PURPOSE: Patients with Usher syndrome type I (USH1) have retinitis pigmentosa, profound congenital hearing loss, and vestibular ataxia. This syndrome is currently thought to be associated with at least six genes, which are encoded by over 180 exons. Here, we present the use of state-of-the-art techniques in the molecular diagnosis of a cohort of 47 USH1 probands. METHODS: The cohort was studied with selective exon capture and next-generation sequencing of currently known inherited retinal degeneration genes, comparative genomic hybridization, and Sanger sequencing of new USH1 exons identified by human retinal transcriptome analysis. RESULTS: With this approach, we were able to genetically solve 14 of the 47 probands by confirming the biallelic inheritance of mutations. We detected two likely pathogenic variants in an additional 19 patients, for whom family members were not available for cosegregation analysis to confirm biallelic inheritance. Ten patients, in addition to primary disease-causing mutations, carried rare likely pathogenic USH1 alleles or variants in other genes associated with deaf-blindness, which may influence disease phenotype. Twenty-one of the identified mutations were novel among the 33 definite or likely solved patients. Here, we also present a clinical description of the studied cohort at their initial visits. CONCLUSIONS: We found a remarkable genetic heterogeneity in the studied USH1 cohort with multiplicity of mutations, of which many were novel. No obvious influence of genotype on phenotype was found, possibly due to small sample sizes of the genotypes under study.
PURPOSE: To compare corneal inflammation after syngeneic and allogeneic penetrating keratoplasty (PK) with miniature Keratoprosthesis (m-KPro) implantation in mice. METHODS: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or m-KPro implantation. Corneal inflammation was assessed by determining the frequencies of CD45(+) leukocytes, CD4(+) T cells, CD11b(+) cells, and Gr-1(+) granulocytes/monocytes by flow cytometry at 2, 4, and 8 weeks post transplantation. In addition, expression levels of the proinflammatory cytokines TNF-α and IL-1β were analyzed using real-time qPCR at 8 weeks post transplantation. RESULTS: Cell frequencies in the syngeneic (syn) and allogeneic (allo) m-KPro groups were higher compared with the syngeneic and allogeneic PK groups, respectively, at all time points. However, after week 4, frequencies of all analyzed immune cells were higher in the alloPK group as compared with synKPro group. At 8 weeks, the expression of TNF-α was higher in synKPro, alloPK, and alloKPro groups compared with the naïve and synPK groups. The expression of IL-1β was significantly higher in both KPro groups as compared with PK groups. CONCLUSIONS: Although the m-KPro device augments the inflammatory response in the cornea after its implantation, allogenicity (of the carrier tissue) is also a significant contributor to corneal inflammation. These data suggest that using syngeneic or decellularized corneal tissue as a Boston-KPro carrier could reduce the postoperative inflammation response.
BACKGROUND: Detecting and monitoring optic neuropathy in patients with craniosynostosis is a clinical challenge due to limited cooperation, and subjective measures of visual function. The purpose of this study was to appraise the correlation of peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain ocular coherence tomography (SD-OCT) with indication of optic neuropathy based on fundus examination. METHODS: The medical records of all patients with craniosynostosis presenting for ophthalmic evaluation during 2013 were retrospectively reviewed. The following data were abstracted from the record: diagnosis, historical evidence of elevated intracranial pressure, current ophthalmic evaluation and visual field results, and current peripapillary RNFL thickness. RESULTS: A total of 54 patients were included (mean age, 10.6 years [range, 2.4-33.8 years]). Thirteen (24%) had evidence of optic neuropathy based on current fundus examination. Of these, 10 (77%) demonstrated either peripapillary RNFL elevation and papilledema or depression with optic atrophy. Sensitivity for detecting optic atrophy was 88%; for papilledema, 60%; and for either form of optic neuropathy, 77%. Specificity was 94%, 90%, and 83%, respectively. Kappa agreement was substantial for optic atrophy (κ = 0.73) and moderate for papilledema (κ = 0.39) and for either form of optic neuropathy (κ = 0.54). Logistic regression indicated that peripapillary RNFL thickness was predictive of optic neuropathy (P < 0.001). Multivariable analysis demonstrated that RNFL thickness measurements were more sensitive at detecting optic neuropathy than visual field testing (likelihood ratio = 10.02; P = 0.002). Sensitivity and specificity of logMAR visual acuity in detecting optic neuropathy were 15% and 95%, respectively. CONCLUSIONS: Peripapillary RNFL thickness measured by SD-OCT provides adjunctive evidence for identifying optic neuropathy in patients with craniosynostosis and appears more sensitive at detecting optic atrophy than papilledema.
A rapidly growing, large (horizontal diameter of 3.1 cm) eyebrow lesion in a nonagenarian patient was found on pathologic examination to demonstrate an admixture of islands of anucleated, washed out eosinophilic "ghost" cells with surrounding nucleated, small germinal basaloid cells. Further analysis disclosed adipophilin granular positivity in the necrotic zones, negative nuclear staining for androgen receptor and strong nuclear positivity for Ki67 in the basaloid cells (proliferation index of 50%). These findings are consistent with a highly mitotically active pilomatrixoma. The lesion recurred after initial resection but returned the same histopathologic features as the primary. Several clinical features were notably atypical for pilomatrixoma-specifically, the age of the patient, rapid lesion growth and recurrence, and clinical appearance and large size of the mass. The immunohistochemical findings can help to distinguish this tumor from other skin neoplasms, especially sebaceous carcinoma in an older individual.
