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Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons

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All Articles in Congenital, Hereditary, and Neonatal Diseases and Abnormalities

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Orotic Aciduria, Aliah L. Fonteh 2018 Liberty University

Orotic Aciduria, Aliah L. Fonteh

Fidei et Veritatis: The Liberty University Journal of Graduate Research

Orotic acid is an intermediate found in the pathway for pyrimidine synthesis. The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes the production of orotic acid by the conversion of the compound dihydroorotate to orotic acid. Orotic acid is commonly produced by this reaction in erythrocytes, hepatocytes, and kidney cells. Chemical modification of orotic acid in the pyrimidine pathway will generate nucleotides involved in DNA and RNA synthesis. Orotic aciduria can occur as a secondary manifestation due to a defect in an enzyme or transporter within the urea cycle, due to competitive inhibition by anti-cancer drugs such as allopurinol and 6-azauridine, or ...


Diagnosis Of A Centronuclear Myopathy Case In Appalachia 20 Years From Symptom Onset., Christopher Burrell, Zachary Wilson, Dominika Lozowska 2018 Marshall University Joan C Edwards School of Medicine

Diagnosis Of A Centronuclear Myopathy Case In Appalachia 20 Years From Symptom Onset., Christopher Burrell, Zachary Wilson, Dominika Lozowska

Marshall Journal of Medicine

Dynamin 2 (DMN2) mutations cause centronuclear myopathy (CNM) and Charcot Marie Tooth (CMT). Herein we discuss the details of a patient's case of adult onset CNM. We also highlight the unique features of this case with regards to the importance of electromyography (EMG), muscle biopsy and genetic testing in identifying CNM, as well as potential for improving outcomes by having a high index or suspicion and emphasizing better access to healthcare in underserved areas.


Widespread Presentation And Spontaneous Regression Of Porokeratotic Eccrine Ostial And Dermal Duct Nevus, Stephanie Petkiewicz, Julia Baltz, Kristine M. Cornejo, April C. Deng, Karen Wiss 2018 University of Ottawa

Widespread Presentation And Spontaneous Regression Of Porokeratotic Eccrine Ostial And Dermal Duct Nevus, Stephanie Petkiewicz, Julia Baltz, Kristine M. Cornejo, April C. Deng, Karen Wiss

Open Access Articles

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is an uncommon hamartomatous growth with disordered keratinization. The lesions typically appear on the limbs, often at birth or in early childhood, as linearly distributed papules and plaques. We report 4 cases of PEODDN, 2 of which showed significant spontaneous regression.


Sumo-Targeted Ubiquitin Ligases (Stubls) Reduce The Toxicity And Abnormal Transcriptional Activity Associated With A Mutant, Aggregation-Prone Fragment Of Huntingtin, Kentaro Ohkuni, Nagesh Pasupala, Jennifer Peek, Grace Lauren Holloway, Gloria D. Sclar, Reuben Levy-Myers, Richard E. Baker, Munira A. Basrai, Oliver Kerscher 2018 National Institutes of Health

Sumo-Targeted Ubiquitin Ligases (Stubls) Reduce The Toxicity And Abnormal Transcriptional Activity Associated With A Mutant, Aggregation-Prone Fragment Of Huntingtin, Kentaro Ohkuni, Nagesh Pasupala, Jennifer Peek, Grace Lauren Holloway, Gloria D. Sclar, Reuben Levy-Myers, Richard E. Baker, Munira A. Basrai, Oliver Kerscher

Open Access Articles

Cell viability and gene expression profiles are altered in cellular models of neurodegenerative disorders such as Huntington's Disease (HD). Using the yeast model system, we show that the SUMO-targeted ubiquitin ligase (STUbL) Slx5 reduces the toxicity and abnormal transcriptional activity associated with a mutant, aggregation-prone fragment of huntingtin (Htt), the causative agent of HD. We demonstrate that expression of an aggregation-prone Htt construct with 103 glutamine residues (103Q), but not the non-expanded form (25Q), results in severe growth defects in slx5Delta and slx8Delta cells. Since Slx5 is a nuclear protein and because Htt expression affects gene transcription, we assessed ...


