Alport Syndrome
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Disease Entity
Disease
Alport syndrome is a genetic disorder. It is identified by kidney disease, hearing loss and eye abnormalities. It was described by A.Cecil Alport in 1927.[1]
Etiology
Alport syndrome is a hereditary glomerular basement membrane disease as a result of mutations in the genes COL4A3/4/5. These genes encode the type IV collagen alpha 3-5 chains. The most frequent inheritance is X-linked dominant, followed by autosomal recessive and autosomal dominant.[2]
Risk Factors
The only risk factor for Alport Syndrome is an affected parent . X-Linked form is the most frequent type with mutations in the COL4A5 gene, the gene encoding the alpha-5 chain of type IV collagen. The alpha-3 and alpha-4 chains are implicated in the less common autosomal recessive and autosomal dominant variants.[2]
General Pathology
Individuals with Alport syndrome may develop hematuria, proteinuria, renal failure (edema and hypertension), hearing loss, lenticonus and retinal flecks.[1]
Pathophysiology
The type-IV collagen is probably common to the basement membranes of the glomerulus, cochlea (stria vascularis), retina (inner limiting membrane and Bruch's membrane) , lens capsule, and cornea (Descemet's and Bowmann membrane). However, the alpha 3(IV) and 4(IV) as well as the alpha 5(IV) collagen chains are usually absent from the affected basement membranes, because the abnormal alpha 5(IV) molecule interferes with the stability of all three. The loss of these collagen molecules from the affected basement membranes results in an abnormal ultrastructural appearance.[3]
The α1α1α2 network is found in Alport's affected basement membranes. They are less structurally stable and more susceptible to biomechanical strain.
The affected basement membrane in the kidney causes improper filtering of the blood, allowing blood and/or protein to pass into the urine. It can cause progressive damage to the kidneys and ultimately result in renal failure.[1]
During late childhood, people with Alport syndrome also frequently develop sensorineural hearing loss because type-IV collagen is an important element of certain inner ear structures, especially the organ of Corti. This results in an abnormal conduction of sound waves, electrical signals, to the brain.[1]
Ocular abnormalities can be found where α3α4α5 type-IV collagen plays an essential role:
Corneal alterations are seen in Bowman's and Descemet's membranes whose functions are to join the three main layers (epithelium, stroma and endothelium). Weakness and low adherence to epithelium and to endothelium explains recurrent erosions and posterior corneal dystrophy, respectively. Additionally, vesicles seen in posterior corneal dystrophy are products secondary to vacuolar degeneration of dying cells, i.e. multilayered epithelial cell protuberances from Descemet’s membrane.[3] Lens capsule also has similar defects, as seen in the cornea, which can generate partial splits that may result in rupture and/or a protrusion in the thinnest portion resulting in lenticonus.[3]
Cataracts can be seen as well. Lenticonus ceases to progress after cataract formation. Posterior lenticonus also occurs but is less common.[3]
Retinal abnormalities are localized in the inner limiting membrane/nerve fiber layer and may interfere with the homeostasis of the retinal environment: nutrition of the overlying cells, removal of debris, and maintenance of the watertight barrier.[3][4]
Primary prevention[2]
- Screening when there is an immediate family history of X-Linked Alport Syndrome: At-risk family members should be screened for hematuria on at least 2 occasions and offered other screening tests as indicated. Other coincidental causes of hematuria must be excluded.
- Genetic test: if a particular genetic mutation has been identified in one member of the family, testing for this particular defect can be offered to first generation family members.
- Genetic Counseling.
Diagnosis
History[2]
Alport syndrome presents in childhood (average onset of symptoms is between 5 and 20 years old) beginning with chronic hematuria and resulting in renal failure around 40 years of age, depending on the type of mutation they carry. Hearing continues to deteriorate into adulthood. Lenticonus, capsular rupture and cataract gradually worsen but can be corrected with cataract surgery and lens replacement. Retinopathy progresses but does not affect vision or require treatment. Men with X-Linked Alport Syndrome are affected more severely than women. Autosomal dominant or recessive have the same frequency and severity for men and women. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. [5]
Physical examination
Renal symptoms
hematuria, edema, hypertension[6]
Audiometry
high-tone bilateral sensorineural hearing loss[6]
Slit-lamp
- The most frequent ocular signs [3][6]:
- Anterior lenticonus with “oil droplet” sign and usually axial, 2–7 mm.[7]
- Dot-and-fleck retinopathy with “lozenge” sign (dull macular reflex): appears as white or yellow granulations that are superficially located.
- Less common:[3][6]
- corneal posterior polymorphous dystrophy: endothelial vesicles are seen to form in clusters (“doughnuts") or bands (“snail tracks”)
- secondary calcifications of hypercalcemia (if renal failure) in conjunctiva and sclera.
- corneal erosions seen in anterior cornea.
- corneal opacities.
- microcornea.
- cataract.
- posterior lenticonus.
- spontaneous capsular rupture.
- lamellar macular holes.
- disturbances of foveal pigmentation, including a bull’s eye or vitelliform maculopathy.
