Categories
Ocular System ORGAN SYSTEMS Otolaryngeal system (ENT)

Alport syndrome

Familial renal disorder of collagen IV network of basement membranes characterized by glomerulonephritis, end-stage kidney disease, and hearing loss.

Familial renal disorder of collagen IV network of basement membranes characterized by glomerulonephritis, end-stage kidney disease, and hearing loss.

  • Also known as hereditary nephritis

History

In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome.

Arthur Cecil Alport, M.D.
Arthur Cecil Alport, M.D. (1880 – 1959) was a South African physician who first identified the Alport syndrome in a British family in 1927 when he was a University of Edinburgh Medical School graduate

Etiology

Genetic mutations:

COL4A(3/4/5) genes encoding alpha-3, alpha-4, and alpha-5 of collagen IV α345 network of basement membranes. Defect in these genes results in glomerulonephritis, end-stage kidney disease, and hearing loss.
  1. X-linked AS (XLAS) (M/C, 80%)
    • COL4A5-linked
    • Presents early
  2. Autosomal recessive AS (ARAS)
    • COL4A3, 4-linked
    • Presents early
  3. Autosomal dominant Alport Syndrome (ADAS)
    • COL4A3, 4-linked
    • Presents late
Electron micrographs: Alport Syndrome
Electron micrographs of kidney biopsies to show the difference in the glomerular basement membrane (GBM), in a normal glomerulus, a glomerulus in thin basement membrane, and a glomerulus in someone with Alport syndrome. | Large Or Particularly. (2019) Alport Syndrome | UNC Kidney Center. Retrieved February 11, 2019, from https://unckidneycenter.org/kidneyhealthlibrary/glomerular-disease/alport-syndrome/

Presentation

I. Renal minifestations:

The spectrum of renal involvement ranges from isolated, non-progressive hematuria to progressive nephropathy characterized by hematuria, proteinuria, and chronic kidney disease (CKD) and end-stage renal disease (ESRD)
  • Hematuria (M/C & earliest manifestation)
  • Proteinuria (in males with XLAS and in males & females with ARAS & ADAS)
  • Hypertension (in males with XLAS and in males and females with ARAS and ADAS)
  • Renal insufficiency