Opposing Roles Of Fancj And Hltf Protect Forks And Restrain Replication During Stress, Min Peng, Ke Cong, Nicholas J. Panzarino, Sumeet Nayak, Jennifer Calvo, Bin Deng, Lihua Julie Zhu, Monika Morocz, Lili Hegedus, Lajos Haracska, Sharon B. Cantor 2018 University of Massachusetts Medical School

Opposing Roles Of Fancj And Hltf Protect Forks And Restrain Replication During Stress, Min Peng, Ke Cong, Nicholas J. Panzarino, Sumeet Nayak, Jennifer Calvo, Bin Deng, Lihua Julie Zhu, Monika Morocz, Lili Hegedus, Lajos Haracska, Sharon B. Cantor

Open Access Articles

The DNA helicase FANCJ is mutated in hereditary breast and ovarian cancer and Fanconi anemia (FA). Nevertheless, how loss of FANCJ translates to disease pathogenesis remains unclear. We addressed this question by analyzing proteins associated with replication forks in cells with or without FANCJ. We demonstrate that FANCJ-knockout (FANCJ-KO) cells have alterations in the replisome that are consistent with enhanced replication stress, including an aberrant accumulation of the fork remodeling factor helicase-like transcription factor (HLTF). Correspondingly, HLTF contributes to fork degradation in FANCJ-KO cells. Unexpectedly, the unrestrained DNA synthesis that characterizes HLTF-deficient cells is FANCJ dependent and correlates with S1 ...


The Effects Of Tracheal Occlusion On Wnt Signaling In A Rabbit Model Of Congenital Diaphragmatic Hernia, Martina M. Mudri 2018 The University of Western Ontario

The Effects Of Tracheal Occlusion On Wnt Signaling In A Rabbit Model Of Congenital Diaphragmatic Hernia, Martina M. Mudri

Electronic Thesis and Dissertation Repository

Purpose: Tracheal occlusion (TO) reverses pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH), but its effect on epithelial-mesenchymal transition (EMT) in lung development remains poorly understood. The purpose of this study was to a) confirm the CDH rabbit model produced PH which was reversed by TO and b) determine the effects of CDH +/- TO on EMT pathways.

Methods: CDH was created at 23 days, TO at 28 days and lung collection at 31 days gestation in fetal rabbits. Lung body weight ratio (LBWR), mean terminal bronchiole density (MTBD), and expression of mRNA and micro-RNA was determined.

Results: Fifteen CDH, 15 ...


Nuclear Localization Of Huntingtin Mrna Is Specific To Cells Of Neuronal Origin, Marie C. Didiot, Chantal M. Ferguson, Socheata Ly, Andrew H. Coles, Abigail O. Smith, Alicia A. Bicknell, Lauren M. Hall, Ellen Sapp, Dimas Echeverria, Athma A. Pai, Marian DiFiglia, Melissa J. Moore, Lawrence J. Hayward, Neil Aronin, Anastasia Khvorova 2018 University of Massachusetts Medical School

Nuclear Localization Of Huntingtin Mrna Is Specific To Cells Of Neuronal Origin, Marie C. Didiot, Chantal M. Ferguson, Socheata Ly, Andrew H. Coles, Abigail O. Smith, Alicia A. Bicknell, Lauren M. Hall, Ellen Sapp, Dimas Echeverria, Athma A. Pai, Marian Difiglia, Melissa J. Moore, Lawrence J. Hayward, Neil Aronin, Anastasia Khvorova

RNA Therapeutics Institute Publications

Huntington's disease (HD) is a monogenic neurodegenerative disorder representing an ideal candidate for gene silencing with oligonucleotide therapeutics (i.e., antisense oligonucleotides [ASOs] and small interfering RNAs [siRNAs]). Using an ultra-sensitive branched fluorescence in situ hybridization (FISH) method, we show that approximately 50% of wild-type HTT mRNA localizes to the nucleus and that its nuclear localization is observed only in neuronal cells. In mouse brain sections, we detect Htt mRNA predominantly in neurons, with a wide range of Htt foci observed per cell. We further show that siRNAs and ASOs efficiently eliminate cytoplasmic HTT mRNA and HTT protein, but ...


