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Tracking Neurodegeneration in Early Wolfram Syndrome

追踪早期 Wolfram 综合征的神经退行性变

基本信息

批准号：
10452695
负责人：
TAMARA G HERSHEY
金额：
$ 58.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452695
关键词：
Adult Affect Apoptosis Atrophic Axon Biological Blindness Brain Brain Stem Calcium Cells Cerebellum Cessation of life Child Childhood Clinic Clinical Clinical Trials Collaborations Complex Complex Analysis Data Data Set Deterioration Diabetes Insipidus Diabetes Mellitus Diffusion Diffusion Magnetic Resonance Imaging Disease Edema Endocrine Equilibrium Europe Family Fiber Functional disorder Funding Future Genes Goals Grant Homeostasis Image Infiltration Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus International Intervention Investigation Knowledge Magnetic Resonance Imaging Measurement Measures Mediating Mutation Myelin Nature Nerve Degeneration Neurobiology Neurologic Neurologic Symptoms Oligodendroglia Online Mendelian Inheritance In Man Optic Nerve Outcome Measure Pathogenicity Pathologic Patients Pattern Phenotype Physicians Placebos Pontine structure Process Production Prognosis Proteins Research Research Personnel Sampling Severities Siblings Site Smell Perception Structure of beta Cell of islet Subgroup Symptoms Testing Time Universities Visual Acuity WFS1 gene Wolfram Syndrome Work base clinical efficacy deafness efficacy study endoplasmic reticulum stress hearing impairment high risk imaging modality improved insight myelination neurodevelopment neuron loss novel phenotypic data primary outcome prisma rare genetic disorder rate of change recruit spectrograph white matter

项目摘要

Wolfram syndrome (WFS; OMIM #222300) is a rare autosomal recessive disease clinically defined in 1938 as the combination of childhood-onset insulin dependent diabetes, optic nerve atrophy, diabetes insipidus and deafness. Based on early descriptions, neurological features were thought to appear later in the disease with death occurring in middle adulthood. Importantly, the major causative gene (WFS1) was identified in 1998. This discovery allowed researchers to determine that the WFS1 gene encodes the protein wolframin, which helps protect cells from endoplasmic reticulum (ER) stress-mediated apoptosis, potentially via intracellular calcium homeostasis. Pathogenic mutations in WFS1 can result in death or dysfunction of cells that are under high ER stress, such as insulin-producing pancreatic β cells, causing insulin dependent diabetes. In addition, knowing the causative gene has allowed us to identify patients by their WFS1 mutation rather than the classic set of symptoms, leading to the increasing realization that the WFS1-related phenotype (including neurologic symptoms) is much more variable than previously understood. The first iteration of this grant (HD070855 “Tracking Neurodegeneration in Early Wolfram Syndrome”) contributed to this shift in understanding. In this time, we have built a successful annual research clinic for WFS, met or exceeded our recruitment goals for patients and controls, validated a clinical severity rating scale for WFS, described an unexpectedly early neurophenotype of reduced balance, smell identification and ventral pons volume, identified alterations in traditional diffusion tensor imaging (DTI) metrics that suggest hypomyelination as a pervasive neuropathological feature of WFS and provided justification for the selection of two primary outcomes (visual acuity and ventral pons volume) in a newly funded clinical efficacy study in WFS (Barrett, PI). Our findings suggest two lines of investigation going forward. First, we hypothesize that ER stress- related dysfunction could inhibit production of myelin during neurodevelopment in WFS, as active and developing oligodendrocytes (cells that produce myelin in the brain) are more vulnerable to ER stress than mature ones. However, standard DTI methods conflate inflammatory processes (which can also be associated with ER stress) in the extra-axonal space with metrics of axonal and myelin integrity, leading to potentially confounded measurements. We propose to collect novel, validated diffusion sequences on a new state of the art MRI scanner (Siemens Prisma) and apply cutting-edge analysis approaches to measure white matter integrity throughout the brain and in the optic nerve, improving our ability to draw conclusions about axonal and myelin integrity over time. Second, larger and more diverse samples are needed to determine the predictors of WFS degeneration. We will pool key variables from WU with baseline and placebo conditions from a new clinical trial in the UK, rapidly increasing our sample and allowing for more complex analyses. Findings from this work may indicate future targets for brain-specific intervention, identify outcome measures or high-risk subgroups for clinical trials targeting neurological symptoms and will lay the groundwork for additional international collaborations. These data will also greatly expand our understanding of the cross-sectional and longitudinal phenotype of WFS1-mutation related disorders, rather than classically defined Wolfram Syndrome. Such knowledge will have a significant impact on patients and families by allowing physicians to provide more accurate prognoses. Finally, forms of ER stress-mediated apoptosis have been implicated in more common neurodegenerative, endocrine and neurodevelopmental diseases, which may benefit from the insights gained here.

Wolfram综合征（Wolfram syndrome， WFS; omim# 222300）是一种罕见的常染色体隐性遗传病，于1938年被临床定义为

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

DOI：
10.1002/humu.23233
发表时间：
2017-07
期刊：
Human mutation
影响因子：
3.9
作者：
Astuti D;Sabir A;Fulton P;Zatyka M;Williams D;Hardy C;Milan G;Favaretto F;Yu-Wai-Man P;Rohayem J;López de Heredia M;Hershey T;Tranebjaerg L;Chen JH;Chaussenot A;Nunes V;Marshall B;McAfferty S;Tillmann V;Maffei P;Paquis-Flucklinger V;Geberhiwot T;Mlynarski W;Parkinson K;Picard V;Bueno GE;Dias R;Arnold A;Richens C;Paisey R;Urano F;Semple R;Sinnott R;Barrett TG
通讯作者：
Barrett TG

Early brain vulnerability in Wolfram syndrome.

DOI：
10.1371/journal.pone.0040604
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Hershey T;Lugar HM;Shimony JS;Rutlin J;Koller JM;Perantie DC;Paciorkowski AR;Eisenstein SA;Permutt MA;Washington University Wolfram Study Group
通讯作者：
Washington University Wolfram Study Group

Dynamic control of posture across locomotor tasks.

DOI：
10.1002/mds.25592
发表时间：
2013-09-15
期刊：
MOVEMENT DISORDERS
影响因子：
8.6
作者：
Earhart, Gammon M.
通讯作者：
Earhart, Gammon M.

Enhancement of taste by retronasal odors in patients with Wolfram syndrome and decreased olfactory function.

沃尔夫拉姆综合征患者鼻后气味增强味觉，嗅觉功能下降。

DOI：
10.1093/chemse/bjad004
发表时间：
2023
期刊：
Chemical senses
影响因子：
3.5
作者：
Alfaro,Raul;Nicanor-Carreón,JessicaG;Doty,Tasha;Lugar,Heather;Hershey,Tamara;Pepino,MartaYanina
通讯作者：
Pepino,MartaYanina