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Article ; Online: Clinical course of growth in patients with congenital neuromuscular disease in a single multidisciplinary neuromuscular clinic.

Watne, Laura / Yang, Michele L

Journal of pediatric rehabilitation medicine

2016 Volume 9, Issue 1, Page(s) 13–21

Abstract: Objective: To assess the effect of nutritional interventions on growth and on respiratory status in patients with congenital myopathy (CM), congenital muscular dystrophy (CMD), and congenital myasthenic syndrome (CMS).: Methods: Retrospective cohort ... ...

Abstract	Objective: To assess the effect of nutritional interventions on growth and on respiratory status in patients with congenital myopathy (CM), congenital muscular dystrophy (CMD), and congenital myasthenic syndrome (CMS). Methods: Retrospective cohort study based on case-note review of 18 patients affected by CM, CMD, and CMS, followed at a single pediatric neuromuscular center, between 2006 and 2014. Results: Seventy-two percent of patients required placement of a gastrostomy tube for bulbar weakness or for growth failure. Of those patients, 10 had 1 year follow up anthropometric data and 6 had 2 year follow up anthropometric data. Height percentiles and z-scores were significantly improved in patients after 1 year, while weight and BMI percentiles and z-scores were not. Weight and height percentiles and z-scores were significantly improved in patients at 2 year follow up, while BMI percentiles and z-scores were not. The number of respiratory illnesses was not significantly different before or after placement of the feeding tube. Of the patients who did not have placement of a gastrostomy tube, 4 had 1 year follow up anthropometric data and 3 had 2 year follow up anthropometric data. Gastrostomy tube fed patients had significantly higher mean weight percentiles and z-scores compared to orally fed patients. There was no significant difference in height or BMI between the gastrostomy fed and orally fed groups. Individual growth curves highlight the effect of intervention on weight and height. Conclusions: This is a single multidisciplinary center experience describing the effect of nutritional interventions on growth in patients with congenital neuromuscular disorders. While the number of patients and their data in this report are limited, it highlights that the growth in this group of patients is unique but that the low weight and short stature respond to nutritional interventions with changes typically seen after 2 years of intervention.
MeSH term(s)	Body Height ; Body Mass Index ; Body Weight ; Child Development ; Child, Preschool ; Cohort Studies ; Enteral Nutrition ; Female ; Follow-Up Studies ; Gastrostomy ; Humans ; Infant ; Infant, Newborn ; Male ; Neuromuscular Diseases/complications ; Neuromuscular Diseases/rehabilitation ; Respiration Disorders/complications ; Retrospective Studies ; Weight Gain
Language	English
Publishing date	2016
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2403637-7
ISSN	1875-8894 ; 1874-5393
ISSN (online)	1875-8894
ISSN	1874-5393
DOI	10.3233/PRM-160357
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Article ; Online: Unusually severe muscular dystrophy upon in-frame deletion of the dystrophin rod domain and lack of compensation by membrane-localized utrophin.

Gorokhova, Svetlana / Schessl, Joachim / Zou, Yaqun / Yang, Michele L / Heydemann, Peter T / Sufit, Robert L / Meilleur, Katherine / Donkervoort, Sandra / Medne, Livija / Finkel, Richard S / Bönnemann, Carsten G

Med (New York, N.Y.)

2023 Volume 4, Issue 4, Page(s) 245–251.e3

Abstract: Background: Utrophin, a dystrophin homolog, is consistently upregulated in muscles of patients with Duchenne muscular dystrophy (DMD) and is believed to partially compensate for the lack of dystrophin in dystrophic muscle. Even though several animal ... ...

