Alport Syndrome (Collagen IV-Related Nephropathies)

Clinical Characteristics
Ocular Features: 

X-linked Alport syndrome is a basement membrane disease with important ocular manifestations.  The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location.  Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive.  It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity.  In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination.  All males with anterior lenticonus should be evaluated for Alport syndrome. 

Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted.  The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat.  Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients.  More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer.  The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula.  There is no night blindness or visual impairment from the retinal involvement.  Fluorescein angiography shows patchy areas of hyperfluorescence.  The amount of visual impairment depends primarily on the extent of lens involvement.

Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings.   In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign.  However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500).

Systemic Features: 

Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder.  It occurs in both sexes but more commonly in males in which it has an earlier onset.  Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity.  In males, the onset of hearing loss often occurs before kidney disease is evident.  Hearing loss is less frequent and less severe in females.  However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease.  In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement.

Genetics

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies.  It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant.  All result from a defect in type IV collagen found in basement membranes.  About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3.  Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated.  The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission.

Treatment
Treatment Options: 

Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection.  Allograft survival rates are generally excellent though.  Lens extraction is beneficial where the media is compromised.

References
Article Title: 

Alport syndrome: a genetic study of 31 families

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families.
Hum Genet. 1992 Dec;90(4):420-6.

PubMed ID: 
1483700

References

Thomas AS, Baynham JT, Flaxel CJ. MACULAR HOLES, VITELLIFORM LESIONS, AND MIDPERIPHERAL RETINOSCHISIS IN ALPORT SYNDROME. Retin Cases Brief Rep. 2015 Jul 21. [Epub ahead of print].

PubMedID: 26200386

Ahmed F, Kamae KK, Jones DJ, Deangelis MM, Hageman GS, Gregory MC, Bernstein PS. Temporal Macular Thinning Associated With X-Linked Alport Syndrome. JAMA Ophthalmol. 2013 Apr 9:1-6.

PubMedID: 23572034

Kruegel J, Rubel D, Gross O. Alport syndrome-insights from basic and clinical research. Nat Rev Nephrol. 2012 Nov 20. [Epub ahead of print].

PubMedID: 23165304

Savige J, Liu J, DeBuc DC, Handa JT, Hageman GS, Wang YY, Parkin JD, Vote B,Fassett R, Sarks S, Colville D. Retinal basement membrane abnormalities and the retinopathy of Alport syndrome. Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1621-7.

PubMedID: 19850830

Seymenofulu G, Baser EF. Ocular manifestations and surgical results in patients with Alport syndrome. J Cataract Refract Surg. 2009 Jul;35(7):1302-6.

PubMedID: 19545823

Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations.
Ophthalmic Genet. 1997 Dec;18(4):161-73. Review.

PubMedID: 9457747

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families.
Hum Genet. 1992 Dec;90(4):420-6.

PubMedID: 1483700

Streeten BW, Robinson MR, Wallace R, Jones DB. Lens capsule abnormalities in Alport's syndrome. Arch Ophthalmol. 1987 Dec;105(12):1693-7.

PubMedID: 3689194