Novel crystallin gamma B mutations in a Kuwaiti family with autosomal dominant congenital cataracts reveal genetic and clinical heterogeneity.

PURPOSE: To explore the disease locus and causative mutation for autosomal dominant congenital cataracts (ADCC) in a Kuwaiti family. There were seven affected and three unaffected subjects in the family. METHODS: Whole-genome linkage analysis was performed using Gene Chip Human Mapping 250 K Arrays to identify regions of linkage. Potential genes within this region were cloned and sequenced to identify the disease-causing mutation. RESULTS: The highest logarithm of odds score (1.5) region 2q34-36.1, spanning the crystallin beta A2 (CRYBA2) gene, showed no sequence changes. Thus, the second highest logarithm of odds score (1.49) region, 2q33-37, spanning the gamma crystalline gene cluster (CRYG), was considered. Sequencing of the CRYGA, B, C, and D genes revealed two novel heterozygous deletions and one trinucleotide polymorphism in the CRYGB gene. These mutations included a heterozygous g.67delG, intron 1 deletion in four of the affected family members with lamellar cataracts and a heterozygous g.167delC, exon 2 deletion inherited from the Egyptian grandmother by her granddaughter, resulting in anterior polar cataracts. Another patient with complete cataracts was a compound heterozygote with both of the above-mentioned mutations. In addition, the novel trinucleotide polymorphism g.20-22 GGT>AAA was detected in three of the family members. CONCLUSIONS: We report the linkage of ADCC to chromosome 2q33-37, which spans the CRYGB gene. This study is the first to report complex heterogeneous mutations in the CRYGB gene resulting in ADCC with three distinct phenotypes (lamellar, anterior polar, and complete cataracts) in the same family.

Molecular and clinical evaluation of primary congenital glaucoma in Kuwait.

PURPOSE: To report the spectrum of the CYP1B1 mutation in Kuwaiti patients with primary congenital glaucoma (PCG). DESIGN: Clinical diagnosis of PCG and laboratory based experimental study. METHODS: Polymerase chain reaction-restriction polymorphism length fragment (PCR-RPLF) and direct sequencing of exon 2 and the coding region of exon 3 of CYP1B1 gene were the methods used for screening 17 PCG patients, their families, and 105 health individuals from the same ethnicity. RESULTS: Four different mutations were detected in CYP1B1 in 70.6% of the screened patients. The most common one (47%) was homozygote Gly61Glu mutation, previously described in Saudi Arabia, Turkey, and Morocco; all patients were products of consanguineous marriages. The second common mutation was a novel missense (Ala388Thr) mutation found in three patients (17.6%) as compound heterozygote with Arg368His in one patient, and with Gly61Glu in another one while the second mutation in third patient was not detected in the CYP1B1 gene. One patient (5.8%) was homozygote for Cyt280X mutation previously reported in only one Japanese family. In addition to these mutations, a novel Val422Gly polymorphic site was found in three of the PCG patients and in 18 of the 210 tested chromosomes of healthy volunteers. CONCLUSIONS: The CYP1B1 mutation spectrum of Kuwaiti PCG patients is similar to that detected in the neighboring countries. No clear genotype-phenotype correlation detected in patients showed different types of CYP1B1 mutation.

Cataract and ocular hypertension in children on inhaled corticosteroid therapy.

PURPOSE: To ascertain the incidence of posterior subcapsular cataract and ocular hypertension in a cohort of children < or = 12 years on inhaled steroid therapy. PATIENTS AND METHODS: In this prospective study, a detailed history regarding corticosteroid therapy was obtained for children attending an asthma clinic. The presence and type of lens changes (cataract) was recorded and intraocular pressure (IOP) was measured. The children underwent another eye examination 2 years later. RESULTS: Ninety-five patients were enrolled in the study. Mean patient age was 7 +/- 3 years, and mean duration of inhaled steroid therapy was 2 +/- 1 years. Thirty-six percent of patients received inhaled steroids exclusively, 61% received inhaled steroids with a short course of oral steroids, and 3% received inhaled steroids with a long course of oral steroids. Only 3 (3%) patients had cortical changes that were not visually significant, and none had posterior subcapsular or nuclear cataract. There was no significant differences between children with cataract and those without cataract with respect to age; duration of asthma; and duration, average daily dose, and cumulative dose of inhaled steroids. IOP ranged from 11 to 20 mm Hg (mean, 16 +/- 3 mm Hg). None of the children had ocular hypertension or glaucoma. Ninety patients underwent eye examination 2 years later; none was found to develop posterior subcapsular cataract or increased IOP. CONCLUSION: This study indicates the use of inhaled steroids in children with asthma is probably safe as far as not inducing posterior subcapsular cataract or ocular hypertension.

Ophthalmic assessment of children before renal transplantation.

OBJECTIVE: To evaluate the usefulness of routine ophthalmic examination before renal transplantation in children. METHODS: We reviewed the records of ophthalmic assessments of renal transplant recipients at The Hospital for Sick Children, Toronto, Ont., from January 1989 to June 1996. If abnormalities had been found, we determined whether they had previously been documented, were related to the renal disease or other systemic disease, had required intervention or had affected visual function. We calculated the maximum statistical chance of detecting a meaningful eye problem at the pretransplantation assessment. We also estimated the direct cost of the ophthalmic assessment and the effect, if any, of the findings on the patient's medical management. RESULTS: We included 107 charts. Before the ophthalmic assessment, 32 patients (30%) had known eye problems. The ocular examination detected abnormalities in 46 patients (43%); the abnormalities had not been detected previously in 14 (13%). New, potentially vision-threatening eye disorders were found in 6 (6%) of the patients. No finding affected the short- or long-term management of any patient. CONCLUSION: Children with chronic renal failure had a high prevalence of ocular abnormalities, but most of the abnormalities did not affect visual function. Although ophthalmic assessment before transplantation did not alter the medical management of the renal transplant patients, consultation may be helpful in selected patients, particularly those who are not already under the care of an optometrist or ophthalmologist and those who have a visual complaint.

The outcome of congenital cataract surgery in Kuwait.

AIM: Congenital cataract is the most common cause of treatable blindness in children and the outcome of congenital cataract surgery has not been studied in Kuwait, so the purpose of this study is to evaluate the visual outcome and the postoperative complications. METHODS: Medical records of children who underwent congenital cataract surgery between September 2000 and December 2008 at Al-Bahar Eye Center, Ministry of Health of Kuwait were retrospectively reviewed. In 100 eyes that fill the inclusion criteria visual acuity and postoperative complications were recorded. The mean follow up was 3.9 ± 1.7 years with range from 3 to 6 years. RESULTS: The mean age of congenital/developmental cataract surgery is 8.9 ± 8.7 months for bilateral cases and it was 5.75 ± 4.61 months for unilateral cases. The mean final postoperative BCVA in unilateral cases was 1.0 (20/200) log MAR unit and it was 0.3 (20/40) log MAR unit for the bilateral cases. Four percent of the cases developed postoperative glaucoma and 2% of them developed significant opacification of the posterior capsule. CONCLUSION: Our findings provide evidence of recent improvement over time in the visual prognosis in bilateral, and to a lesser degree, unilateral cataract, in children in Kuwait.

Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.

The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis. TDRD7 is a Tudor domain RNA binding protein that is expressed in lens fiber cells in distinct TDRD7-RGs that interact with STAU1-ribonucleoproteins (RNPs). TDRD7 coimmunoprecipitates with specific lens messenger RNAs (mRNAs) and is required for the posttranscriptional control of mRNAs that are critical to normal lens development and to RG function. These findings demonstrate a role for RGs in vertebrate organogenesis.