Retinal Hypoplasia Research Articles

Novel Heterozygous Missense Variant in GRIA4 Gene Associated With Neurodevelopmental Disorder With or Without Seizures and Gait Abnormalities.

Objective: Neurodevelopmental disorder with or without seizure and gait abnormalities (NEDSGA, MIM * 617864) is a newly described autosomal dominant inherited disease caused by a heterozygous variant in the GRIA4 gene. GRIA4 plays an essential role in excitatory synaptic transmission. In this study, we presented the clinical and genetic features of a female patient carrying a novel de novo variant in GRIA4 and further reviewed the previously reported five different patients. Methods: Evaluation of the patient included a detailed history and clinical examination. Trio-whole exome sequencing (WES) was performed to identify pathogenic variants in NEDSGA. Sanger sequencing was further used to validate the variants. Results: We described the clinical features of an infant diagnosed with NEDSGA caused by a GRIA4 variant, who presented with severe developmental delay, limb hypertonia, generalized seizure, retinal hypoplasia, and chorioretinal hyperpigmentation. The patient developed tricuspid regurgitation, and imaging examination revealed a patent foramen ovale. Trio-WES identified a novel de novo heterozygous missense variant c.1918G>T, p.Ala640Ser in the GRIA4 gene. Multiple in silico tools predicted deleterious effects of p.Ala640Ser. Conclusion: A novel heterozygous missense variant in the GRIA4 gene (c.1918G>T) identified in the proband expanded the genotypic and phenotypic spectrum of disorders associated with GRIA4 variants. This is the first NEDSGA case reported in China. Our findings provide valuable information for the differential diagnosis of neonatal onset neurodevelopmental disorders.

Baraitser–Winter syndrome: An additional Egyptian patient with skeletal anomalies, bilateral iris and choroid colobomas, retinal hypoplasia and hypoplastic scrotum

We report a 3.5year old male child, second in order of birth of non consanguineous Egyptian parents with Baraitser–Winter syndrome (BRWS). The patient had bilateral colobomas of the iris and choroid. Our patient had also retinal hypoplasia, which was not reported previously in this syndrome, bilateral congenital ptosis, hypertelorism, moderate mental retardation, short stature, short neck, hyperextensibility of the joints of the hands, talipes equinovarus, kyphoscoliosis and unilateral hypoplastic scrotum and testis.

Retinal vessel diameters decrease with macular ganglion cell layer thickness in autosomal dominant optic atrophy and in healthy subjects

To investigate retinal trunk vessel diameters in subjects with autosomal dominant optic atrophy (ADOA) and mutation-free healthy relatives. This cross-sectional study included 52 ADOA patients with the optic atrophy 1 (OPA1) exon 28 (c.2826_2836delinsGGATGCTCCA) mutation (age 8.6-83.5 years) (best-corrected visual acuity (BCVA) 8-94 Early Treatment Diabetic Retinopathy Study (ETDRS) letters) and 55 mutation-free first-degree healthy relatives (age 8.9-68.7 years, BCVA 80-99). Analysis of fundus photographs provided integrated magnification-corrected measures of retinal vessel diameters (central retinal artery equivalent, CRAE, and central retinal vein equivalent, CRVE). Statistical analysis was corrected for age, gender, spherical equivalent refraction, axial length and mean arterial blood pressure (MABP) in a mixed model analysis. Retinal arteries and veins were thinner in ADOA than in healthy controls (CRAE (mean ± 2 standard deviations (SD)) 153.9 ± 41.0 μm and CRVE 236.1 ± 42.0 μm in ADOA, CRAE 172.5 ± 25.0 μm (p = 0.0004) and CRVE 254.2 ± 37.6 μm (p = 0.0019) in healthy controls). MABP was comparable in the two groups (p = 0.18), and in both groups, CRAE decreased with increasing MABP (p = 0.01 and p < 0.0001, respectively). In ADOA, CRAE and CRVE decreased with age (p = 0.011 and p = 0.020, respectively) and CRAE decreased with decreasing BCVA (p = 0.011). In patients with ADOA and in healthy controls, CRAE decreased with decreasing average macular ganglion cell-inner plexiform layer (GC-IPL) thickness (p = 0.0017 and p = 0.0057, respectively). Narrow retinal arteries and veins were associated not only with the severity of ADOA but with ganglion cell volume in patients with ADOA and in healthy subjects. This suggests that narrow vessels are a consequence rather than the cause of inner retinal hypoplasia or atrophy, although longitudinal studies are needed to confirm this hypothesis.

