Juvenile-Onset Diabetes and Congenital Cataract: "Double-Gene" Mutations Mimicking a Syndromic Diabetes Presentation.

Monogenic forms of diabetes may account for 1-5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in CRYBB1, a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the CRYBB1 mutation, and both the mother and one unaffected sibling were heterozygous for the ABCC8 mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of ABCC8 mutations is well documented, but this is the first report of an incomplete penetrance of a CRYBB1 mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity.

[Screening of diabetic retinopathy and maculopathy in Lebanese population using retinography and SD-OCT: The role of telemedicine]. / DÉPISTAGE de la RÉTINOPATHE et de la MACULOPATHIE DIABÉTIQUE au LIBAN par RÉTINOGRAPHIE et par SD-OCT: INTÉRÊT de la TÉLÉMÉDECINE.

PURPOSE: Diabetes and diabetic retinopathy (DR) are nowadays a major public health threat. The aim of this study is the screening of DR and diabetic maculopathy (DM) in a primary medical care center in Lebanon. We study also the interest of retinography and of SD-OCT in a telemedicine screening program. METHODS: This is a transversal study of patients with type 2 diabetes and with a regular follow-up in a primary medical care center in Beirut. For every patient, a retinography and an SD-OCT of the macula were obtained. Photos were sent by Internet to the Ophthalmology Department of Hôtel-Dieu de France to be evaluated by a retina specialist. Visual acuity and DR risk factors were assessed. RESULTS: 119 patients were included in this study. Mean age was 51.7 ± 10.2 years (54 females and 65 males). Mean diabetes duration was 12.15 years (SD 6:2). Mean of last three measurements of glycated hemoglobin was 8.1 ± 1.34%. Diabetic retinopathy was detected in 36 patients by retinography (30.3%). Diabetic maculopathy was confirmed by SD-OCT in 13 patients. Visual acuity was significantly correlated with central macular thickness. Mean diabetes duration, mean of last three measurements of glycated hemoglobin, peripheral neuropathy, positive macroalbuminuria and treatment with insulin were independently associated to diabetic retinopathy. CONCLUSION: Teleophthalmology is an efficient way for screening diabetic retinopathy in the Lebanese population. National screening program should be undertaken to adapt teleophthalmology on a larger scale.

Effect of hemodialysis on visual acuity, intraocular pressure, and macular thickness in patients with chronic kidney disease.

BACKGROUND: The aim of this study was to evaluate the effects of hemodialysis (HD) on visual acuity, intraocular pressure (IOP), and central foveal thickness (CFT) in patients with chronic kidney disease. MATERIALS AND METHODS: Forty-nine eyes from 49 chronic kidney-disease patients were analyzed. Causes of chronic kidney disease included diabetes mellitus (n=9 patients), hypertensive nephrosclerosis (n=15 patients), and other causes (n=25 patients). All patients underwent HD in the Dialysis Unit of Hôtel-Dieu de France Hospital. Best-corrected visual acuity, CFT, and IOP were evaluated before and after HD. CFT was measured with spectral domain optical coherence tomography, and IOP was measured with Goldmann applanation tonometry. RESULTS: Neither decimal best-corrected visual acuity (pre-HD 0.71±0.32, post-HD 0.72±0.31; P=0.877) nor CFT (pre-HD 251.39±39.29, post-HD 253.09±39.26; P=0.272) significantly changed after HD. However, mean IOP significantly decreased from 13.99±2.48 before HD to 12.65±2.41 mmHg after HD (P=0.001). IOP change was significantly correlated with serum albumin levels (P=0.008) and weight changes (P=0.047). CONCLUSION: HD can affect various ocular parameters. This is particularly true of IOP, which decreases significantly following HD.

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient.

Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alström syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alström syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

[Prevalence and risk factors of retinopathy in a young Lebanese population with well controlled type I diabetes]. / Prévalence et facteurs de risque de la rétinopathie dans une jeune population libanaise diabétique de type 1 bien contrôlée.

