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Optic Nerve Hypoplasia (ONH) is the leading cause of childhood blindness in developed nations and its prevalence has been rising. Yet, we know little about the genetic, molecular, or cellular mechanisms underlying ONH. A previous study described ONH in a cohort of patients with mutations in CASK, an X-linked gene with established roles in neural development and synaptic function. I have demonstrated that heterozygous deletion of CASK in mice (Cask+/-) recapitulates many of the phenotypes observed in patients with CASK mutations, including ONH. This includes reduced optic nerve size, reduced numbers of retinal ganglion cells (RGCs), reduced RGC axonal diameter, and deficits in vision-related tasks. Further analysis on a homozygous partial loss of function variant (Caskfl/fl) also displayed ONH with reduced numbers of RGCs. In order to understand the mechanisms underlying CASK-associated ONH, I explored whether RGCs, the projection neurons of the retina and the cells whose axons comprise the optic nerve, generate CASK. Indeed, mRNA analysis revealed expression of CASK by a large cohort of RGCs. In order to assess whether loss of CASK from a majority of RGCs leads to ONH, I crossed a conditional allele of CASK (CASKfl/fl) with transgenic mice that express Cre Recombinase (Cre) in RGCs. Deletion of CASK from RGCs did not further alter ONH size nor RGC survival. These results demonstrate that loss of CASK signaling in this discrete neuronal populations is not sufficient to lead to further disruption in the assembly of the subcortical visual circuit, suggesting a non-cell autonomous mechanism for loss of CASK in ONH. / Doctor of Philosophy / The connection between the eye and the brain is crucial for successful vision. Impairment of this connection by either loss of the retinal neurons that project axons to the brain or damage to the nerve (optic nerve) lead to blindness. This occurs in a disease called Optic Nerve Hypoplasia (ONH), which is the leading cause of childhood blindness in developed countries. Discovering the risk factors associated with this disease and mechanisms underlying the disease can help us build tools to treat and repair the optic nerve. Previously, mutations in the CASK gene were found in patients with ONH. Here, I developed a mouse model of CASK mutations to phenocopy the human patients, and used this model to explore the development of ONH. For example, with this mouse model I described for the first time, the timeline of disease progression. Surprisingly, I also showed that loss of CASK specifically from the neurons whose axons generate the optic nerve did not lead to ONH, suggesting that ONH may develop from a failure of a network of cells, rather than just one population of cells.

Indiana University-Purdue University Indianapolis (IUPUI)

Thesis (M.S.)--University of Michigan, 1943.

