Clinical Variability of Primary Congenital Glaucoma in a Spanish Family With Cyp1b1 Gene Mutations

Morales-Fernández, Laura; Martinez-de-la-Casa, José M.; García-Bella, Javier; Méndez, Cármen; Saenz-Frances, Federico; Garcia, Maite; Escribano, Julio; García‐Feijoó, Julián

doi:10.1097/ijg.0000000000000067

Cited by 11 publications

(11 citation statements)

References 16 publications

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“…Genotypes of patients PCG 49 and PCG 69 have previously been reported [6, 24]. Three patients had no brother or sister and were the only affected members of their families “Fig 1A”.…”

Section: Resultsmentioning

confidence: 89%

“…Three patients had no brother or sister and were the only affected members of their families “Fig 1A”. Two of the patients were siblings (PCG 49, II:2 and II:4) and belonged to an seven member family with three affected subjects who carried the same genotype but manifested the disease at different ages “Fig 1A”, clearly illustrating the clinical variability present in CYP1B1 -associated glaucoma [24]. Three out of the five cases were compound heterozygotes, one was homozygote, and the last one was a single heterozygote.…”

Section: Resultsmentioning

confidence: 99%

“…Carriers are denoted by black dots in symbols; +: wild-type allele. Genealogy PCG 49 has previously been reported [6, 24] B: Location in the polypeptide chain of the CYP1B1 mutations identified in the probands . Alpha-helix regions are indicated in green and indicated with capital letters (A’-K).…”

Section: Resultsmentioning

confidence: 99%

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Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma

et al. 2017

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Mutations in the CYP1B1 gene are currently the main known genetic cause of primary congenital glaucoma (PCG), a leading cause of blindness in children. Here, we analyze for the first time the CYP1B1 genotype activity and the microscopic and clinical phenotypes in human PCG. Surgical pieces from trabeculectomy from patients with PCG (n = 5) and sclerocorneal rims (n = 3) from cadaver donors were processed for transmission electron microscopy. Patients were classified into three groups depending on goniodysgenesis severity, which was influenced by CYP1B1 enzymatic activity. The main histological changes observed in the outflow pathway of patients with PCG and mutations in CYP1B1 were: i) underdeveloped collector channels and the Schlemm’s canal; ii) abnormal insertion of the ciliary muscle; iii) death of the trabecular endothelial cells. Our findings could be useful in improving treatment strategy of PCG associated with CYP1B1 mutations.

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“…Genotypes of patients PCG 49 and PCG 69 have previously been reported [6, 24]. Three patients had no brother or sister and were the only affected members of their families “Fig 1A”.…”

Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma

et al. 2017

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“…An important subgroup of patients of PCG associated with mutations in the CYP1B1 could have been excluded; these patients have more severe PCG, an earlier age of onset, greater corneal alterations, and comparatively more surgical procedures. 23,24 Our PCG cohort probably consisted of mild-to-moderate glaucoma cases. The average age at diagnosis in the PCG group was almost 2 years (23.24 AE 9.28 months); it is possible that most severe cases, which tend to be diagnosed at younger ages, were excluded, resulting in an underestimation of the difference in RNFL thickness between normal and PCG eyes.…”

Section: Discussionmentioning

confidence: 99%

Retinal nerve fiber layer thickness in children with primary congenital glaucoma measured by spectral domain optical coherence tomography

Perucho-González

Martinez-de-la-Casa

Sáenz-Francés

et al. 2019

Journal of American Association for Pediatric Ophthalmology and

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To evaluate retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography (SD-OCT) in a population of children diagnosed with primary congenital glaucoma (PCG). METHODS In this cross-sectional study, 59 eyes of 59 children diagnosed with PCG and 87 eyes of 87 healthy children were evaluated by SD-OCT to measure the RNFL. The global average peripapillary RNFL thickness and sectional RNFL thickness were evaluated in both groups. Differences in global average and sectional thickness were analyzed. RESULTS Mean age in the PCG group was 9.61 AE 3.23 years; in the control group, 8.47 AE 2.99 years (P 5 0.0516). There were statistically significant differences (P \ 0.007) in all sectors between both groups. CONCLUSIONS SD-OCT is a promising tool for evaluating the eyes of children diagnosed with PCG. Future research should examine the test-retest variability of SD-OCT parameters and their ability to diagnose progression in these children.

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“…Our group has reported that approximately 30% of Spanish PCG patients carry loss-of-function CYP1B1 variants, with most of these variants resulting in null genotypes6. Even among the cases with null enzymatic activity, remarkable phenotypic variation is present6715. These facts, along with the existence of incomplete penetrance and the discovery of a significant proportion of patients who carry non-dominant heterozygous CYP1B1 mutations6, suggest that more than one gene is involved in PCG.…”

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confidence: 97%

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

Ferre-Fernández

Aroca-Aguilar

Medina-Trillo

et al. 2017

Sci Rep

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Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.

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Clinical Variability of Primary Congenital Glaucoma in a Spanish Family With Cyp1b1 Gene Mutations

Abstract: This clinical case reveals the etiological relationship between CYP1B1 mutations and PCG. In addition, it indicates a highly variable clinical picture associated with a single disease genotype mainly affecting disease onset and progression.

Cited by 11 publications

References 16 publications

Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma

Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma

Retinal nerve fiber layer thickness in children with primary congenital glaucoma measured by spectral domain optical coherence tomography

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development

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