Ophthalmological Features Associated With COL4A1 Mutations

Abstract

To investigate the wide variability of ocular manifestations associated with mutations in the COL4A1 gene that encodes collagen IV␣1. Methods: We clinically evaluated 7 patients from 2 unrelated families in whom ocular features segregated with COL4A1 mutations that were identified by direct sequencing. Results: The G2159A transition (c.2159GϾA) that leads to the missense mutation p.Gly720Asp was identified in family A. An ocular phenotype of variable severity was observed in all affected relatives. The missense mutation c.2263GϾA, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Conclusions: The COL4A1 mutations may be associated with various ophthalmologic developmental anomalies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cerebrovascular disorders should be added to the list of signs potentially associated with ARA. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in the clinical treatment of patients with apparently isolated ARA, even when neurological symptoms or signs are lacking.

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature

“…For this, a PubMed search was performed, identifying 27 articles with clinical and mutation data on COL4A1 7,8,[10][11][12][13][14][15][16][17][18][19][20][21][22][29][30][31][32][33][34][35][36][37][38][39][40] and 3 articles with data on COL4A2 mutations. [26][27][28] A total of 137 individuals with a COL4A1 mutation from 60 families and 15 individuals with a COL4A2 mutation from 7 families have been reported.…”

“…This indicates that brain MRI in patients with Axenfeld Rieger anomaly may provide a clue for the diagnosis of a COL4A1-related disorder. 11,18 HANAC syndrome…”

“…The disorder related to COL4A1 mutations is now known as a systemic disease, including a broad spectrum of cerebrovascular lesions: porencephaly and transmantle lesions, causing hydranencephaly or schizencephaly; lesions of the kidneys, leading to nephrosis and hematuria; lesions of the eyes, causing cataract, microphthalmia, and blindness; lesions of the heart, causing arrhythmia; and lesions of the skeletal muscles, causing dystrophic changes, weakness, and myoglobinuria. [10][11][12][13][14][15][16][17][18][19][20][21][22] COL4A1 and COL4A2 encode proα1(IV) and proα2(IV) chains, respectively, which assemble to form a heterotrimeric helix with a constant 2:1 ratio (proα1(IV)) 2 (proα2 (IV)). This type IV collagen is a component of nonfibrillary collagen, a main constituent of the basement membranes of many tissues, among them vascular endothelia.…”

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

“…[7][8][9][10][11] Eye abnormalities, such as cataract, anterior segment dysgenesis, and retinal tortuosity, were occasionally reported together with the brain defects. [9][10][11][12] Concomitantly, several Col4a1 ENU mutant mice were analyzed, showing severe brain disease and eye alterations similar to the ones observed in patients. 7,[13][14][15] We have characterized a distinct systemic phenotype associated with COL4A1 mutations in six families, which we named hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC).…”

COL4A2 mutation associated with familial porencephaly and small-vessel disease

“…Ocular features can be associated with COL4A1 mutations such as retinal arteriolar tortuosity, ocular cataract, anterior segment dysgenesis and microcornea. 9,[12][13][14][15] Other manifestations are cardiac arrhythmia, renal cysts, haematuria, hepatic cysts, muscle cramps and elevated creatine kinases. The HANAC syndrome (hereditary angiopathy, nephropathy, aneurysms and muscle cramps) has been specifically associated with mutations in exons 24 and 25 of the COL4A1 gene.…”