Orientador: Maria da Luz Rosario de Sousa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-06T12:41:12Z (GMT). No. of bitstreams: 1 Hoffmann_RosanaH.Schlittler_M.pdf: 1436970 bytes, checksum: 15a723068d00073e76dd8a336913bb2c (MD5) Previous issue date: 2006 / Resumo: As mudanças ocorridas durante a formação do esmalte dental são marcadas permanentemente em sua estrutura e comumente se apresentam como opacidades demarcadas, opacidades difusas ou hipoplasias - de esmalte. - O desenvolvimento de defeitos de esmalte pode fornecer indícios de sua etiologia e isto pode ter implicações tanto clínicas quanto epidemiológicas. Desta forma, os objetivos desta dissertação apresentados na forma de dois artigos foram: 1 - Verificar a prevalência de hipoplasia, opacidade demarcada e opacidade difusa em pré-escolares e escolares no município de Indaiatuba (SP) no ano de 2004 nas dentições decídua e permanente, bem como analisar a associação entre a presença desses defeitos de esmalte e cárie dentária; 2 - Verificar a prevalência de hipoplasia, opacidade demarcada e opacidade difusa em pré-escolares de 18 municípios da região de Campinas e Piracicaba (SP) no ano de 2004 na dentição decídua, bem como analisar a associação entre a presença desses defeitos de esmalte e cárie dentária. No estudo 1, a amostra foi de 624 pré-escolares de 5 anos de escolas públicas e particulares e 309 escolares de 12 anos de escolas públicas de Indaiatuba. No estudo 2 a amostra foi composta por 4.259 pré-escolares de 5 anos de 18 municípios da região de Campinas e Piracicaba. Avaliou-se a prevalência de cárie dentária através dos Índices ceo-d (dentição decídua) e CPO-D (dentição permanente) e a prevalência dos defeitos de esmalte através do Índice DOE. A existência de associação entre defeitos de esmalte e cárie dentária foi verificada com o teste Qui-quadrado. O valor para rejeição da hipótese nula foi p:sO,05. No estudo 1, na dentição decídua, encontrou-se uma prevalência para hipoplasia, opacidade demarcada e opacidade difusa de 8,7%, 20,9% e 17,1%, respectivamente. Já na dentição permanente, foi encontrada a prevalência de 5,5% para hipoplasia, 20,1% para opacidade demarcada e 26,2% para opacidade difusa. Entre as crianças de 5 anos com experiêRcia de cárie (ceo>O), foi observado uma associação entre cárie dentária com as alterações de esmalte (opacidade demarcada, hipoplasia e opacidade difusa) entretanto entre as crianças de 12 anos (dentição permanente) apenas as hipolasias e opacidades demarcadas foram associadas a presença de cárie. No estudo 2, foi encontrada menor prevalência de opacidades demarcadas e hipoplasias nos pré-escolares livres de cárie (p<0,05). O mesmo não ocorreu com as opacidades difusas, ou seja, não houve diferença entFe os indivíduos com ceo=O e ceo>O (p=0,88). Quando se verificou a associação entre cárie dentária e defeitos de esmalte segundo a etnia, esta relação perdeu o significado no grupo dos não brancos (p=0,880) entretanto no grupo de bra'ncos a cárie dentária manteve associação com defeitos de esmalte (p=O,OOO). Desta forma, cabe salientar a importância da discriminação dos tipos de defeitos em levantamentos epidemiológicos, visto Que os resultados deste estudo indicaram maior chance de crianças virem a ter cárie dentária, tanto na dentição decídua como na permanente na presença de defeitos de esmalte, porém mais estudos são necessários para comprovação desta associação / Abstract: Changes in enamel during development are permanently recorded, and commonly present as demarcated opacity, diffuse opacity or enamel hypoplasia. Developmental enamel defects may provide clues regarding their etiology, resulting in clinical, epidemiological and anthropological implications. Therefore, the aims of the present study based on two manuscripts were: 1) to analyze hypoplasia, demarcated and diffuse opacity prevalence of deciduous and permanent teeth and verify the association of enamel defects and dental caries among preschool and scholars children in lndaiatuba, São Paulo in 2004; and 2) to analyze hypoplasia, demarcated and diffuse opacity prevalence on deciduous teeth and verify the association of enamel defects and dental caries among preschool children in 18 municipalities of Campinas aod Piracicaba region,in 2004. At manuscript 1, the sample consisted of 624 5-year olds from public and private schools and 309 12-year olds from public schools. At manuscript 2, the sample consisted of 4,259 5-year olds from 18 municipalities in Campinas and Piracicaba region. ln both studies the dmft lndex was used to analyze caries prevalence in deciduous teeth. ln the second study the DMFT was used to analyze caries prevalence in permanent teeth. The DDE lndex was used to assess enamel defects. The Chi-square test verified the possible association between enamel defects and dental caries. At manuscript 1, the prevalence of hypoplasia, demarcated and diffuse opacity in the primary dentition was 8.7%, 20.9%, and 11 %, respectively, while in the permanent dentition, such prevalence was 5.5%, 20.1%, and 21.7%, respectively. An association between dental caries and enamel defects (hypoplasia, demarcated opacity and diffuse opacity) was observed among children presenting caries experience (dmft>O) at age 5. However, in 12-year olds only hypoplasia and demarcated opacity were observed to be associated with caries presence. At manuscript 2, lower prevalence of demarcated opacity and hypoplasia among caries free preschool children. There was no difference among individuais presenting dmf=O and dmf>O (p=O.88) for diffuse opacities. At manuscript 2, the association between dental caries and enamel defects was verified according to ethnicity, this association lost its meaning at non white group (p=O.880); however, statistic significance was observed for dental caries associated with enamel defects in the white group (p=O.OOO). Thus, different types of defects should be more emphasized in epidemiological surveys because these defects might indicate a higher risk of dental caries as in both deciduous and permanent dentition; therefore, further studies are needed to investigate this association / Mestrado / Cariologia / Mestre em Odontologia