- temporal macular thinning.
Symptoms[2]
- Chronic hematuria
- Edema
- Hypertension
- Hearing loss
Ocular symptoms[1][3]
- Acute episodes of pain, watering, photophobia and blurred vision caused by corneal erosions.
- Progressive visual loss caused by corneal posterior polymorphous dystrophy.
- Lenticular myopia caused by anterior lenticonus.
- Astigmatism.
- Decreased visual acuity caused by cataract.
- Central visual loss caused by macular holes. They respond poorly to surgery.
Retinopathy
The α3α4α5 type IV collagen network is present in the normal ILM and in the retinal pigment epithelium basement membrane of Bruch's membrane. In Alport syndrome, the ILM/nerve fiber layer and Bruch's membrane are both thinned. The thinning of these membranes contributes to the appearance of retinopathy and macular holes. The dot-and-fleck retinopathy is seen like white or yellow granulations that are superficially located with “lozenge” sign (dull macular reflex as a result of the demarcation between the perimacular retinopathy and the thinned macula). This may present as a hyperreflectivity on OCT of the ILM/nerve fiber layer in the distribution of the nerve fiber layer corresponding with the location of the retinopathy. A thinned ILM may be more susceptible to tractional forces from the vitreous, interfere with the transport of nutrients, or impair the clearance of waste products.[8][4] The central retinopathy varies from scattered whitish-yellow dots and flecks to a dense, almost confluent annulus around the region of temporal retinal thinning.[9] The central and peripheral retinopathies seem to have an identical pathogenesis in X-linked and autosomal recessive Alport syndrome. Retinopathy has a prognostic value in determining early-onset renal failure if present. Fundus albipunctatus, other causes of generalized drusen and the pigmentary retinopathies, that are usually accompanied by night blindness and progressive visual loss, should be considered in retinopathy differential diagnosis.[9] Dot-and-fleck retinopathy and temporal macular thining does not affect vision. On the other hand, macular holes affect central vision and have a poor response to surgery.[1][10]
Anterior lenticonus
The defective IV-collagen induces thinning and fragility of the lens capsule resulting in lenticonus. Several studies have demonstrated changes by electron microscopy as multiple linear dehiscences in the inner 2/3 of the capsule, containing fibrillar material and vacuoles. In addition to the histological change of the anterior capsule, the weakened structure is stressed during accommodation, as the anterior lens curvature becomes more convex centrally, rarely resulting in capsular rupture.[11] Cataract surgery with intraocular lens implantation results in successful visual recovery. During surgery, centrally protruded fragile lens capsule must be meticulously handled to create a well-centered continuous curvilinear capsulorhexis. Femtosecond laser-assisted capsulorhexis has been shown to be a safe procedure in these patients.[12] Cataract surgery can be successful even in the presence of a spontaneously ruptured capsule before surgery.[13] Recent evidence suggests that cataract surgery, however, may predispose to early development of a macular hole [10] Posterior lenticonus may also occur but is less common.[3]
Corneal Pathology
- Recurrent erosions: due to defective adhesion between epithelium and Bowman's membrane. They typically occur in individuals with early-onset renal failure and extra-renal features. Sometimes, corneal erosions are found in different members of the same family, but they do not appear to be associated with specific mutations.[3]
- Posterior polymorphous corneal dystrophy: the cause is similar as in recurrent erosions, defective adhesion between corneal layers. It can be asymptomatic or patients complaint of gritty, watering eyes and photophobia. Advanced cases may require corneal transplantation, however, the majority require only symptomatic treatment. Diagnosis can be made by slit-lamp examination, confocal microscopy or anterior segment Optical Coherence Tomography.[3]
Clinical diagnosis[2]
The diagnosis of Alport syndrome is highly likely if one of the following situations is presented:
- there is glomerular hematuria and a family history of Alport syndrome with no other cause for the hematuria
- bilateral high-tone sensorineural hearing loss, lenticonus, or fleck retinopathy is present
- the GBM lacks the collagen IV a 5 chain.
Diagnosis procedures[2]
- Test for micro-albuminuria/proteinuria
- Audiometry
- An ophthalmologic examination
- Renal biopsy for GBM ultrastructure, collagen IV composition, and an assessment of damage
Genetic testing
The diagnosis is confirmed if one of the following results occurs:
- A lamellated GBM
- A COL4A5 mutation
- Two COL4A3 or COL4A4 mutations
Differential diagnosis[1]
TBMN: Thin basement membrane nephropathy (TBMN). In many individuals with the disorder, the same genes appear to be involved. Unlike those with Alport syndrome, few extra-renal findings are present, and symptoms are less severe, with progression to renal impairment rarely found.
Management
General treatment
Early diagnosis and treatment can delay the progression to ESRD and potentially reverse some clinical issues such as lenticonus.
