Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. © 2012 Wiley Periodicals, Inc.

Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case-control study.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and C-reactive protein (CRP) may be positively associated with the risk of epithelial ovarian cancer (EOC) but no previous studies have investigated their associations with non-epithelial ovarian cancers (NEOC). METHODS: A case-control study was nested within the Finnish Maternity Cohort. Case subjects were 58 women diagnosed with sex cord-stromal tumors (SCST) and 30 with germ cell tumors (GCT) after recruitment. Control subjects (144 for SCST and 74 for GCT) were matched for age, parity, and date of blood donation of the index case. RESULTS: Doubling of IGF-I concentration was not related to maternal risk of either SCST (OR 0.97, 95% CI 0.58-1.62) or GCT (OR 1.13, 95% CI 0.51-2.51). Similarly, doubling of CRP concentrations was not related to maternal risk of either SCST (OR 1.10, 95% CI 0.85-1.43) or GCT (OR 0.93, 95% CI 0.68-1.28). CONCLUSIONS: Pre-diagnostic IGF-I and CRP concentrations during the first trimester of pregnancy were not associated with increased risk of NEOC in the mother. Risk factors for NEOC may differ from those of EOC.

Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the β-isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.

Extrapleural Pneumonectomy With Venous Confluence Resection for Stage IVA Thymic Tumors.

We report 4 patients with stage IVA thymic tumors who underwent extrapleural pneumonectomy and thymectomy with venous confluence resection using a temporary percutaneous venous jugular-femoral bypass technique. The superior vena cava was replaced in 2 patients, and the innominate vein was resected in 2 patients. Complete tumor resection was obtained in all patients. There was no 90-day postoperative mortality. One patient died at 6 months postoperatively of an unrelated cause, without recurrent disease, and 3 are alive and disease-free with a follow-up ranging from 19 to 80 months. Extrapleural pneumonectomy can be combined with thymectomy and venous confluence resection for stage IVA thymic tumors.

Essential role for Pbx1 in corneal morphogenesis.

PURPOSE: The Pbx TALE (three-amino-acid loop extension) homeodomain proteins interact with class 1 Hox proteins, which are master regulators of cell fate decisions. This study was performed to elucidate the role of the Pbx1 TALE protein in the corneal epithelium of mice. METHODS: Pbx1(f/f) mice were crossed with mice containing Cre recombinase under the control of the K14 promoter. Subsequently, the eyes of these mice were dissected and prepared for histologic or molecular analysis. RESULTS: Tissue-specific deletion of Pbx1 in the corneal epithelium of mice resulted in corneal dystrophy and clouding that was apparent in newborns and progressively worsened with age. Thickening of the cornea epithelium was accompanied by stromal infiltration with atypical basal cells, severe disorganization of stromal collagen matrix, and loss of corneal barrier function. High epithelial cell turnover was associated with perturbed expression of developmental regulators and aberrant differentiation, suggesting an important function for Pbx1 in determining corneal identity. CONCLUSIONS: These studies establish an essential role of the Pbx1 proto-oncogene in corneal morphogenesis.

Light-induced retinal degeneration correlates with changes in iron metabolism gene expression, ferritin level, and aging.

PURPOSE: Retinal degeneration is associated with iron accumulation in several rodent models in which iron-regulating proteins are impaired. Oxidative stress is catalyzed by unbound iron. METHODS: The role of the heavy chain of ferritin, which sequesters iron, in regulating the thickness of the photoreceptor nuclear layer in the 4- and 16-month-old wild-type H ferritin (HFt(+/+)) and heterozygous H ferritin (HFt(+/-)) mice was investigated, before and 12 days after exposure to 13,000-lux light for 24 hours. The regulation of gene expression of the various proteins involved in iron homeostasis, such as transferrin, transferrin receptor, hephaestin, ferroportin, iron regulatory proteins 1 and 2, hepcidin, ceruloplasmin, and heme-oxygenase 1, was analyzed by quantitative (q)RT-PCR during exposure (2, 12, and 24 hours) and 24 hours after 1 day of exposure in the 4-month-old HFt(+/+) and HFt(+/-) mouse retinas. RESULTS: Retinal degeneration in the 4-month-old HFt(+/-) mice was more extensive than in the HFt(+/+) mice. Yet, it was more extensive in both of the 16-month-old mouse groups, revealing the combined effect of age and excessive light. Injury caused by excessive light modified the temporal gene expression of iron-regulating proteins similarly in the HFt(+/-) and HFt(+/+) mice. CONCLUSIONS: Loss of one allele of H ferritin appears to increase light-induced degeneration. This study highlighted that oxidative stress related to light-induced injury is associated with major changes in gene expression of iron metabolism proteins.

Time processing in visual cortices: How the visual brain encodes and keeps track of time

Time is embedded in any sensory experience: the movements of a dance, the rhythm of a piece of music, the words of a speaker are all examples of temporally structured sensory events. In humans, if and how visual cortices perform temporal processing remains unclear. Here we show that both primary visual cortex (V1) and extrastriate area V5/MT are causally involved in encoding and keeping time in memory and that this involvement is independent from low-level visual processing. Most importantly we demonstrate that V1 and V5/MT are functionally linked and temporally synchronized during time encoding whereas they are functionally independent and operate serially (V1 followed by V5/MT) while maintaining temporal information in working memory. These data challenge the traditional view of V1 and V5/MT as visuo-spatial features detectors and highlight the functional contribution and the temporal dynamics of these brain regions in the processing of time in millisecond range. The present project resulted in the paper entitled: 'How the visual brain encodes and keeps track of time' by Paolo Salvioni, Lysiann Kalmbach, Micah Murray and Domenica Bueti that is now submitted for publication to the Journal of Neuroscience.

Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer.

BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-1 have been associated with increased risk of breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. The current study was conducted to further characterize the association of IGF-1 during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women less than 40 years of age, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred and nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched to each case on age and date at blood donation. Serum IGF-1 concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).RESULTS: No significant associations were observed between serum IGF-1 concentrations and breast cancer risk in both the overall analysis (OR 1.08 (95% CI 0.80-1.47) and in analyses stratified by histological subtype, lag-time to cancer diagnosis, age at pregnancy or age at diagnosis.CONCLUSIONS: There was no association between IGF-1 and maternal breast cancer risk during early pregnancy in this large nested case-control study.Impact:Serum IGF-1 concentrations during early pregnancy may not be related to maternal risk of breast cancer.

Development and validation of the Transition to Retirement Questionnaire

The aim of this study was to present the initial validation of a new questionnaire, the Transition to Retirement Questionnaire (TRQ) and to study its relationship with resistance to change and personality dimensions. Based on Schlossberg's typology of the retired, the TRQ is designed to assess five dimensions related to personal perceptions of transition to retirement, retirement, and personal plans and activities. The sample consisted of 1,054 professionally active or retired adults from the Swiss French-speaking Canton of Vaud. Exploratory principal components and confirmatory factor analyses highlighted a five-factor solution that fit coherently with Schlossberg's typology. Moreover, TRQ dimensions were related to resistance to change tendencies and personality dimensions. The TRQ seems to be an interesting tool for use in research but also for interventions with young retirees or people preparing for retirement.

Morphologic and electroretinographic phenotype of SR-BI knockout mice after a long-term atherogenic diet.

PURPOSE: To evaluate functional and ultrastructural changes in the retina of scavenger receptor B1 (SR-BI) knockout (KO) mice consuming a high fat cholate (HFC) diet. METHODS: Three-month-old male KO and wild-type (WT) mice were fed an HFC diet for 30 weeks. After diet supplementation, plasma cholesterol levels and electroretinograms were analyzed. Neutral lipids were detected with oil red O, and immunohistochemistry was performed on cryostat ocular tissue sections. The retina, Bruch's membrane (BM), retinal pigment epithelium (RPE), and choriocapillaris (CC) were analyzed by transmission electron microscopy. RESULTS: Using the WT for reference, ultrastructural changes were recorded in HFC-fed SR-BI KO mice, including lipid inclusions, a patchy disorganization of the photoreceptor outer segment (POS) and the outer nuclear layer (ONL), and BM thickening with sparse sub-RPE deposits. Within the CC, there was abnormal disorganization of collagen fibers localized in ectopic sites with sparse and large vacuolization associated with infiltration of macrophages in the subretinal space, reflecting local inflammation. These lesions were associated with electroretinographic abnormalities, particularly increasing implicit time in a- and b-wave scotopic responses. Abnormal vascular endothelial growth factor (VEGF) staining was detected in the outer nuclear layer. CONCLUSIONS: HFC-fed SR-BI KO mice thus presented sub-RPE lipid-rich deposits and functional and morphologic alterations similar to some features observed in dry AMD. The findings lend further support to the hypothesis that atherosclerosis causes retinal and subretinal damage that increases susceptibility to some forms of AMD.

Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study.

Escitalopram is a serotonin reuptake inhibitor prescribed for depression and anxiety. There is a paucity of information regarding safety in pregnancy. The objective of this study was to determine whether escitalopram is associated with an increased risk for major malformations or other adverse outcomes following use in pregnancy. The authors analyzed pregnancy outcomes in women exposed to escitalopram (n = 212) versus other antidepressants (n = 212) versus nonteratogenic exposures (n = 212) and compared the outcomes. Among the escitalopram exposures were 172 (81%) live births, 32 (15%) spontaneous abortions, 6 (2.8%) therapeutic abortions, 3 stillbirths (1.7%), and 3 major malformations (1.7%). The only significant differences among groups was the rate of low birth weight (<2500 g) and overall mean birth weight (P = .225). However, spontaneous abortion rates were higher in both antidepressant groups (15% and 16%) compared with controls (8.5%; P = .066). There were lower rates of live births (P = .006), lower overall birth weight (P < .001), and increased rates of low birth weight (<2500 g; P = .009) with escitalopram. Spontaneous abortion rates were nearly double in both antidepressant groups (15% and 16%) compared with controls (8.5%) but not significant (P = .066). Escitalopram does not appear to be associated with an increased risk for major malformations but appears to increase the risk for low birth weight, which was correlated with the increase in infants weighing <2500 g. In addition, the higher rates of spontaneous abortions in both antidepressant groups confirmed previous findings.

TRPV4-associated skeletal dysplasias.

Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis. © 2012 Wiley Periodicals, Inc.