PURPOSE: To assess the prevalence of diabetic retinopathy (DR) in a young population with type I diabetes in Lebanon, to compare it to its prevalence worldwide according to the literature, and to analyze its potential risk factors. METHODS: Screening for DR by fundus examination was performed in patients > 10 years and diabetic for over 8 years attending the Chronic Care Center (CCC) in Lebanon. Data regarding patients' age, duration of their diabetes, body mass index, systolic and diastolic blood pressure, smoking habits, dyslipidemia, microalbuminuria, mean HbA1c over the past five years, number of insulin injections, parents' educational level and geographical origin, were collected. RESULTS: 220 teenagers and young adults (103 males and 117 females) aged between 12 and 46 years (mean age 24.2 y) were included in the study. The prevalence of DR was 14.6%, comparable to recent studies of similar populations. A non-proliferative DR was found in 25 children (11.4%) and a proliferative DR in 7 patients (3.2%). The mean duration of diabetes was 153 +/- 6.0 y and mean HbA1c 8.0 +/- 1.1%. The prevalenc of DR was not significantly influenced by genders (p = 0.52), smoking habits (p = 0.125), monitoring of blood glucose (p = 0.812), dyslipidemia (p = 0.435), and obesity. However, patients with DR were significantly older than those without DR (p < 0.001), had a longer duration of diabetes (p < 0.001), and higher systolic and diastolic pressures (p < 0.001 and p = 0.01 respectively). The presence of nephropathy was directly correlated with DR (p < 0.001). Finally, the parents' region of origin and educational level were significant risk factors for the presence of DR (p = 0.05 and p < 0.001 respectively). CONCLUSION: The prevalence of DR in young type I diabetic patients followed in the CCC in Lebanon is relatively low and comparable to that published worldwide, with a decrease during the last 25 years, due to a multidisciplinary approach and a centralized control of risk factors.

[Refractive disorders in a group of the Lebanese population of Armenian descent: a pilot study]. / Troubles réfractifs dans un groupe de la population Libanaise d'origine Arménienne: etude pilote.

AIM: To calculate the prevalence of emmetropia, myopia, hyperopia, and amblyopia. METHOD: Cross sectional, descriptive, population-based study, studying 212 randomly selected Lebanese patients of Armenian origin, aged from 15 to 45 years, from June 1st till September 30th 2003. The patients presenting with no exclusion factors are examined, before and after cycloplegia. Mean keratometry and mean ocular axial length are measured for each eye. RESULTS: 212 patients are examined. Mean age is 33.6 years. Sex ratio F/M is 1.94. The prevalence of hyperopia, emmetropia and myopia is 14.6%, 51%, and 34.4% before cycloplegia, and 50%, 16.5% and 33.5% after cycloplegia, respectively. 14.9% of patients wearing myopic corrections were not found myopic after cycloplegia. The prevalence of amblyopia is 19.8%. Most of hyperopic patients do not wear eyeglasses (p = 0.00000101), whereas most of the myopic patients wear eyeglasses (p = 0.00000024). CONCLUSION: Prevalence of hyperopia is very high (50%) in this group of Lebanese Armenian population, as well as amblyopia (19.8%). Moreover, 6.7% of myopic patients wearing eyeglasses are not truly myopic.

WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.

Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.

Ocular findings among thalassemia patients.

PURPOSE: The study aims at studying the ophthalmologic status in a group of thalassemia patients. DESIGN: A cross-sectional study. METHODS: Eighty-four thalassemia patients were randomly selected and underwent an ophthalmologic examination. RESULTS: Visual acuity (VA) was affected in 13 patients and retinal pigment epithelial changes were detected in 21 patients. Decrease in VA was found to be significantly associated with type of thalassemia (P < .05) and having splenectomy (P = .05). Retinal pigment epithelium changes, conversely, were significantly associated with type of iron chelation. CONCLUSIONS: The occurrence of ophthalmologic problems in Lebanese thalassemic patients is common. These patients, especially those with severe anemia, should be screened for such complications. However, the results were not conclusive on whether these complications are attributable to the anemia, the iron overload, or a side effect of the iron chelating agents.