Alport Syndrome and Thin Basement Memnbrane

Question 1

Alport Syndrome and Thin Basement Membrane

Answer 1

Epidemiology

Alport syndrome involves inherited nephritis, sensorineural hearing loss, and ocular abnormalities.

Prevalence ~1/50,000 live births

Question 2

Alport Syndrome and Thin Basement Membrane

Answer 2

Pathogenesis

Background: There are six genetically distinct collagen type IV chains (α1, α2, α3, α4, α5, α6) that form three triple helical protomers [α1, α1, α2], [α3, α4, α5], and [α5, α5, α6], where

[α1, α1, α2] protomer is present in all basement membranes.

Question 3

Alport Syndrome and Thin Basement Membrane

Answer 3

[α3, α4, α5] protomer is present in kidney, lung, testis, cochlea, and eye.

[α5, α5, α6] protomer is present in skin, smooth muscle, esophagus, and kidney.

Question 4

Alport Syndrome and Thin Basement Membrane

Answer 4

COL4A1 and COL4A2 at 13q34, encodes α1, α2 respectively.

COL4A3 and COL4A4 at 2q35-37, encodes α3, α4 respectively.

COL4A5 and COL4A6 on chromosome X, encodes α5, α6 respectively.

Question 5

Alport Syndrome and Thin Basement Membrane

Answer 5

Mutations of α5 and α6 chains are X-linked.

Question 6

Alport Syndrome and Thin Basement Membrane

Disease state:

Answer 6

Mutations affecting any of the α3, α4, or α5(IV) chains impair the deposition of the entire triple helical complex into the GBM collagen network, leading to alterations in the GBM composition that predispose the kidney to glomerulosclerosis

Question 7

Alport Syndrome and Thin Basement Membrane

Disease state:

Answer 7

In most patients with α5(IV) mutations, the α3, α4, and α5(IV) chains are all absent from the GBM despite continuing transcription of the α3(IV) and α4(IV) genes. The GBM is characterized by the absence of the α3, α4, and α5(IV) chains and persistence of the fetal distribution of α1 and α2(IV) chains.

Question 8

Alport Syndrome and Thin Basement Membrane

Disease state:

Answer 8

In patients with autosomal recessive Alport syndrome, primary mutations in the α3(IV) chain prevent the expression of the α3, α4, and α5(IV) chains in GBM.

Question 9

Alport Syndrome and Thin Basement Membrane

Disease state:

Answer 9

Large deletion or nonsense mutations lead to more severe disease than those with missense mutations.

Question 10

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 10

X-linked (80%), mutations involving the COL4A5 gene which codes the α5(IV) chain. Female heterozygous carriers: almost all have hematuria, but with variable outcome.

Question 11

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 11

Only a minority develop ESRD presumably due to “lyonization,” a process whereby only one X chromosome is active per cell. Thus, in most women with X-linked Alport, approximately one-half of the cells express the mutant gene while the other half express the normal gene. Lyonization leads to a generally less severe phenotype than that compared with affected males.

Question 12

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 12

Autosomal recessive (15%), mutations involving either COL4A3 or COL4A4 genes which code for α3(IV) chain (which contains the Goodpasture antigen) and the α4(IV) chain, respectively.

Question 13

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 13

Females are as severely affected as males. Clinical manifestations in both sexes are identical to those of classic X-linked Alport’s in males.

Question 14

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 14

Autosomal dominant (5%) with heterozygous mutations in either the COL4A3 or COL4A4 genes.

Similar clinical and pathologic features as those of X-linked disease, but with slower kidney function decline.

Question 15

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 15

While some heterozygous mutations in the COL4A3 or COL4A4 genes cause autosomal dominant Alport syndrome and progressive kidney failure, others only develop thin basement membrane nephropathy (TBMN), a typically more benign condition where patients present with microscopic hematuria without progression to ESRD.

Question 16

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 16

Genetic factors other than mutations in these collagen genes have been suggested to affect phenotypes.

Question 17

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 17

NOTE: Histopathologic finding of TBMN does not necessarily rule out Alport syndrome due to the possibility of inadequate biopsy or early Alport.

Question 18

Alport Syndrome and Thin Basement Membrane

Genetic inheritance of Alport syndrome and thin basement membrane:

Answer 18

Clinical evaluations for hearing loss and abnormal optical lens, investigation for family history, and follow-up visits are necessary to rule out Alport syndrome. The diagnosis of TBMN is, in effect, a diagnosis of clinical exclusion.

Mutations of the α3-5(IV) chains may also occur de novo.

Question 19

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 19

Renal manifestations of Alport syndrome:

Asymptomatic persistent microscopic or gross hematuria

Boys without hematuria by age 10 are unlikely to have Alport syndrome.

Question 20

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 20

ESRD:

X-linked or autosomal-recessive disease: ESRD usually occurs by age 35, but may be later in life.