Genetic Modification Of Inherited Retinopathy In Mice, Yang Kong 2018 The University of Maine

Genetic Modification Of Inherited Retinopathy In Mice, Yang Kong

Electronic Theses and Dissertations

The retina, as a critical component of the sensory system, consists of multiple cell types, of which, photoreceptors play a key role in receiving, integrating and transmitting light signals. The biofunctions of photoreceptors rely on their proper growth and development, which is predominantly governed by a cluster of molecules that comprise the transcriptional regulation for photoreceptor development. Any disruption of these molecules potentially incurs retinal pathologies.

It is known that deficiencies of nuclear receptor subfamily 2 group E member 3 (NR2E3) or neural retina leucine-zipper (NRL), two molecules in regulating photoreceptor cell development, cause photoreceptor dysplasia. In a sensitized chemical ...


Health Professional Treatment Practices For Pediatric Sickle Cell Disease In Nigeria, Natalie Wichelt 2018 University of Nebraska Medical Center

Health Professional Treatment Practices For Pediatric Sickle Cell Disease In Nigeria, Natalie Wichelt

Service Learning/Capstone Experience

Abstract

Sickle cell disease (SCD) is caused by a genetic defect that results in abnormal hemoglobin genes that can cause devastating health effects like chronic hemolytic anemia and vaso-occlusive crises. Additionally, sickle cell disease can cause defects in the immune system, leaving those with the disease highly susceptible to a variety of different infections. In the pediatric population specifically, the complications of sickle cell disease contribute significantly to the under-five mortality rate of Nigeria. In response to the Millennium Development Goals 4, 5 and 6, as well as with growing national concern over the challenges faced by sickle cell disease ...


Central Precocious Puberty In Boston Boys: A 10-Year Single Center Experience, Lisa Swartz Topor, Kimberly Bowerman, Jason T. Machan, Courtney L. Gilbert, Tairmae Kangarloo, Natalie D. Shaw 2018 Brown University

Central Precocious Puberty In Boston Boys: A 10-Year Single Center Experience, Lisa Swartz Topor, Kimberly Bowerman, Jason T. Machan, Courtney L. Gilbert, Tairmae Kangarloo, Natalie D. Shaw

Open Access Articles

OBJECTIVE: Recent studies in the US and abroad suggest that boys are undergoing puberty at a younger age. It is unknown if this secular trend extends to boys with central precocious puberty (CPP), who sit at the extreme end of the pubertal spectrum, and if neuroimaging should remain a standard diagnostic tool.

STUDY DESIGN: Retrospective chart review of all boys with CPP seen by Endocrinology at a US pediatric hospital from 2001-2010.

RESULTS: Fifty boys had pubertal onset at an average age of 7.31 years (95CI 6.83-7.89), though many did not present until nearly one year thereafter ...


A Rationally Engineered Capsid Variant Of Aav9 For Systemic Cns-Directed And Peripheral Tissue-Detargeted Gene Delivery In Neonates, Dan Wang, Shaoyong Li, Dominic J. Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E. Goetzmann, Terence R. Flotte, Mavis Agbandje-McKenna, Guangping Gao 2018 University of Massachusetts Medical School

A Rationally Engineered Capsid Variant Of Aav9 For Systemic Cns-Directed And Peripheral Tissue-Detargeted Gene Delivery In Neonates, Dan Wang, Shaoyong Li, Dominic J. Gessler, Jun Xie, Li Zhong, Jia Li, Karen Tran, Kim Van Vliet, Lingzhi Ren, Qin Su, Ran He, Jason E. Goetzmann, Terence R. Flotte, Mavis Agbandje-Mckenna, Guangping Gao

Open Access Articles

Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through ...