Medical therapy [1][2][3][6]
Angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and aldosterone inhibitors help to reduce proteinuria. Renal transplantation is only required in end stage renal failure. Eye pads, topical antibiotics and pain relief can be applied to resolve corneal erosions. Corneal transplantation is sometimes required to improve visual acuity for severe corneal disease. Lens removal and intraocular lens implantation surgery are eventually required for most patients with lenticonus and cataract No treatment is required for fleck retinopathy. Macular holes do not respond well to surgery treatment. Hearing-aids to help hearing loss
Medical Follow-up [2]
Alport syndrome patients should visit their nephrologist to control the risk factors for renal failure and common symptoms (hypertension, proteinuria, hematuria...etc) during their entire life. Ototoxic medications and exposure to loud noise should be avoided.
Prognosis
ESDR occurs in 90% of males with X-Linked Alport syndrome (XLAS) versus 12% of females with XLAS by 40 years of age.[1] Renal transplantation as a result of Alport syndrome has a superior patient and graft survival rate compared to other causes.[6] Autosomal recessive Alport Syndrome has an earlier onset of renal failure than Autosomal dominant Alport Syndrome.[1]
Additional Resources
- Porter D, Vemulakonda GA. Blood Pressure. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/anatomy/blood-pressure-list. Accessed January 06, 2023.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Simon Watson, Bush Jeffrey S. Alport Syndrome. StatPearls Publishing. 2018 jan.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F: Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 24: 364–375, 2013.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D.Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am Soc Nephrol. 2015; 10(4):703-9.
- ↑ 4.0 4.1 Fawzi AA, Lee NG, Eliott D, Song J, Stewart JM. Retinal findings in patients with Alport syndrome: expanding the clinical spectrum. Br J Ophthalmol. 2009; 93:1606–1611.
- ↑ Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D. Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am Soc Nephrol. 2015 Apr 7;10(4):703-9. doi: 10.2215/CJN.10581014. Epub 2015 Feb 3. PMID: 25649157; PMCID: PMC4386265.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Zhang Y, Ding J.Renal, auricular and ocular outcomes of Alport syndrome and their current management. Pediatr Nephrol. 2017.
- ↑ Srinivasan K, Sakthivel S. Classic anterior lenticonus in Alport syndrome. J Fr Ophtalmol. 2024 Apr;47(4):104120. doi: 10.1016/j.jfo.2024.104120. Epub 2024 Mar 5. PMID: 38447292.
- ↑ 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; 51: 1621–1627.
- ↑ 9.0 9.1 Shaw E, Colville D, Wang YY, Zhang KW, Dagher H, Savige J.Characterization of the peripheral retinopathy in X-linked and autosomal recessive Alport syndrome.Nephrology Dialysis Transplantation.2007. 22 (1):104-108.
- ↑ 10.0 10.1 Roubelat FP, Gualino V, Fournié PR, Soler VJ. AMNIOTIC MEMBRANE GRAFTING FOR A CASE OF BILATERAL GIANT FULL-THICKNESS MACULAR HOLE IN ALPORT SYNDROME AFTER CATARACT SURGERY. Retin Cases Brief Rep. 2024 Jul 1;18(4):521-525. doi: 10.1097/ICB.0000000000001428. Epub 2023 Oct 9. PMID: 37824682; PMCID: PMC11191552.
- ↑ Sonarkhan S,Ramappa M, Chaurasia S, Mulay K: Bilateral anterior lenticonus in a case of Alport syndrome: A clinical and histopathological correlation after successful clear lens extraction [published online ahead of print June 26, 2014]. BMJ Case Rep. 2014.
- ↑ Barnes AC, Roth AS. Femtosecond laser-assisted cataract surgery in anterior lenticonus due to Alport syndrome. Am J Ophthalmol Case Rep. 2017; 6: 64-66.
- ↑ Agrawal N., Nayak D.P., Haripriya A., Bhuwania P.Phacoemulsification with toric IOL implantation in Alport syndrome with anterior lenticonus having spontaneously ruptured anterior capsule. Eur J Ophthalmolo. 2015; 25(5): e78-80.
- Ladi J, Shah N:Toric multifocal intraocular lens implantation in a case of bilateral anterior and posterior lenticonus in Alport syndrome. Indian J Ophthalmol. 2016 Nov; 64(11): 847-849.
- Herwig MC, Eter N, Holz FG, Loeffler KU: Corneal clouding in Alport syndrome. Cornea.2011; 30: 367–370.
- Teekhasaenee C, Nimmanit S, Wutthiphan S, Vareesangthip K, Laohapand T, Malasitr P, Ritch R: Posterior polymorphous dystrophy and Alport syndrome. Ophthalmology.1991; 98: 1207–1215.
- Jh Choi, Ks Na, Sh Bae, Gh Roh. Anterior lens capsule abnormalities in Alport Syndrome. Korean J Ophthalmol. 2005; 19: 84-89.
- Julián García Feijoó, Sol Aguilar Barbadillo, José Manuel Benítez del Castillo Sánchez. Enfermedades Renales. En: Sánchez Salorio M, Díaz-Llopis M, Benítez del Castillo JM, Rodríguez Ares MT. Manifestaciones oftalmológicas de las enfermedades generales. 77ª Ponencia oficial de la Sociedad Española de Oftalmología. 2001; 13: 407-408.