Abstract	Background: Utrophin, a dystrophin homolog, is consistently upregulated in muscles of patients with Duchenne muscular dystrophy (DMD) and is believed to partially compensate for the lack of dystrophin in dystrophic muscle. Even though several animal studies support the idea that utrophin can modulate DMD disease severity, human clinical data are scarce. Methods: We describe a patient with the largest reported in-frame deletion in the DMD gene, including exons 10-60 and thus encompassing the entire rod domain. Findings: The patient presented with an unusually early and severe progressive weakness, initially suggesting congenital muscular dystrophy. Immunostaining of his muscle biopsy showed that the mutant protein was able to localize at the sarcolemma and stabilize the dystrophin-associated complex. Strikingly, utrophin protein was absent from the sarcolemmal membrane despite the upregulation of utrophin mRNA. Conclusions: Our results suggest that the internally deleted and dysfunctional dystrophin lacking the entire rod domain may exert a dominant-negative effect by preventing upregulated utrophin protein from reaching the sarcolemmal membrane and thus blocking its partial rescue of muscle function. This unique case may set a lower size limit for similar constructs in potential gene therapy approaches. Funding: This work was supported by a grant from MDA USA (MDA3896) and by grant number R01AR051999 from NIAMS/NIH to C.G.B.
MeSH term(s)	Animals ; Humans ; Dystrophin/genetics ; Dystrophin/metabolism ; Utrophin/genetics ; Utrophin/metabolism ; Utrophin/therapeutic use ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/pathology ; Muscles/metabolism ; Muscles/pathology ; Sarcolemma/metabolism ; Sarcolemma/pathology
Chemical Substances	Dystrophin ; Utrophin
Language	English
Publishing date	2023-03-10
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2023.02.005
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Article: Quality and Safety Analysis of 2,999 Telemedicine Encounters During the COVID-19 Pandemic.

Joshi, Charuta N / Yang, Michele L / Eschbach, Krista / Tong, Suhong / Jacobson, Mona P / Stillman, Chelsey / Kropp, Annmarie E / Shea, Stephanie A / Frunzi, Gerard M / Thomas, J Fred / Olson, Christina A

Neurology. Clinical practice

2021 Volume 11, Issue 2, Page(s) e73–e82

Abstract: Objective: To examine whether telemedicine remains safe and of high quality despite rapid expansion of services by comparing telemedicine encounters before and during the COVID-19 pandemic.: Methods: Pre-post study investigating 2,999 telemedicine ... ...

Abstract	Objective: To examine whether telemedicine remains safe and of high quality despite rapid expansion of services by comparing telemedicine encounters before and during the COVID-19 pandemic. Methods: Pre-post study investigating 2,999 telemedicine encounters: February 1, 2020-May 15, 2020, was performed. A total of 2,919 completed visits before and after strict social distancing implementation were analyzed for patient and provider characteristics, encounter characteristics (e.g., history and physical examination), and quality and safety metrics (phone calls ≤ 7 days postvisit, visit-cause-specific hospital admission or mortality ≤ 30 days after visit). Stratified analysis of 3 groups for outcomes (young age, neuromuscular diagnosis, and new encounters) was performed. Results: Patients ranging from 1 month to 33 years of age were seen. Rural patients were less likely to be seen during the pandemic compared with urban patients (8% vs 90%; Conclusions: Despite a markedly and rapidly expanded scope of ambulatory telemedicine care during the COVID-19 pandemic, telemedicine remained a safe and high-quality option for pediatric neurology patients. In addition, populations perceived as high risk for telemedicine (the very young, new patients, and those with neuromuscular diagnoses) can benefit from telemedicine visits, particularly when access to in-person care is limited.
Language	English
Publishing date	2021-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645818-4
ISSN	2163-0933 ; 2163-0402
ISSN (online)	2163-0933
ISSN	2163-0402
DOI	10.1212/CPJ.0000000000001025
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Article ; Online: Left ventricular dysfunction in Duchenne muscular dystrophy.