Qi Q, Kilpeläinen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, Sonestedt E, Chu AY, Renström F, Lin X, Angquist LH, Huang J, Liu Z, Li Y, Asif Ali M, Xu M, Ahluwalia TS, Boer JMA, Chen P, Daimon M, Eriksson J, Perola M, Friedlander Y, Gao Y-T, Heppe DHM, Holloway JW, Houston DK, Kanoni S, Kim Y-M, Laaksonen MA, Jääskeläinen T, Lee NR, Lehtimäki T, Lemaitre RN, Lu W, Luben RN, Manichaikul A, Männistö S, Marques-Vidal P, Monda KL, Ngwa JS, Perusse L, van Rooij FJA, Xiang Y-B, Wen W, Wojczynski MK, Zhu J, Borecki IB, Bouchard C, Cai Q, Cooper C, Dedoussis GV, Deloukas P, Ferrucci L, Forouhi NG, Hansen T, Christiansen L, Hofman A, Johansson I, Jørgensen T, Karasawa S, Khaw K-T, Kim M-K, Kristiansson K, Li H, Lin X, Liu Y, Lohman KK, Long J, Mikkilä V, Mozaffarian D, North K, Pedersen O, Raitakari O, Rissanen H, Tuomilehto J, van der Schouw YT, Uitterlinden AG, Zillikens CM, Franco OH, Shyong Tai E, Ou Shu X, Siscovick DS, Toft U, Verschuren MWM, Vollenweider P, Wareham NJ, Witteman JCM, Zheng W, Ridker PM, Kang JH, Liang L, Jensen MK, Curhan GC, Pasquale LR, Hunter DJ, Mohlke KL, Uusitupa M, Cupples AL, Rankinen T, Orho-Melander M, Wang T, Chasman DI, Franks PW, Sørensen TIA, Hu FB, Loos RJF, Nettleton JA, Qi L. FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals. Hum Mol Genet 2014;23(25):6961-72.Abstract
FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
Osteogenesis imperfecta comprises a rare group of genetic disorders caused by abnormal collagen that results in increased bone fragility and other sequelae. We describe a 37-year-old woman with osteogenesis imperfecta in whom two full-thickness scleral perforations were created by adjacent teeth of 0.5 mm forceps during traction testing while undergoing routine strabismus surgery. This case reviews the ocular findings of osteogenesis imperfecta and highlights the potential risk of ocular surgical complications in these patients.
Acuity is the most commonly used measure of visual function, and reductions in acuity are associated with most eye diseases. Metamorphopsia-a perceived distortion of visual space-is another common symptom of visual impairment and is currently assessed qualitatively using Amsler (1953) charts. In order to quantify the impact of metamorphopsia on acuity, we measured the effect of physical spatial distortion on letter recognition. Following earlier work showing that letter recognition is tuned to specific spatial frequency (SF) channels, we hypothesized that the effect of distortion might depend on the spatial scale of visual distortion just as it depends on the spatial scale of masking noise. Six normally sighted observers completed a 26 alternate forced choice (AFC) Sloan letter identification task at five different viewing distances, and the letters underwent different levels of spatial distortion. Distortion was controlled using spatially band-pass filtered noise that spatially remapped pixel locations. Noise was varied over five spatial frequencies and five magnitudes. Performance was modeled with logistic regression and worsened linearly with increasing distortion magnitude and decreasing letter size. We found that retinal SF affects distortion at midrange frequencies and can be explained with the tuning of a basic contrast sensitivity function, while object-centered distortion SF follows a similar pattern of letter object recognition sensitivity and is tuned to approximately three cycles per letter (CPL). The interaction between letter size and distortion makes acuity an unreliable outcome for metamorphopsia assessment.
The deterioration of retinal tissue in advanced stages of retinitis pigmentosa and age-related macular degeneration and the lack of signaling cues for laminar regeneration are significant challenges highlighting the need for a tissue-engineering approach to retinal repair. In this study, we fabricated a biodegradable thin-film polycaprolactone (PCL) scaffold with varying surface topographies using microfabrication techniques. Mouse retinal progenitor cells (mRPC) cultured on PCL scaffolds exhibited enhanced potential to differentiate towards a photoreceptor fate in comparison to mRPCs cultured on control substrates, suggesting that PCL scaffolds are promising as substrates to guide differentiation of mRPCs towards a photoreceptor fate in vitro prior to transplantation. When co-cultured with the retinal explants of rhodopsin null mice, mRPC/PCL constructs showed increased mRPC integration rates compared to directly applied dissociated mRPCs. Moreover, these mRPC/PCL constructs could be delivered into the sub-retinal space of rhodopsin null mice with minimal disturbance of the host retina. Whether co-cultured with retinal explants or transplanted into the sub-retinal space, newly integrated mRPCs localized to the outer nuclear layer and expressed appropriate markers of photoreceptor fate. Thus, the PCL scaffold provides a platform to guide differentiation and organized deliver of mRPCs as a practical strategy to repair damaged retina.
We describe 2 patients who developed postoperative orbital cerebrospinal fluid (CSF) collection after orbitozygomatic pterional craniotomy. An 18-year-old woman underwent exploratory pterional-orbitozygomatic craniotomy. Five days postoperatively, after removal of a lumbar drain, proptosis and a compressive optic neuropathy developed. Computed tomography demonstrated a CSF collection contiguous with the craniotomy site. Resolution followed percutaneous aspiration and replacement of the lumbar drain. A 57-year-old woman underwent a pterional-orbitozygomatic craniotomy for removal of a left anterior clinoid meningioma, complicated by a large left hemorrhagic stroke requiring decompressive hemicraniectomy. Extracranial CSF collections accumulated in both the orbit and subgaleal spaces. Resolution followed placement of an external ventricular drain. Based on these cases, the mechanism seems to be the combination of iatrogenic formation of a communication with the subarachnoid space and elevated intracranial pressure. Resolution was achieved by normalizing intracranial pressure.