Older Age is Associated With Positional Obstructive Sleep Apnea.

OBJECTIVES: Untreated obstructive sleep apnea (OSA) is associated with cognitive dysfunction; however studies report low adherence rates to standard continuous positive airway pressure (CPAP) treatment in the elderly. Positional OSA (p-OSA) is a subset that can be cured by positional therapy of avoiding supine sleep. However, there is no well-established criteria to identify patients who could benefit from positional therapy as an alternative or adjunct to CPAP. This study investigates if older age is related to p-OSA using different diagnostic criteria. DESIGN: Cross-sectional study. PARTICIPANTS: Participants aged 18 years old or more who underwent polysomnography for clinical reasons at University of Iowa Hospitals and Clinics over a 1-year period from July 2011 to June 2012 were enrolled retrospectively. MEASUREMENT: P-OSA was defined as a high supine-position dependency of obstructive breathing events with potential resolution of OSA in nonsupine positions [high apnea-hypopnea index on supine positions (s-AHI)/ AHI on nonsupine positions (ns0AHI) combined with ns-AHI < 5/hour]. Different cutoff points (2, 3, 5, 10, 15, 20) were applied to determine a meaningful ratio of supine-position dependency of obstructions [s-AHI/ns-AHI]. We compared the proportion of patients with p-OSA between the older age group (≥65 years old) and the propensity score (PS)-matched (upto 1:4) younger age group (<65 years old) using logistic regression analyses. RESULTS: In total, 346 participants were included. The older age group had a higher s-AHI/ns-AHI ratio than the younger age group (mean 31.6 [SD 66.2] versus 9.3 [SD 17.4], median 7.3 [interquartile range [IQR], 3.0-29.6) versus 4.1 (IQR, 1.9-8.7). After PS-matching, the older age group (n = 44) had higher proportion of those with a high s-AHI/ns-AHI ratio and ns-AHI< 5/hour compared with the younger age group (n = 164). (s-AHI/ns-AHI≥10: 54.6% versus 31.7%, OR 2.44 (95% CI, 1.22-4.90); s-AHI/ns-AHI≥15: 47.7% versus 26.2%, OR 2.24 (95% CI, 1.14-4.37); s-AHI/ns-AHI≥20: 40.9% versus 19.5%, OR 2.52 (95% CI, 1.22-5.20)) CONCLUSION: Older patients with OSA are more likely to have severe position dependent OSA, that is potentially more treatable with positional therapy. Thus, clinicians treating older, cognitively impaired geriatric patients unable to tolerate CPAP therapy should consider positional therapy as an adjunct or alternative.

Variant lattice corneal dystrophy associated with compound heterozygous mutations in the TGFBI gene.

BACKGROUND/AIMS: To report the clinical, histopathological and genetic features of a variant of lattice corneal dystrophy (LCD) associated with two pathogenic mutations in the transforming growth factor-B-induced (TGFBI) gene. METHODS: Clinical characterisation was performed by slit lamp examination and in vivo confocal microscopic imaging (IVCM). Histopathological characterisation was performed with light microscopic examination of an excised corneal button and a peripheral blood samples were collected for TGFBI screening. RESULTS: A 42-year-old woman presented with progressive photophobia and decreased visual acuity in both eyes. Slit lamp examination demonstrated punctate and linear branching opacities in the mid and posterior corneal stroma, corresponding to hyper-reflective opacities noted on IVCM and amyloid deposition noted on histopathological examination of an excised corneal button. TGFBI screening revealed two previously reported heterozygous missense mutations: c.337G>A (p.(Val113Ile)) in exon 4 and c.1673T>C (p.(Leu558Pro)) in exon 12. Screening of an affected sibling with a similar phenotype revealed that she was also heterozygous for both mutations, while screening of another sibling with punctate but not linear stromal opacities revealed that she was heterozygous for only the p.(Leu558Pro) mutation. CONCLUSIONS: The p.(Val113Ile) mutation results in an alteration of the atypical LCD phenotype associated with the p.(Leu558Pro) mutation. This represents only the second report of the alteration of the phenotype of a TGFBI dystrophy by a second, non-homozygous pathogenic mutation, and thus provides insight into the phenotype-genotype correlation of the TGFBI dystrophies.