Congenital Heart Defects And Ciliopathies Associated With Renal Phenotypes, George C. Gabriel, Gregory J. Pazour, Cecilia W. Lo 2018 University of Pittsburgh

Congenital Heart Defects And Ciliopathies Associated With Renal Phenotypes, George C. Gabriel, Gregory J. Pazour, Cecilia W. Lo

Open Access Articles

Congenital heart disease (CHD) is one of the most common birth defects, and recent studies indicate cilia-related mutations play a central role in the genetic etiology of CHD. As cilia are also known to have important roles in kidney development and disease, it is not surprising that renal anomalies were found to be enriched among CHD mutant mice recovered in a large-scale mouse forward genetic screen. Indeed 42% of mutations identified to cause both CHD and renal anomalies were cilia-related. Many of these cilia mutations comprise cilia transition zone or inversin compartment components, consistent with the known role of these ...


Identification Of Oral Clefts As A Risk Factor For Hearing Loss During Newborn Hearing Screening, Patricia L. Purcell, Kathleen CY Sie, Todd C. Edwards, Debra Lochner Doyle, Karin Neidt 2018 University of Washington

Identification Of Oral Clefts As A Risk Factor For Hearing Loss During Newborn Hearing Screening, Patricia L. Purcell, Kathleen Cy Sie, Todd C. Edwards, Debra Lochner Doyle, Karin Neidt

Journal of Early Hearing Detection and Intervention

Objective: This study assessed whether children with oral clefts are appropriately classified as at-risk for hearing loss at the time of newborn hearing screening and describes their screening and diagnostic results.

Design: Birth certificates were used to identify children with cleft lip and palate or isolated cleft palate born in Washington State from 2008–2013. These were cross-referenced with the state’s Early Hearing Detection, Diagnosis and Intervention (EHDDI) database. Multivariate logistic regression was used to examine associations.

Results: Birth records identified 235 children with cleft lip and palate and 116 with isolated cleft palate. Six children were listed as ...


A Fresh Look At Huntingtin Mrna Processing In Huntington's Disease, Lindsay S. Romo, Emily S. Mohn, Neil Aronin 2018 University of Massachusetts Medical School

A Fresh Look At Huntingtin Mrna Processing In Huntington's Disease, Lindsay S. Romo, Emily S. Mohn, Neil Aronin

RNA Therapeutics Institute Publications

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA before it ...


Congenital Chagas Disease In The United States: Cost Savings Through Maternal Screening, Eileen Stillwaggon, Victoria Perez-Zetune, Stephanie R. Bialek, Susan P. Montgomery 2018 Gettysburg College

Congenital Chagas Disease In The United States: Cost Savings Through Maternal Screening, Eileen Stillwaggon, Victoria Perez-Zetune, Stephanie R. Bialek, Susan P. Montgomery

Economics Faculty Publications

Chagas disease, caused by Trypanosoma cruzi, is transmitted by insect vectors through transfusions, transplants, insect feces in food, and from mother to child during gestation. Congenital infection could perpetuate Chagas disease indefinitely, even in countries without vector transmission. An estimated 30% of infected persons will develop lifelong, potentially fatal, cardiac or digestive complications. Treatment of infants with benznidazole is highly efficacious in eliminating infection. This work evaluates the costs of maternal screening and infant testing and treatment of Chagas disease in the United States. We constructed a decision-analytic model to find the lower cost option, comparing costs of testing and ...


Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo 2018 University of Massachusetts Medical School

Aerobic Glycolysis Is Essential For Normal Rod Function And Controls Secondary Cone Death In Retinitis Pigmentosa, Lolita Petit, Shan Ma, Joris Cipi, Shun-Yun Cheng, Marina Zieger, Nissim Hay, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Aerobic glycolysis accounts for approximately 80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic ...


