Clinical and genetic features in autosomal recessive and X-linked Alport syndrome

Wang, Yanyan; Sivakumar, Vanessa; Mohammad, Mardhiah; Colville, Deb; Storey, Helen; Flinter, Frances; Dagher, Hayat; Savige, Judy

doi:10.1007/s00467-013-2643-0

Cited by 33 publications

(22 citation statements)

References 17 publications

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“…Central fleck retinopathy is present in 60% of men and at least 15% of women with X-linked Alport syndrome and 50% of individuals with recessive disease (Figure 4, A-C) (52). It is more common with early-onset renal failure and lenticonus.…”

Section: Retina: Central Fleck Retinopathy and Peripheral Coalescing mentioning

confidence: 99%

Ocular Features in Alport Syndrome

Savige

Sheth

Leys

et al. 2015

Clinical Journal of the American Society of Nephrology

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Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV a3a4a5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. 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. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging.

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Section: Retina: Central Fleck Retinopathy and Peripheral Coalescing mentioning

confidence: 99%

Ocular Features in Alport Syndrome

Savige

Sheth

Leys

et al. 2015

Clinical Journal of the American Society of Nephrology

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171

150

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“…Our cohort characteristics are similar to those previously reported with respect to median age 38 (IQR = 20-52) of commencement of renal replacement therapy (dialysis or preemptive transplantation). 1-5,11,15,18 In cohorts of individuals from similar health care environments to ours, the median age of commencement is comparable: for example, 141 Alport syndrome patients (62% male) in Australia and New Zealand between 1997 and 2010 who had a mean age of commencement of renal replacement therapy of 37.7. 1 …”

Section: Discussionmentioning

confidence: 57%

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome

Langsford

Tang

Djurdjev

et al. 2016

Can J Kidney Health Dis

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Background:A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described.Objective:The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients.Design:Retrospective observational cohort study.Setting:British Columbia, Canada, chronic renal disease registry 1995-2012.Patients:37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome.Measurements:Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline).Methods:In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient’s serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline).Limitations:Histological or genetic evidence of Alport syndrome is not available in all patients.Results:Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m2, 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed.Conclusions:The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions.

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“…The rate of hearing impairment in autosomal recessive AS varies from 40 % to 100 % (Oka et al 2014;Wang et al 2014). In our cases, the father experienced hearing impairment, while none of the siblings have had difficulty in hearing so far.…”

Section: Discussionmentioning

confidence: 89%

Early RAAS Blockade Exerts Renoprotective Effects in Autosomal Recessive Alport Syndrome

Uchida

Kumagai

Nozu

et al. 2016

Tohoku J. Exp. Med.

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Alport syndrome is a progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes that encode collagen type IV alpha 3, alpha 4, and alpha 5 chains, respectively. Because of abnormal collagen chain, glomerular basement membrane becomes fragile and most of the patients progress to end-stage renal disease in early adulthood. COL4A5 mutation causes X-linked form of Alport syndrome, and two mutations in either COL4A3 or COL4A4 causes an autosomal recessive Alport syndrome. Recently, renin-angiotensin-aldosterone system (RAAS) blockade has been shown to attenuate effectively disease progression in Alport syndrome. Here we present three Japanese siblings and their father all diagnosed with autosomal recessive Alport syndrome and with different clinical courses, suggesting the importance of the early initiation of RAAS blockade. The father was diagnosed with Alport syndrome. His consanguineous parents and his wife were healthy. All three siblings showed hematuria since infancy. Genetic analysis revealed that they shared the same gene mutations in COL4A3 in a compound heterozygous state: c.2330G>A (p.Gly777Ala) from the mother and c.4354A>T (p.Ser1452Cys) from the father. Although RAAS blockade was initiated for the older sister and brother when their renal function was already impaired, it did not attenuate disease progression. In the youngest brother, RAAS blockade was initiated during normal renal function stage. After the initiation, his renal function has been normal with the very mild proteinuria to date at the age of 17 years. We propose that in Alport syndrome, RAAS blockade should be initiated earlier than renal function is impaired.

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Clinical and genetic features in autosomal recessive and X-linked Alport syndrome

Abstract: Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

Cited by 33 publications

References 17 publications

Ocular Features in Alport Syndrome

Ocular Features in Alport Syndrome

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome

Early RAAS Blockade Exerts Renoprotective Effects in Autosomal Recessive Alport Syndrome

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