Rubeosis iridis in "pseudogliomas"

A total of 85 eyes (75 patients) with pseudogliomas (i.e., certain conditions which simulate retinoblastoma, were examined histopathologically to determine the incidence of rubeosis iridis. Neovascularization of the anterior surface of the iris was found in 70 eyes (82%). The principal associated changes in these eyes were moderate to severe inflammation of the uveal tract and retinal detachment. These findings are interpreted as indicating that inflammation, retinal detachment, and/or ischemia are effective stimulants in producing iris neovascularization, and rubeosis is not a significant factor in differentiating eyes with retinoblastoma from those eyes with pseudogliomas.     

Congenital Bilateral Retinal Detachment in Two Siblings with Osteoporosis-Pseudoglioma Syndrome

The birth of a bilaterally blind child is catastrophic for families and a challenging diagnostic and management problem for ophthalmologists. Early identification of the underlying cause and its genetic basis helps initiate possible treatment, delineate prognosis, and identify risks for future pregnancies. In some cases, an early diagnosis can also influence the treatment of other family members. We report two sisters with bilateral retinal detachment and retro-lental masses from birth with no detectable NDP or FZD4 mutations. They were born to parents without detectable retinal anomalies. At 1 year of age, the elder sister had low impact bone fractures, and further evaluation identified severe osteopenia and multiple spinal compression fractures. Molecular testing identified biallelic lipoprotein receptor-related protein 5 (LRP5) mutations (NM_002335.3:c. [889dupA]; [2827?+?1G?>?A]) confirming a diagnosis of osteoporosis–pseudoglioma (OPPG) syndrome. After this diagnosis, the father and mother were found to have low bone mass and the father started on therapy. We conclude that early detection of LRP5 mutations is important for initiation of treatment of reduced bone density in the patients and their carrier relatives.     

Associations in clinical genetics with a comment on the paper by Evans et al on tracheal agenesis

We report on a sibship with one brother and two MZ twin sisters affected with osteoporosis-pseudoglioma syndrome. An analysis of the present and literature data showed that vitreoretinal dysplasia or phthisis bulbi and X-ray evidence of osteoporosis must be considered minimal diagnostic criteria. Mental retardation, ligamentous laxity, and other reported anomalies are highly variable manifestations in the syndrome. Segregation analysis confirmed autosomal recessive transmission. The geographic origin of reported families suggests a higher gene frequency in Mediterranean countries.     

X-Linked recessive primary retinal dysplasia: clinical findings in affected males and carrier females

Three unrelated families (two Jewish and one Druze) are reported, in which a total of eight males exhibited the ophthalmological findings of primary retinal dysplasia. Since our affected male members only have eye findings, this disorder is readily differentiated from Nome's disease in which other parts of the nervous system are involved. The family pedigrees along with the clinical features support an X-linked recessive mode of transmission for this condition. Female carriers for this gene may show varying types of retinal fold changes. In addition, most of these same presumed female carriers also demonstrated changes in the stroma of their irides, resulting in a gray to grayish-blue color. At present, it is not possible to state definitely whether or not this latter observation is a feature of the carrier state.     

A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family

AIM:To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND).METHODS:Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken.RESULTS:Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids.CONCLUSION:A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation.     

A novel c.240_241insGG mutation in NDP gene in a family with Norrie disease

Background

Norrie disease (ND) is a rare, X‐linked recessive disorder with the main characteristic of early childhood blindness. The aim of the present study was to identify the genetic cause of the disease and the phenotypic characteristics of the patients in an Iranian family with four affected males with ND.

Methods

Norrie disease pseudoglioma (NDP) gene was sequenced and clinical examination was performed on patients.

Results

A GG dinucleotide insertion in exon 3 (c.240_241insGG) of NDP was detected in all patients. The mutation caused a frameshift and an early stop codon (p.Phe81Glyfs*23).

Conclusions

A novel mutation was found in the NDP gene in the affected males of the family. As the mutation was absent in the normal male members of the family, it should be the genetic cause of the disease.