Birth History As A Predictor Of Adverse Birth Outcomes: Evidence From State Vital Statistics Data, Dejun Su, Kaeli Samson, Ashvita Garg, Corrine Hanson, Ann L. Anderson Berry, Ge Lin Kan, Ming Qu 2018 University of Nebraska Medical Center

Birth History As A Predictor Of Adverse Birth Outcomes: Evidence From State Vital Statistics Data, Dejun Su, Kaeli Samson, Ashvita Garg, Corrine Hanson, Ann L. Anderson Berry, Ge Lin Kan, Ming Qu

Community Health Sciences Faculty Publications

One of the most important predictors of preterm births (PTBs) or low-birth-weight births (LBWBs) is whether a mother has had a history of these birth outcomes. This study examined how different characterizations of birth history (e.g., any previous incidence of PTBs or LBWBs, immediate previous birth that was preterm or of low birth weight, and number of previous PTBs or LBWBs) were associated with PTBs or LBWBs. Based on birth records (n = 98,776) reported to the vital statistics electronic registration system in Nebraska from 2005 to 2014, mothers with a history of PTBs or LBWBs were more likely ...


The Effect Of Diet On Craniofacial Growth In Osteogenesis Imperfecta Mouse Model, Summer H. Ladd 2018 University of North Texas Health Science Center at Fort Worth

The Effect Of Diet On Craniofacial Growth In Osteogenesis Imperfecta Mouse Model, Summer H. Ladd

Theses and Dissertations

Osteogenesis imperfecta (OI, or “brittle bone disease”) is a rare disorder that is caused by genetic point mutations (COL1A1/COL1A2) that affect type 1 collagen. In OI type III (severe) patients, limb bones are more susceptible to skeletal fractures and the bones of the craniofacial region are underdeveloped. Some OI type III patients also suffer from dental malocclusions or fractures (dentinogenesis imperfecta, DI). The goals of this project are 1) to describe the facial phenotype in an OI mouse model, to see if this model can be used to test potential behavioral and pharmaceutical interventions; and 2) to determine if ...


Extraction And Analysis Of Vector Flow Imaging Data In A Pediatric Population, Bailey Stinnett 2018 University of Arkansas, Fayetteville

Extraction And Analysis Of Vector Flow Imaging Data In A Pediatric Population, Bailey Stinnett

Biomedical Engineering Undergraduate Honors Theses

Vector flow imaging (VFI) is a new ultrasound technology that provides real time, angle-independent visualization of flow velocities in the heart and great vessels. Thus far, VFI has been used for superficial applications due to the limited penetration depth of available transducer probes; however, this depth in smaller pediatric patients enables adequate aortic views. In this project, VFI was used to study pediatric aortic stenosis (PAS)—a congenital heart defect that results in the narrowing of the aorta and/or aortic valve. The decision to refer PAS patients for surgical or catheter-based intervention is initially based on Doppler ultrasound. VFI ...


In Vitro Aortic Arch Flow Model For Vector Flow Imaging Testing, Jackson Mosley 2018 University of Arkansas, Fayetteville

In Vitro Aortic Arch Flow Model For Vector Flow Imaging Testing, Jackson Mosley

Biomedical Engineering Undergraduate Honors Theses

Pediatric stenosis is the narrowing of the aorta at the aortic valve, above the aortic valve, or below the aortic valve. Typically, this disease’s severity is diagnosed by conventional Doppler ultrasound methods, or echocardiography. Conventional Doppler can sometimes overestimate the pressure gradient over the area of stenosis, diagnosing some cases of PAS to be more severe than they actually are. This causes earlier intervention than is desired in children. A new US modality, Vector Flow Imaging (VFI), is an angle-independent US imaging method that can potentially more accurately quantify peak blood flow velocities and pressure gradients across stenotic sections ...


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