James, Katherine A / Gralla, Jane / Ridall, Leslie A / Do, ThuyQuynh N / Czaja, Angela S / Mourani, Peter M / Ciafaloni, Emma / Cunniff, Christopher / Donnelly, Jennifer / Oleszek, Joyce / Pandya, Shree / Price, Elinora / Yang, Michele L / Auerbach, Scott R

Cardiology in the young

2020 Volume 30, Issue 2, Page(s) 171–176

Abstract: Background: Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction.: Methods and results: Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed ... ...

Abstract	Background: Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction. Methods and results: Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed between 1 January, 1982 and 31 December, 2011, were identified from the Muscular Dystrophy Surveillance Tracking and Research Network database. Two non-mutually exclusive groups were created: patients with ≥2 echocardiograms and non-invasive positive pressure ventilation-compliant patients with ≥1 recorded ejection fraction. Quantitative left ventricular dysfunction was defined as an ejection fraction <55%. Qualitative dysfunction was defined as mild, moderate, or severe. Progression of quantitative left ventricular dysfunction was modelled as a continuous time-varying outcome. Change in qualitative left ventricle function was assessed by the percentage of patients within each category at each age. Forty-one percent (n = 403) had ≥2 ejection fractions containing 998 qualitative assessments with a mean age at first echo of 10.8 ± 4.6 years, with an average first ejection fraction of 63.1 ± 12.6%. Mean age at first echo with an ejection fraction <55 was 15.2 ± 3.9 years. Thirty-five percent (140/403) were non-invasive positive pressure ventilation-compliant and had ejection fraction information. The estimated rate of decline in ejection fraction from first ejection fraction was 1.6% per year and initiation of non-invasive positive pressure ventilation did not change this rate. Conclusions: In our cohort, we observed that left ventricle function in patients with Duchenne muscular dystrophy declined over time, independent of non-invasive positive pressure ventilation use. Future studies are needed to examine the impact of respiratory support on cardiac function.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Cohort Studies ; Echocardiography ; Glucocorticoids/therapeutic use ; Humans ; Infant ; Infant, Newborn ; Male ; Muscular Dystrophy, Duchenne/complications ; Muscular Dystrophy, Duchenne/drug therapy ; Muscular Dystrophy, Duchenne/pathology ; Muscular Dystrophy, Duchenne/physiopathology ; Stroke Volume ; Ventricular Dysfunction, Left/pathology ; Ventricular Dysfunction, Left/physiopathology ; Young Adult
Chemical Substances	Glucocorticoids
Language	English
Publishing date	2020-01-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1078466-4
ISSN	1467-1107 ; 1047-9511
ISSN (online)	1467-1107
ISSN	1047-9511
DOI	10.1017/S1047951119002610
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Article ; Online: Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

Dang, Utkarsh J / Damsker, Jesse M / Guglieri, Michela / Clemens, Paula R / Perlman, Seth J / Smith, Edward C / Horrocks, Iain / Finkel, Richard S / Mah, Jean K / Deconinck, Nicolas / Goemans, Nathalie M / Haberlová, Jana / Straub, Volker / Mengle-Gaw, Laurel / Schwartz, Benjamin D / Harper, Amy / Shieh, Perry B / De Waele, Liesbeth / Castro, Diana /

Yang, Michele L / Ryan, Monique M / McDonald, Craig M / Tulinius, Mar / Webster, Richard I / Mcmillan, Hugh J / Kuntz, Nancy / Rao, Vamshi K / Baranello, Giovanni / Spinty, Stefan / Childs, Anne-Marie / Sbrocchi, Annie M / Selby, Kathryn A / Monduy, Migvis / Nevo, Yoram / Vilchez, Juan J / Nascimento-Osorio, Andres / Niks, Erik H / De Groot, Imelda J M / Katsalouli, Marina / Van Den Anker, John N / Ward, Leanne M / Leinonen, Mika / D'Alessandro, Andrea L / Hoffman, Eric P

Neurology

2024 Volume 102, Issue 5, Page(s) e208112

Abstract: Background and objectives: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to ... ...

