Alport Syndrome

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 by Bayan Al Othman, MD on June 30, 2020.



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.

This affected basement membranes in kidney cause improper filtering of the blood and allows blood and/or protein to pass into the urine. It can damage progressively the kidneys and end 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 affection cause an anormal conduction of sound waves into electrical signals for the brain.[1]

Ocular clinic can be found where α3α4α5 type-IV collagen play an essential role:

Corneal alterations are seen in Bowman's and Descemet's membranes whose functions are to join the three main layers (epithelium, estroma and endothelium). Weakness and low adherence to epithelium and to endotehlium explains recurrent erosions and posterior corneal distrophy respectively. Additionally, vesicles of posterior corneal distrophy are products from vacuolar degeneration of dying cells or multilayered epithelial cell protuberances from Descemet’s membrane.[3] Lens capsule also has the same problem than cornea and generates partial splits that may rupture. Also, it can occurs a protrusion in the thinnest part whose outcome will be a lenticonus.[3]

Cataracts can be developed too. Lenticonus ceases to progress after cataract formation. Posterior lenticonus also occurs but is less common.[3]

Retina's injuries are localized in the inner limiting membrane/nerve fiber layer and may interfere with the homeostasis of retinal environment: nutrition of the overlying cells, removal of debris, and maintenance of the watertight barrier.[3][4]

Primary prevention[2]

  • Screening of any family with X-Linked Alport Syndrome: At-risk family members should be screened for hematuria on at least 2 occasions and offered other screening tests. Other coincidental causes of hematuria must be excluded.
  • Genetic test: if mutation has been identified in one member of the family.
  • Genetic Counseling.

Diagnosis

History[2]

Alport syndrome is presented in young children (the most frequent age of begining of the symptoms is between 5 and 20 years old) who suffer from chronic hematuria to renal failure before 40 years old, depending on the type of mutation they carry. Hearing continues to deteriorate in adulthood. The lenticonus also worsens but can be corrected with lens replacement. The retinopathy progresses but does not affect vision or require treatment. Men with X-Linked Alport Syndrome are affected more roughly than women. Autosomal dominant or recessive have the same frequency and severity for men and women.

Physical examination

Renal symptoms

hematuria, edema, hypertension[5]

Audiometry

high-tone bilateral sensorineural hearing loss[5]

Slit-lamp

  1. The most frequent ocular signs [3][5]:
    • Anterior lenticonus with “oil droplet” sign and usually axial, 2–7 mm.
    • Dot-and-flecks retinopathy with “lozenge” sign (dull macular reflex): it's seen like white or yellow granulations that are superficially located.
  2. Less common:[3][5]
    • corneal posterior polimorphous dystrophy: endotelial vesicles are seen in form of clusters (“dougnuts) or bands (“snail tracks”)
    • secondary calcifications of hipercalcemia (if renal failure) in conjunctiva and sclera.
    • corneal erosions seen in anterior cornea.
    • corneal opacities.
    • microcornea.
    • cataract.
    • posterior lenticonus.
    • spontaneous capsule rupture.
    • lammellar macular holes.
    • disturbances of foveal pigmentation, including a bull’s eye or vitelliform maculopathy.
    • temporal macular thining.

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 acuity visual 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). Besides, it presents an 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, being all of them the origin of dot-and-flecks retinopathy.[6][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.[7] The central and peripheral retinopathies seems 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.[7] Dot-and-fleck retinopathy and temporal macular thining does not affect vision. On the other hand, macular holes affect central vision and have a poorly response to surgery.[1]

Anterior lenticonus

The defective IV-collagen induces thining and fragility lens capsule arousing as a lenticonus. Several studies have demostrated changes analysed by electron microscopy as multiple linear dehiscences in the inner 2/3 of capsule, containing fibrillar material and vacuoles. In addition to the histological changes of the anterior capsule, the weakened structure is stressed during accommodation, as the anterior lens curvature becomes more convex centrally or, rarely, capsule may rupture.[8] This problem can be solved by removing lens surgically, which has positive outcomes. During surgery, central protruded fragile lens capsule must meticulously be handled to create well-centered continuous curvilinear capsulorhexis. Femtosecond laser-assisted capsulorhexis has been shown to be a safe procedure.[9] Additionally, some surgeries have been succesfull in spite of presenting spontaneous capsular rupture before surgery.[10] Posterior lenticonus also occurs but is less common.[3]

Corneal Pathology

  • Recurrent erosions: due to deffective adhesion between epithelium and Bowman's membrane. They typically occur in individuals with early-onset renal failure and extrarenal 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 distrophy: the cause is similar as in recurrent erosions, deffective adhesion between layers. It can be asymptomatic or patients complaint about gritty, watering eyes and photophobia. Some advanced cases may require corneal transplantation. The other ones, just symptomatic treatment. It can be detected 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:

  1. there are glomerular hematuria and a family history of Alport syndrome with no other cause for the hematuria
  2. bilateral high-tone sensorineural hearing loss, lenticonus, or fleck retinopathy is present
  3. the GBM lacks the collagen IV a 5 chain.

Diagnosis procedures[2]

  1. Test for microalbuminuria/proteinuria
  2. Audiometry
  3. An ophthalmologic examination
  4. 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

Actual treatments can delay the progression to ESRD and some of them can reverse some clinical issues as lenticonus or renal transplantation.

Medical therapy [1][2][3][5]

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and aldosterone inhibitors to reduce proteinuria. Renal transplantation for 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 (hipertension, proteinuria, hematuria...etc) during their entire life. It should be avoided to give ototoxic medications and exposure them to high noise.

Prognosis

ESDR appears in 90% of males X-Linked alport syndrome instead of 12% of females XLAS by 40 years of age.[1] Renal transplantation caused by Alport syndrome has a superior patient and graft survival than by other causes.[5] Autosomic recessive Alport Syndrome has an earlier onset of renal failure than Autosomic dominant Alport Syndrome.[1]

References

  1. 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. 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. 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. 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.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Zhang Y, Ding J.Renal, auricular and ocular outcomes of Alport syndrome and their current management. Pediatr Nephrol. 2017.
  6. 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.
  7. 7.0 7.1 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.
  8. 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.
  9. 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.
  10. 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.
  1. 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.
  2. Herwig MC, Eter N, Holz FG, Loeffler KU: Corneal clouding in Alport syndrome. Cornea.2011; 30: 367–370.
  3. 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.
  4. Jh Choi, Ks Na, Sh Bae, Gh Roh. Anterior lens capsule abnormalities in Alport Syndrome. Korean J Ophthalmol. 2005; 19: 84-89.
  5. 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.