Functional impact of ZEB1 mutations associated with posterior polymorphous and Fuchs' endothelial corneal dystrophies.

PURPOSE: To assess the impact of zinc finger E-box binding homeobox 1 (ZEB1) gene mutations associated with posterior polymorphous corneal dystrophy 3 (PPCD3) and Fuchs' endothelial corneal dystrophy (FECD). METHODS: Thirteen of the 27 previously reported ZEB1 truncating mutations associated with PPCD3 and the six previously reported ZEB1 missense mutations associated with FECD were generated and transiently transfected into a corneal endothelial cell line. Protein abundance was determined by immunoblotting, while intracellular localization was determined by fluorescence confocal microscopy. RESULTS: Three of the 13 ZEB1 truncated mutants, and none of the missense mutants, showed significant decrease in mutant ZEB1 protein levels. Predominant nuclear localization was observed for truncated ZEB1 mutant proteins with a predicted molecular weight of less than 92 kilodaltons. The two largest mutant proteins that lacked a putative nuclear localization signal (NLS), p.(Ser638Cysfs*5) and p.(Gln884Argfs*37), primarily localized to the cytoplasm, while the NLS-containing mutant proteins, p.(Glu997Alafs*7) and p.(Glu1039Glyfs*6), primarily localized to the nucleus. All the missense ZEB1 mutant proteins were exclusively present in the nucleus. CONCLUSIONS: ZEB1 truncating mutations result in a significant decrease and/or impaired nuclear localization of the encoded protein, indicating that ZEB1 haploinsufficiency in PPCD3 may result from decreased protein production and/or impaired cellular localization. Conversely, as the reported ZEB1 missense mutations do not significantly impact protein abundance or nuclear localization, the effect of these mutations on ZEB1 function and their relationship to FECD, if any, remain to be elucidated.

Classification of posterior polymorphous corneal dystrophy as a corneal ectatic disorder following confirmation of associated significant corneal steepening.

IMPORTANCE: The identification of steep corneal curvatures in a significant percentage of patients with posterior polymorphous corneal dystrophy (PPCD) confirms this previously reported association and suggests a role for the ZEB1 protein in keratocyte function. OBJECTIVE: To determine whether PPCD is characterized by significant corneal steepening. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at university-based and private ophthalmology practices of 38 individuals (27 affected and 11 unaffected) from 23 families with PPCD. EXPOSURE: Slitlamp examination and corneal topographic imaging were performed for individuals with PPCD and unaffected family members. Saliva or blood samples were obtained from each individual for DNA isolation and ZEB1 sequencing. Corneal ZEB1 expression was measured using immunohistochemistry. MAIN OUTCOMES AND MEASURES: Percentage of individuals affected with PPCD and controls with an average keratometric value greater than 48.0 diopters (D) in each eye; the mean keratometric value averaged for both eyes of individuals with PPCD and controls; and the correlation of ZEB1 mutation with keratometric value. RESULTS: ZEB1 coding region mutations were identified in 7 of the 27 affected individuals. Ten of the 38 individuals (26.3%) had average keratometric values greater than 48.0 D OU: 10 of 27 individuals with PPCD (37.0%; 6 of 7 individuals with ZEB1 mutations [85.7%] and 4 of 20 individuals without ZEB1 mutations [20.0%]) and 0 of 11 unaffected individuals (P = .04 for unaffected vs affected individuals; P = .004 for individuals with PPCD with vs without ZEB1 mutation). The mean keratometric value of each eye of affected individuals (48.2 D) was significantly greater than that of each eye of unaffected family members (44.1 D) (P = .03). Affected individuals with ZEB1 mutations demonstrated a mean keratometric value of 53.3 D, which was significantly greater than that of affected individuals without ZEB1 mutations (46.5 D; P = .004). Fluorescence immunohistochemistry demonstrated ZEB1 expression in keratocyte nuclei. CONCLUSIONS AND RELEVANCE: Abnormally steep corneal curvatures are identified in 37% of all individuals with PPCD and 86% of affected individuals with PPCD secondary to ZEB1 mutations. ZEB1 is present in keratocyte nuclei, suggesting a role for ZEB1 in keratocyte function. Therefore, ZEB1 may play a role in both corneal stromal and endothelial development and function, and PPCD should be considered both an endothelial dystrophy and an ectatic disorder.