     

A mutation in the signal sequence of LRP5 in a family with an osteoporosis‐pseudoglioma syndrome (OPPG)‐like phenotype indicates a novel disease mechanism for trinucleotide repeats

We extend the spectrum of phenotypes caused by mutations in the Wnt/Norrin coreceptor low‐density lipoprotein receptor‐related protein 5 (LRP5) by identifying two novel types of mutation in related individuals whose presenting features were profound muscle hypotonia, mild mental retardation, blindness, and growth retardation. One mutation removes 6 out of 9 consecutive leucine residues in the LRP5 signal peptide (c.43_60del or p.Leu15_Leu20del), which impairs polypeptide entry into the endoplasmic reticulum (ER), trafficking to the cell membrane, and signal transduction. The second mutation resulted from nonhomologous recombination between Alu repeat sequences, which deleted exons 14–16 and would produce a nonfunctional, truncated, and frameshifted polypeptide, if expressed [chr11:g.(13871447_1387511)_(13879636_13879700)del (NW_925106.1) or p.Pro1010GlnfsX38]. We confirmed that the length of the LRP5 signal peptide poly‐leucine repeat is polymorphic in the general population, and, importantly, we were able to demonstrate in independent in vitro assays that different allele sizes affect receptor processing and signal transduction. Consequently, this polymorphism may have physiologic effects in vivo. This latter finding is relevant since through a genomewide search we identified nearly 400 human proteins that contain poly‐leucine repeats within their signal peptide. We chose 18 of these proteins and genotyped the underlying trinucleotide repeat in healthy Caucasian individuals. More than one length allele was observed in one‐half of the proteins. We therefore propose that natural variation in poly‐leucine‐stretches within signal peptides constitutes a currently unrecognized source of variability in protein translation and expression. Hum Mutat 0, 1–8, 2009. © 2009 Wiley‐Liss, Inc.     

OPS候选基因区域物理图和基因图构建

目的 :构建骨质疏松 假性神经性胶质瘤综合征 (Osteoporosis pseudogliomasyndrome,OPS)致病基因候选区域的物理图和基因图。方法 :利用NCBI中的同源性比较工具BLAST在htgs和nr等数据库 ,采用计算机杂交技术 ,筛选含有与OPS紧密连锁的多态位点的基因组克隆 ,构建该区的物理图。据此从位于该区的基因组克隆中筛选EST ,再用EST筛选已知基因 ,建立该区的基因图。结果 :筛选到 9个含有与OPS紧密连锁的多态位点的基因组克隆和一个已知基因。结论 :成功构建了OPS候选区域物理图 ,并筛选到LRP5这一已知基因。     

Retinal dysplasia

Retinal dysplasia is defined as an abnormal growth and differentiation of embryonic retina being more a secondary lesion rather than a disease. Clinically, the disorder may present itself in a surprisingly wide range of severity or of degree from retinal folds to vascularized masses in the vitreous cavity. The condition may appear monosymptomatically, involving only the eye, or as complex disorders with multisystemic anomalies. The histopathologic findings in this disorder recognize characteristic structural deviations of the retina and the pathogenesis seems to be related to the lack of the normal histogenesis of the pigment epithelium. Impaired genetic mechanisms seem to contribute to the etiology of some forms of retinal dysplasia.     

纯合子定位法在骨质疏松-假性神经胶质瘤综合征精确定位中的应用

目的：探讨纯合子定位法在罕见常染色体隐性遗传病致病基因精确定位中的作用。方法：采用聚合酶链反应扩增简单序列长度多态方法，在8个骨质疏松－假性神经胶质瘤综合征（osteoporosispseudoglioma syndrome,OPS)患者家系中对OPS侯选区的14个多态位点进行基因型分析，通过纯合子分析对OPS致病基因进行精确定位。结果：将OPS致病候选区域确定在D11S1296和D11S4136之间，该区域约为1cM。结论：纯合子定位法在罕见常染色体隐性遗传病基因定位和缩小的致病基因候选区域有重要作用。