Diagnosing papillorenal syndrome: see the optic papilla

Sirs, In their article “A clinico-genetic study of renal coloboma syndrome in children”, Cheong and colleagues accurately point out that a variety of PAX2 mutations, one of which they had discovered, can cause the described phenotype of associated ocular, renal and urinary tract anomalies seen in this autosomal dominant condition [1]. However, it should also be noted that many patients with the “renal coloboma” disorder do not have any identifiable mutations in the PAX2 gene [2, 3]. The syndrome is not defined by PAX2 genetic analysis, but by clinical findings. Cheong and co-workers employed the syndrome’s older “renal-coloboma” nomenclature [1] as opposed to the subsequent “papillorenal” designation. Precise language is important in this case, since confusion created by the term “coloboma” has led many investigators to consider incomplete closure of the embryonic optic fissure to be the cause of an optic nerve anomaly in cases where there is no supportive evidence for such an etiology [2]. Accordingly, the preferred OMIM appellation now is “papillorenal syndrome” [4] (OMIM #120330). It should be noted that the prefix “papillo” indicates the optic papilla as the site of the ocular abnormality and not that of the renal papillae. While the term “papillorenal” is also not fully descriptive of all the possible associated ocular or urinary tract anomalies (such as vesicoureteral reflux), it avoids the misnomer of “coloboma” and implications, thereof, of an unrelated pathophysiologic pathway. Cheong et al. correctly emphasize that there is considerable variability of ocular and urinary tract findings [1]. Among that variability, however, one constant feature exists and is clearly visible in the ocular fundus photographs they published: the lack of central retinal blood supply. Instead of central vessels within the optic papilla, the disc is variably excavated centrally; the cilioretinal vessels originate outside and at the periphery of the optic nerve supplying the retina (“vacant discs”). These disc vessels circumferentially make hairpin turns over the neuroretinal rim toward the retina. Though often asymptomatic, the absence of central retinal vasculature can be associated with retinal hypoplasia, causing visual field defects. In some instances, this can lead to secondary serous retinal detachments [5] which, if occurring early in development, can lead to relative microphthalmia. This bilaterally visible vascular anomaly of the optic papilla testifies to a systemically deficient process of angiogenesis (as opposed to vasculogenesis) [6]. Angiogenesis is most critical to the development of both eye and kidney, the most perfused tissues per gram weight of the human body. Angiogenic factors are involved in the budding of vascular endothelial cells from pre-existing vessels laid down by vasculogenesis [6]. These same factors also affect the budding of other tubular structures Pediatr Nephrol (2008) 23:1893–1894 DOI 10.1007/s00467-008-0870-6

Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes.

