensorineural deafness, proteinuria, and the presence of the characteristic lamellation of the basement

membrane (GBM) associated with Alport syndrome on renal biopsy [20-22]. By comparison, female carriers

with only asymptomatic hematuria by the age of 30 to 40 years have a very small risk of developing ESRD.

Leiomyomatosis

Leiomyomas are benign tumors characterized by visceral smooth muscle overgrowthwithin the respiratory, gastrointestinal, and female reproductive tracts. They are found in 2 to 5 percent of
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