Indiana University-Purdue University Indianapolis (IUPUI)

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) family protein, which is encoded by a gene of identical name present on the X chromosome. CASK may participate in presynaptic scaffolding, gene expression regulation, and cell junction formation. CASK is essential for survival in mammals. Heterozygous mutations in the CASK gene (in females) produce X-linked intellectual disability (XLID) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, OMIM# 300749). CASK mutations are also frequently associated with optic nerve hypoplasia (ONH) which is the most common cause of childhood blindness in developed countries. Some patients with mutations in CASK have been also diagnosed with optic nerve atrophy (ONA) and glaucoma. We have used floxed CASK (CASKfloxed), CASK heterozygous knockout (CASK(+/-)), CASK neuronal knockout (CASKNKO) and tamoxifen inducible CASK knockout (CASKiKO) mouse models to investigate the mechanism and pathology of CASK-linked ONH. Our observations indicate that ONH occurs with 100% penetrance in CASK(+/-) mice, which also displayed microcephaly and disproportionate cerebellar hypoplasia. Further, we found that CASK-linked ONH is a complex developmental neuropathology with some degenerative components. Cellular pathologies include loss of retinal ganglion cells (RGC), astrogliosis, axonopathy, and synaptopathy. The onset of ONH is late in development, observed only around the early postnatal stage in mice reaching the plateau phase by three weeks of birth. The developmental nature of the disorder is confirmed by deleting CASK after maturity since CASKiKO mice did not produce any obvious optic nerve pathology. Strikingly the CASKfloxed mice expressing ~49% level of CASK did not manifest ONH despite displaying a slightly smaller brain and cerebellar hypoplasia indicating that ONH may not simply be an extension of microcephaly. We discovered that deleting CASK in neurons produced lethality before the onset of adulthood. The CASKNKO mice exhibited delayed myelination of the optic nerve. Overall this work suggests that CASK is critical for neuronal maturation and CASK-linked ONH is a pervasive developmental disorder of the subcortical visual pathway. Finally, in a side project, I also described a new methodology of targeting neurons using receptor-mediated endocytosis which would help target retinal neurons for therapeutic purposes in the future. / Ph. D. / 7 in 10,000 children suffer from childhood blindness, for whom all the visual information from the outside world is completely blocked. Although classified as a rare disease, optic nerve hypoplasia (ONH), or the underdevelopment of optic nerve, is the leading cause of childhood blindness in developed countries, accounting for 15% of childhood blindness. Only a handful of genes have been shown to associate with ONH. The CASK gene, whose protein product calcium/calmodulin-dependent serine protein kinase (CASK) plays a role in presynaptic scaffolding, is one of them. Mutations in the CASK gene not only produce ONH, but also microcephaly and intellectual disability. Investigating the mechanism of CASK-linked ONH will provide critical data to understand the molecular basis of optic nerve formation and maturation. Here we have used the CASK heterozygous knockout mouse model to replicate the ONH and microcephaly seen in female human patients. We discovered that the onset of CASK-linked ONH corresponded to the late third trimester developmental stage in humans, thus ONH is developmental in nature. ONH pathologies include thinning of optic nerves, axonal atrophy, and synaptopathy. In contrast to the postnatal death of constitutive CASK loss of function in mice, CASK ablation in adult mice did not lead to lethality. CASK deletion also delays neuronal myelination. Overall, our results indicate that CASK is critical for postnatal maturation of the central nervous system and mutations of the CASK gene is sufficient to lead to ONH. Early intervention and proper gene therapy may treat CASK-linked ONH.

Kidney and inferior vena cava (IVC) abnormalities with extensive deep vein thrombosis (DVT) is a very rare cause of DVT and has a diverse clinical presentation. Computed tomography (CT) angiography is the gold standard for diagnosis and treatment including thrombectomy, thrombolysis and systemic anticoagulation. We present a rare case of active young healthy male admitted with acute onset of right lower extremity pain and swelling who was found to have extensive DVT on doppler ultrasound. CT abdomen showed extensive clot burden involving right common femoral vein extending into internal and external iliac veins associated with IVC hypoplasia and hypoplastic left kidney. Patient underwent urgent thrombectomy, catheter directed thrombolysis and was discharged home in stable condition on oral anticoagulation.