Abstract	Background and objectives: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). Methods: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. Results: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, Discussion: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. Trial registration information: ClinicalTrials.gov Identifier: NCT03439670. Classification of evidence: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
MeSH term(s)	Humans ; Male ; Biomarkers ; Muscular Dystrophy, Duchenne/drug therapy ; Prednisone/adverse effects ; Pregnadienediols/adverse effects ; Child, Preschool ; Child
Chemical Substances	Biomarkers ; Prednisone (VB0R961HZT) ; Pregnadienediols ; VBP15 compound
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208112
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Article: Health Care Transition Experiences of Males with Childhood-onset Duchenne and Becker Muscular Dystrophy: Findings from the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) Health Care Transitions and Other Life Experiences Survey.

Paramsothy, Pangaja / Herron, Adrienne R / Lamb, Molly M / Kinnett, Kathi / Wolff, Jodi / Yang, Michele L / Oleszek, Joyce / Pandya, Shree / Kennedy, Annie / Cooney, Darryl / Fox, Deborah / Sheehan, Daniel

PLoS currents

2018 Volume 10

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2018-08-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2583641-9
ISSN	2157-3999
ISSN	2157-3999
DOI	10.1371/currents.md.7de8a1c6798d7a48d38ea09bd624e1cd
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Article ; Online: CNS myelination requires cytoplasmic dynein function.

Yang, Michele L / Shin, Jimann / Kearns, Christina A / Langworthy, Melissa M / Snell, Heather / Walker, Macie B / Appel, Bruce

Developmental dynamics : an official publication of the American Association of Anatomists

2015 Volume 244, Issue 2, Page(s) 134–145

Abstract: Background: Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration, and retrograde axon transport are among the ... ...

Abstract	Background: Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration, and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. Results: We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. Conclusions: In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination.
MeSH term(s)	Animals ; Axonal Transport/physiology ; Axons/metabolism ; Brain/cytology ; Brain/embryology ; Cytoplasmic Dyneins/genetics ; Cytoplasmic Dyneins/metabolism ; Gene Expression Regulation, Developmental/physiology ; Mutation ; Myelin Sheath/genetics ; Myelin Sheath/metabolism ; Oligodendroglia/cytology ; Oligodendroglia/metabolism ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	Zebrafish Proteins ; Cytoplasmic Dyneins (EC 3.6.4.2) ; DYNC1H1 protein, zebrafish (EC 3.6.4.2)
Language	English
Publishing date	2015-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.24238
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Article ; Online: Consider muscle disease in children with elevated transaminase.

Wright, Melissa A / Yang, Michele L / Parsons, Julie A / Westfall, John M / Yee, Audrey S

Journal of the American Board of Family Medicine : JABFM

2012 Volume 25, Issue 4, Page(s) 536–540

Abstract: The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markers of hepatocellular injury but are highly concentrated in muscle cells. Consequently, muscular dystrophies such as Duchenne muscular dystrophy, lead to ... ...

Abstract	The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markers of hepatocellular injury but are highly concentrated in muscle cells. Consequently, muscular dystrophies such as Duchenne muscular dystrophy, lead to hypertransaminasemia. Elevation in ALT and AST is most striking during the early stages of disease, before onset of or when only subtle signs of muscle disease are present. Thus, the incidental finding of elevated ALT/AST may be the presenting sign of muscle disease in many children and provides an opportunity for early diagnosis. Many physicians, however, pursue extensive workup for liver disease in children who present with the incidental finding of elevated ALT/AST. This results in delayed diagnosis and initiation of treatment and increased expense and may lead to unnecessary invasive procedures. We report 12 patients with muscle disease who presented with a variety of symptoms and were found to have an incidental finding of elevated ALT/AST. We propose a rapid screening process for evaluating children with the incidental finding of elevated ALT/AST to shorten the time to diagnosis of muscle disease.
MeSH term(s)	Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Biomarkers/blood ; Child ; Child, Preschool ; Clinical Enzyme Tests ; Early Diagnosis ; Female ; Humans ; Incidental Findings ; Infant ; Male ; Muscle Weakness/diagnosis ; Muscular Dystrophies/diagnosis ; Unnecessary Procedures
Chemical Substances	Biomarkers ; Aspartate Aminotransferases (EC 2.6.1.1) ; Alanine Transaminase (EC 2.6.1.2)
Language	English
Publishing date	2012-07
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2239939-2
ISSN	1558-7118 ; 1557-2625
ISSN (online)	1558-7118
ISSN	1557-2625
DOI	10.3122/jabfm.2012.04.110183
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Article ; Online: Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis.