II. Bilateral high-frequency sensorineural hearing loss (SNHL)

III. Ocular manifestations:

  • Anterior lenticonus (PATHOGNOMIC): Lens capsule cannot maintain shape of lens
  • Dot-and-fleck retinopathy: Whitish/yellowish flecks/granulations in perimacular region)
  • Perimacular flecks
  • Posterior polymorphous corneal dystrophy (rare)
  • Recurrent corneal erosion
Lens abnormalities: Alport syndrome
Lens abnormalities. (A) Lenticonus appearance on slit-lamp examination showing an anterior dimple or oil droplet (arrow) in a man with X-linked Alport syndrome, renal impairment, and posterior polymorphous corneal dystrophy. The oil droplet is also obvious on direct ophthalmoscopy. (B) Anterior segment view showing the anterior bulging of the lens (arrows) with a Scheimpflug camera (Pentacam) in the patient from A. (C) Electron microscopy of an anterior lens capsule obtained at surgery showing the thinned capsule (arrow) and vertical tears (upper panel) compared with normal (arrow in lower panel). The abnormal lens was from a man with X-linked Alport syndrome, renal failure, lenticonus, and retinopathy. | Savige, J., Sheth, S., Leys, A., Nicholson, A., Mack, H. G., & Colville, D. (2015). Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance. Clinical Journal of the American Society of Nephrology, 10(4), 703 LP-709. https://doi.org/10.2215/CJN.10581014
Corneal abnormalities
Corneal abnormalities. (A) Mild scarring caused by recurrent corneal erosions shown on slit-lamp examination in a man with X-linked Alport syndrome (arrow), renal failure, and perimacular retinopathy. The patient’s mother is also affected with renal disease and similar corneal changes. (B) Posterior polymorphous corneal dystrophy (arrow) with diffuse and vesicular lesions posteriorly at the level of Descemet’s membrane on slit-lamp examination in a man with X-linked Alport syndrome, renal failure, lens replacement for lenticonus, and perimacular retinopathy. (C) A slit-lamp view of posterior polymorphous corneal dystrophy showing the characteristic doughnut-like vesicles posteriorly (arrow). (D) Specular microscopy of the corneal endothelium in the patient in C showing that the doughnut-like lesions are vesicles with thick dark borders around clusters of endothelial cells (arrow). | Savige, J., Sheth, S., Leys, A., Nicholson, A., Mack, H. G., & Colville, D. (2015). Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance. Clinical Journal of the American Society of Nephrology, 10(4), 703 LP-709. https://doi.org/10.2215/CJN.10581014
Retinal abnormalities: Alport syndrome
Retinal abnormalities. (A) Central/perimacular fleck retinopathy sparing the foveola and located principally in the temporal retina (arrow) in a man with X-linked Alport syndrome, renal failure, and lenticonus. (B and C) Perimacular fleck retinopathy in a woman with X-linked Alport syndrome, renal impairment, and hearing loss (arrows). The flecks are pronounced in the temporal retina. They are more obvious and can be distinguished from the normal retinal sheen on the red-free image (arrows). (D and E) Peripheral coalescing fleck retinopathy in a woman with X-linked Alport syndrome, normal renal function, and hearing loss. The flecks are >2 disc diameters from the foveola and more obvious on the redfree image (arrows). (F) Peripheral retinopathy with widespread evenly distributed retinal flecks (arrows) in an ultrawide field scan (Optos camera) in a man with X-linked disease. The lozenge and central fleck retinopathy are not obvious in this view. (G) Pigment disturbance with bull’s eye maculopathy. There is a ring of hypopigmentation with central hyperpigmentation in a woman with X-linked Alport syndrome, renal impairment, and peripheral retinopathy (arrow). (H) Lozenge from temporal extension of the normal round foveolar reflex (arrow) caused by retinal thinning in a man with X-linked Alport syndrome, renal failure, hearing loss, lenticonus, and perimacular fleck retinopathy. (I) Temporal retinal thinning seen on a cross-section of the retina from a man with X-linked Alport syndrome, renal failure, and hearing loss. (J) Temporal thinning confirmed in the patient from I indicating that the temporal thickness is in the <5th percentile (red). (K–N) Retinal shadow suggesting (K) macular hole in a woman with autosomal recessive Alport syndrome, hearing loss, and lenticonus. (L) The holes are more obvious on a black and white image of the macula and temporal retina. (M) The lamellar holes are confirmed with three well demarcated areas of thinning seen on optimal coherence tomography (OCT) (<200-µm thick). (N) These correspond to three areas of lamellar thinning on OCT. (O) Full-thickness giant macular hole in a woman with Alport syndrome and renal failure. | Savige, J., Sheth, S., Leys, A., Nicholson, A., Mack, H. G., & Colville, D. (2015). Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance. Clinical Journal of the American Society of Nephrology, 10(4), 703 LP-709. https://doi.org/10.2215/CJN.10581014

Rare features:

  • Associated aortic disease
  • Diffuse leiomyomatosis

Diagnosis

Genetic testing:

  • COL4A(3,4,5)

Skin/kidney biopsy:

  • Immunohistochemistry
  • Electron microscopy
    • GBM
      • Thick & abnormal
      • “Woven basket appearance”
        • Lamina densa split

Differential diagnosis:

Approach to distinguish between alport syndrome and thin basement membrane nephropathy
An approach to distinguish between Alport syndrome and thin basement membrane nephropathy as the cause of persistent glomerular hematuria. | Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/235371682_fig1_Figure-1-An-approach-to-distinguish-between-Alport-syndrome-and-thin-basement-membrane [accessed 13 Jun, 2017]

Management

There is no cure. Treatment is focused on limiting the progression of proteinuria and kidney disease. 

Symptomatic treatment:

  • Proteinuria:
    • Angiotensin-converting enzyme inhibitors (ACEi)
    • Angiotensin receptor blockers (ARBs)
  • Anterior lenticonus:
    • Replacement lens
  • Kidney failure:
    • Dialysis
    • Renal transplant

Leave a Reply