Retinal disease in the C3 glomerulopathies and the risk of impaired vision

Savige, Judy; Amos, Louella B.; Ierino, Frank; Mack, Heather G; Symons, R.C. Andrew; Hughes, Peter; Nicholls, Kathy; Colville, Deb

doi:10.3109/13816810.2015.1101777

Cited by 30 publications

(33 citation statements)

References 48 publications

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“…Although retinal drusen are present on examination in almost all cases of DDD, Savige et al have noted that, as with our case, visual acuity is usually near normal even in the presence of abundant drusen [ 8 ]. The condition causes end stage renal disease in 50% of subjects within 10 years [ 1 ], and occasionally also impairs visual acuity and the field of vision [ 2 , 8 ], predominantly by the development of subretinal neovascular membranes, macular detachment and central serous retinopathy [ 5 ]. Interestingly, Savige et al noted that the six patients in their review all recorded nyctalopia [ 8 ] whilst our patient did not note reduced night vision.…”

Section: Discussionsupporting

confidence: 63%

A long history of dense deposit disease

Cunningham

Kotagiri

2018

BMC Ophthalmol

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BackgroundDense Deposit Disease is a rare condition affecting the Bruch’s membrane and the glomerular basement membrane. We report the progression of the ocular manifestations over a 30 year follow up period, longer than any previous report.Case presentationA 44 year old male presented with pigmentary changes at the macula noted by his optician. Best corrected visual acuity at presentation was good in both eyes. Fundoscopy showed pigmentary changes and drusen, and investigation using intravenous fundus fluorescein angiography did not demonstrate any choroidal neovascular membrane. The patient subsequently developed renal failure and received a dual renal transplant. The transplanted kidneys also failed over the coming year. The patient’s vision gradually deteriorated and comparison between the images in 2010 and 1985 demonstrated a clear progression of the macula changes. Optical coherence tomography showed multiple subretinal hyper reflective drusenoid deposits. These deposits were also noted to be autofluorescent on blue auto-fluorescence. The young age at presentation of drusen, combined with the history of recurrent kidney failure and progression of subretinal deposits led to a diagnosis of dense deposit disease.ConclusionsDense deposit disease is a rare condition affecting Bruch’s membrane, but should be considered in the differential diagnosis of any patient under the age of 50 years presenting with drusen.

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Section: Discussionsupporting

confidence: 63%

A long history of dense deposit disease

Cunningham

Kotagiri

2018

BMC Ophthalmol

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“…Thus, patients with C3G should be referred to the ophthalmologist, even if they are asymptomatic, in order to be screened for this condition. However, the clinical course of retinal drusen does not appear to correlate with that of renal disease [38].…”

Section: Clinical Presentationmentioning

confidence: 94%

“…In addition to renal manifestations, a number of other extrarenal manifestations have also been associated with C3G. For instance, retinal drusen and atrophy have been described in both DDD and C3GN [38]. Although the underlying pathogenesis is poorly understood, it is believed that complement fragments may accumulate in retinal Bruch's membrane following the same mechanism as that of C3G.…”

Section: Clinical Presentationmentioning

confidence: 99%

Update on C3 Glomerulopathy: A Complement-Mediated Disease

Caravaca-Fontán

Lucientes

Cavero

et al. 2020

Nephron

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C3 glomerulopathy (C3G) is a clinicopathologic entity secondary to dysregulation of the alternative complement pathway in plasma and the glomerular microenvironment. The current consensus definition of C3G relies on immunofluorescence staining criteria. However, due to its high clinical variability, these criteria may not be accurate enough in some clinical scenarios. Thus, a new pathogenic classification based on a cluster analysis of clinical, histologic, and genetic data has recently been proposed, which could also help identify patients at higher risk of progression. Several pathogenic abnormalities in complement genes have been described, and the role of autoantibodies in the disease is increasingly recognized, but still the genotype-phenotype correlations in C3G are poorly understood. C3G may be diagnosed in both children and adults. The spectrum of clinical manifestations is wide, although one of the most common clinical presentations is proteinuria with relatively preserved kidney function. In order to standardize the evaluation of kidney biopsies from these patients, a histopathologic index was recently proposed, including both parameters of activity and chronicity. However, this index has not yet been val-idated in independent cohorts. Currently, no targeted therapies are available in clinical settings for the treatment of C3G, although several new molecules are under investigation. Treatment with corticosteroids plus mycophenolate mofetil has been shown to be associated with improved renal outcomes, as compared to other immunosuppressive regimens. Yet, the main determinants of treatment response with this regimen and the influence of the underlying pathogenic drivers have not been extensively studied. The therapeutic response to eculizumab, an anti-C5 monoclonal antibody, has been shown to be highly heterogeneous. Thus, its current clinical indication in C3G is restricted to rapidly progressive forms of the disease. To summarize, in recent years, several important advances have taken place in the understanding of C3G, but still further studies are warranted to elucidate the best therapeutic strategies that could improve prognosis of this entity.

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“…One offspring has no mutant variant and no haematuria. Filled-in symbols have a clinical phenotype, of at least haematuria deposit disease (haematuria, proteinuria, renal failure, retinal drusen [75]). Renal failure typically develops in the late teenage years.…”

Section: Biallelic and Digenic Mutations Affect The Clinical Phenotypmentioning

confidence: 99%

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

et al. 2018

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Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.

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Retinal disease in the C3 glomerulopathies and the risk of impaired vision

Cited by 30 publications

References 48 publications

A long history of dense deposit disease

A long history of dense deposit disease

Update on C3 Glomerulopathy: A Complement-Mediated Disease

Expert consensus guidelines for the genetic diagnosis of Alport syndrome

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