Autosomal dominant: ESRD occurs later in life, generally by age 45 to 60.

Question 21

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 21

In X-linked females, recurrent gross hematuria, proteinuria, hearing loss, and diffuse GBM thickening are associated with worse renal outcomes.

Question 22

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 22

Extra-renal manifestations of Alport syndrome:

Sensorineural hearing loss:

Thought to be due to impaired adhesion of the auditory sensory cell containing organ of Corti to the inner ear basilar membrane which lacks the normal α3-4-5(IV) collagen network.

Question 23

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 23

Initial hearing loss is in high-frequency range.

Rate of hearing loss is similar to the rate of kidney disease progression.

Question 24

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 24

Ocular abnormalities:

Anterior lenticonus due to abnormal (α3, α4, and α5[IV]) and associated with thinning of the lens capsule.

Question 25

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 25

Other ocular findings: spherophakia, anterior polar and posterior cortical cataract, corneal changes with recurrent corneal erosions

Retinal findings: drusen, perifoveal dot and fleck retinopathy, neovascularization

Question 26

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 26

Leiomyomas:

Associated with X-linked Alport, but rare

Affected patients carry deletions that involve COL4A5 extending into the adjacent COL4A6 gene. Deletions involving both the COL4A5 and COL4A6 are thought to cause misregulation of neighboring genes and resultant smooth muscle overgrowth.

Question 27

Alport Syndrome and Thin Basement Membrane

Clinical Manifestations

Answer 27

In addition to leiomyomas, arterial aneurysms have been reported in young males and may involve thoracic, abdominal aorta, and even intracranial artery.

Question 28

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 28

LM: Interstitial foamy macrophages in the absence of significant proteinuria or nephrotic syndrome. Global and/or segmental glomerulosclerosis may be present in more advanced disease

Question 29

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 29

EM: Classic Alport: GBM with irregular thinning and thickening, layered or lamellated “basket-weave” appearance in the thickened area due to GBM injury and remodeling, and subepithelial scalloping. There are no electron dense deposits.

Question 30

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 30

IF: Pattern of staining depends on chain being stained for and type of mutation.

Staining for the α3(IV) or α5(IV) chain will be positive within the normal GBM since the protomers [α3, α4, α5] are distributed within the GBM.

Question 31

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 31

IF: In an X-linked Alport male (mutation of the α5(IV) chain), staining for α3,4 and 5 (IV) chains is typically negative due to the lack of [α3, α4, α5] protomer formation.

In an X-linked Alport female (mutation of the α5(IV) chain), IF staining for α3,4 and 5(IV) is segmental due to lyonization.

Question 32

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 32

In an autosomal recessive Alport, no α3(IV)- α5(IV) labeling may be detected in the GBM, but α5(IV) from the [α5, α5, α6] protomer will be positive in Bowman’s capsule and basement membrane of collecting ducts.

Question 33

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 33

Diagnosis
Clinical syndrome, particularly if known family history

Kidney or skin biopsy:

Kidney biopsy: Note that classic lamellation of GBM may not be present in early disease.

Question 34

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 34

Skin biopsy is stained for α5(IV) chain. Absent or segmental staining suggests X-linked Alport. Normal staining may signify:

Autosomal-recessive Alport syndrome involving either α3 or α4(IV) chains.

Question 35

Alport Syndrome and Thin Basement Membrane

Histopathology

Answer 35

Mutation of α5(IV) that affects the function but not structure of the chain.

Diseases other than Alport

Question 36

Alport Syndrome and Thin Basement Membrane

Management

Answer 36

Slow progression of kidney disease: (ACEI or ARB) reduces proteinuria and rate of disease progression.

Question 37

Alport Syndrome and Thin Basement Membrane

Kidney Transplantation

Answer 37

Recurrent disease does not occur in the transplanted graft because the donor kidney has a normal GBM.

Question 38

Alport Syndrome and Thin Basement Membrane

Kidney Transplantation

Answer 38

Anti-GBM disease occurs in 3% to 4% of affected males who receive transplants. X-linked females do not develop posttransplant anti-GBM disease because they generally do carry a normal copy of the affected gene and do express the normal counterpart.

Question 39

Alport Syndrome and Thin Basement Membrane

Kidney Transplantation

Answer 39

In males with X-linked disease, antibodies are directed primarily against the α5(IV) chain, but antibodies against the α3(IV) chain are also found in some patients.

Question 40

Alport Syndrome and Thin Basement Membrane

Kidney Transplantation

Answer 40

In patients with autosomal recessive Alport syndrome who develop posttransplant anti-GBM disease, the predominant target of anti-GBM antibodies is the α3(IV) chain.

Question 41

Alport Syndrome and Thin Basement Membrane

Kidney Transplantation

Answer 41

Retransplantation in patients who have developed posttransplant anti-GBM is questionable due to high risk of recurrence.