Graham, Robert J / Muntoni, Francesco / Hughes, Imelda / Yum, Sabrina W / Kuntz, Nancy L / Yang, Michele L / Byrne, Barry J / Prasad, Suyash / Alvarez, Rachel / Genetti, Casie A / Haselkorn, Tmirah / James, Emma S / LaRusso, Laurie B / Noursalehi, Mojtaba / Rico, Salvador / Beggs, Alan H

Archives of disease in childhood

2019 Volume 105, Issue 4, Page(s) 332–338

Abstract: Purpose: Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and ... ...

Abstract	Purpose: Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM. Design: RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care. Results: Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7-5.6) vs 30.2 years (IQR 19.4-30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7-30.2) vs 1.8 years (IQR 0.2-not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1-not estimable) vs 0.2 years (IQR 0.1-2.1)). Conclusions: High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies. Trial registration number: NCT02231697.
MeSH term(s)	Age Factors ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Myopathies, Structural, Congenital/mortality ; Myopathies, Structural, Congenital/physiopathology ; Myopathies, Structural, Congenital/therapy ; Premature Birth/epidemiology ; Respiration, Artificial/statistics & numerical data ; Retrospective Studies
Language	English
Publishing date	2019-09-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	524-1
ISSN	1468-2044 ; 0003-9888 ; 1359-2998
ISSN (online)	1468-2044
ISSN	0003-9888 ; 1359-2998
DOI	10.1136/archdischild-2019-317910
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Article ; Online: A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.

Beck, David B / Subramanian, T / Vijayalingam, S / Ezekiel, Uthayashankar R / Donkervoort, Sandra / Yang, Michele L / Dubbs, Holly A / Ortiz-Gonzalez, Xilma R / Lakhani, Shenela / Segal, Devorah / Au, Margaret / Graham, John M / Verma, Sumit / Waggoner, Darrel / Shinawi, Marwan / Bönnemann, Carsten G / Chung, Wendy K / Chinnadurai, G

Neurogenetics

2019 Volume 20, Issue 3, Page(s) 129–143

Abstract: We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the ... ...

Abstract	We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes.
MeSH term(s)	Adolescent ; Alcohol Oxidoreductases/genetics ; Alcohol Oxidoreductases/metabolism ; Alleles ; Apoptosis ; Ataxia/complications ; Ataxia/genetics ; Brain Neoplasms/genetics ; Cell Line, Tumor ; Child ; Child, Preschool ; Chromatin/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Fibroblasts/metabolism ; Glioblastoma/genetics ; Humans ; Intellectual Disability/complications ; Intellectual Disability/genetics ; Male ; Muscle Hypotonia/complications ; Muscle Hypotonia/genetics ; Mutation, Missense ; Phenotype ; Protein Binding ; Proteomics ; Tooth Abnormalities/complications ; Tooth Abnormalities/genetics ; Young Adult
Chemical Substances	Chromatin ; DNA-Binding Proteins ; Alcohol Oxidoreductases (EC 1.1.-) ; C-terminal binding protein (EC 1.1.1.-)
Language	English
Publishing date	2019-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1339887-8
ISSN	1364-6753 ; 1364-6745
ISSN (online)	1364-6753
ISSN	1364-6745
DOI	10.1007/s10048-019-00578-1
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