Phosphorylation of proteins on serine/threonine residues preceding proline is a key signaling mechanism. The conformation and function of a subset of these phosphorylated proteins is regulated by the prolyl isomerase Pin1 through isomerization of phosphorylated Ser/Thr-Pro bonds. Although young Pin1(-/-) mice have been previously shown to develop normally, we show here that they displayed a range of cell-proliferative abnormalities, including decreased body weight and testicular and retinal atrophies. Furthermore, in Pin1(-/-) adult females, the breast epithelial compartment failed to undergo the massive proliferative changes associated with pregnancy. Interestingly, many of these Pin1-deficient phenotypes such as retinal hypoplasia and mammary gland impairment are also the characteristic of cyclin D1-deficient mice. Cyclin D1 levels were significantly reduced in many tissues in Pin1-deficient mice, including retina and breast epithelial cells from pregnant mice. Moreover, Pin1 directly bound to cyclin D1 phosphorylated on Thr-286-Pro increased cyclin D1 in the nucleus and stabilized cyclin D1. These results indicate that Pin1 positively regulates cyclin D1 function at the transcriptional level, as demonstrated previously, and also through posttranslational stabilization, which together explain why Pin1 loss-of-function phenotypes in the mouse resemble cyclin D1-null phenotypes. Our results provide genetic evidence for an essential role of Pin1 in maintaining cell proliferation and regulating cyclin D1 function.

Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice.

The cell cycle of cultured cells appears to be regulated by opposing actions of the cyclins together with their partners, the cyclin-dependent kinases (Cdk), and their inhibitors (Cki). Consistent with this situation null mutations in the genes for cyclin D1 and Cki p27(Kip1) in mice give opposite phenotypes of dwarfism and gigantism. To test their genetic interactions, we generated mice nullizygous for both genes. Correction of cyclin D1 or p27 null to wild-type phenotypes was observed for many but not all traits. These included, for cyclin D1(-/-) mice, body weight, early lethality, retinal hypoplasia, and male aggressiveness and, for p27(-/-) mice, body weight, retinal hyperplasia, and embryo implantation. p27(-/-) traits that were not corrected were the aberrant estrus cycles, luteal cell proliferation, and susceptibility to pituitary tumors. This mutual correction of these phenotypes is the first genetic demonstration of the interaction of these inhibitory and stimulatory cell cycle-regulatory molecules in vivo. The molecular basis for the correction was analyzed in the neonatal retina. Retinal cellularity was rescued in the cyclin D1 null mouse by loss of p27 with only a partial restoration of phosphorylation of retinoblastoma protein (Rb) and Cdk4 activity but with a dramatic elevation of Cdk2 activity. Our data provide in vivo genetic validation of cell culture experiments that indicated that p27 acts as a negative regulator of cyclin E-Cdk2 activity and that it can be titrated away by cyclin D-Cdk4 complexes. It also supports the suggestion that the cyclin E/Cdk2 pathway can largely bypass Rb in regulating the cell cycle in vivo.

Aniridia: recent achievements in paediatric practice.

Aniridia is a rare panocular disorder which primarily involves not only the iris, but also the retina, optic nerve, lens and cornea. Visual acuity deteriorates as a result of nystagmus, glaucoma, cataract, corneal opacities and retinal hypoplasia. Aniridia may appear as an isolated disorder, most often familial with autosomal dominance or sporadically in association with at least 12 syndromes. Both familial isolated and Wilms tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation syndrome-associated aniridia have been traced to a mutation of the PAX6 gene on band 11p13. Since genetic diagnosis of this disorder is already possible, counselling affected families should be preceded by karyotype studies and linkage analysis in familial cases of isolated aniridia. In sporadic cases of isolated aniridia or WAGR syndrome, we suggest that PAX6 mutation analysis be employed.

Juvenile Nephronophthisis, Congenital Hepatic Fibrosis and Retinal Hypoplasia in Twins

Juvenile nephronophthisis has been recognized recently as an important cause of chronic renal failure in childhood and adolescence. This report describes clinical and morphological findings in monozygotic twins in whom the triad of juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia coexisted. The findings are discussed in relation to previous reports of nephronophthisis associated with either retinal abnormalities or congenital hepatic fibrosis. The occurrence of similar ocular and hepatic anomalies with the other cystic kidney diseases, polycystic disease and medullary sponge kidney disease is reviewed. A spectrum of oculo-hepato-renal syndromes is identified with many interrelated features which suggest a shared basic aetiology.