Influence of β 2  adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy

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Abstract

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß ₂ adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3–25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly ( P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

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Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy.

John Bach, Yuka Ishikawa, Heakyung Kim (1997)

To evaluate the effects of a new respiratory management protocol on respiratory morbidity and hospitalization rates for patients with Duchenne muscular dystrophy (DMD). A retrospective cohort study. Using a protocol in which oxyhemoglobin desaturation was prevented or reversed by the use of noninvasive intermittent positive pressure ventilation (IPPV) and assisted coughing as needed, the hospitalization rates and days for 24 protocol DMD ventilator users were compared with those of 22 nonprotocol DMD tracheostomy IPPV users. The 22 conventionally managed patients were hospitalized a mean of 72.2+/-112 days when undergoing tracheostomy. This included a 16.1+/-5.4-day period of translaryngeal intubation. The 24 protocol patients were hospitalized a mean of 6.0+/-2.4 days (p<0.005) when beginning ventilator use. Over their next 126.2 patient-years of ventilator use, the 24 protocol patients had significantly lower rates of hospitalization (p<0.008) and hospitalization days (p<0.005) than had the tracheostomy IPPV users over a 167.2 patient-year period. This is true although 14 of the 24 protocol patients went on to require 24-h noninvasive IPPV for 4.5+/-3.6 years. Five of the 14 have yet to be hospitalized. The use of inspiratory and expiratory aids can prolong survival while significantly decreasing the pulmonary morbidity and hospitalization rates associated with conventional resort to tracheostomy IPPV.

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Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

Zaïda Koeks, Catherine L. Bladen, David Salgado … (2017)

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

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Technical report: diagnosis and management of childhood obstructive sleep apnea syndrome.

Daniel S. Schechter, (2002)

This technical report describes the procedures involved in developing the recommendations of the Subcommittee on Obstructive Sleep Apnea Syndrome in children. The group of primary interest for this report was otherwise healthy children older than 1 year who might have adenotonsillar hypertrophy or obesity as underlying risk factors of obstructive sleep apnea syndrome (OSAS). The goals of the committee were to enhance the primary care clinician's ability to recognize OSAS, identify the most appropriate procedure for diagnosis of OSAS, identify risks associated with pediatric OSAS, and evaluate management options for OSAS. A literature search was initially conducted for the years 1966-1999 and then updated to include 2000. The search was limited to English language literature concerning children older than 2 and younger than 18 years. Titles and abstracts were reviewed for relevance, and committee members reviewed in detail any possibly appropriate articles to determine eligibility for inclusion. Additional articles were obtained by a review of literature and committee members' files. Committee members compiled evidence tables and met to review and discuss the literature that was collected. A total of 2115 titles were reviewed, of which 113 provided relevant original data for analysis. These articles were mainly case series and cross-sectional studies; overall, very few methodologically strong cohort studies or randomized, controlled trials concerning OSAS have been published. In addition, a minority of studies satisfactorily differentiated primary snoring from true OSAS. Reports of the prevalence of habitual snoring in children ranged from 3.2% to 12.1%, and estimates of OSAS ranged from 0.7% to 10.3%; these studies were too heterogeneous for data pooling. Children with sleep-disordered breathing are at increased risk for hyperactivity and learning problems. The combined odds ratio for neurobehavioral abnormalities in snoring children compared with controls is 2.93 (95% confidence interval: 2.23-3.83). A number of case series have documented decreased somatic growth in children with OSAS; right ventricular dysfunction and systemic hypertension also have been reported in children with OSAS. However, the risk growth and cardiovascular problems cannot be quantified from the published literature. Overnight polysomnography (PSG) is recognized as the gold standard for diagnosis of OSAS, and there are currently no satisfactory alternatives. The diagnostic accuracy of symptom questionnaires and other purely clinical approaches is low. Pulse oximetry appears to be specific but insensitive. Other methods, including audiotaping or videotaping and nap or home overnight PSG, remain investigational. Adenotonsillectomy is curative in 75% to 100% of children with OSAS, including those who are obese. Up to 27% of children undergoing adenotonsillectomy for OSAS have postoperative respiratory complications, but estimates are varied. Risk factors for persistent OSAS after adenotonsillectomy include continued snoring and a high apnea-hypopnea index on the preoperative PSG. OSAS is common in children and is associated with significant sequelae. Overnight PSG is currently the only reliable diagnostic modality that can differentiate OSAS from primary snoring. However, the PSG criteria for OSAS have not been definitively validated, and it is not clear that primary snoring without PSG-defined OSAS is benign. Adenotonsillectomy is the first-line treatment for OSAS but requires careful postoperative monitoring because of the high risk of respiratory complications. Adenotonsillectomy is usually curative, but children with persistent snoring (and perhaps with severely abnormal preoperative PSG results) should have PSG repeated postoperatively.

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Contributors

Eli F. Kelley:

ORCID: http://orcid.org/0000-0001-8337-2253

320-290-0291 , kelley.eli@mayo.edu

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 16 October 2019

Publication date PMC-release: 16 October 2019

Publication date (Print): 2019

Volume: 20

Electronic Location Identifier: 221

Affiliations

[1 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Kinesiology, , University of Minnesota, ; Minneapolis, MN USA

[2 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Cardiovascular Diseases, , Mayo Clinic, ; RO_GE_MN_10, 1216 2nd Street SW, Rochester, MN 55902 USA

[3 ]ISNI 0000 0000 9752 8549, GRID grid.413079.8, University of California Davis Medical Center, ; Sacramento, CA USA

[4 ]ISNI 0000 0001 2164 4508, GRID grid.264260.4, Binghamton University – SUNY, ; Binghamton, NY USA

[5 ]ISNI 0000 0004 0482 1586, GRID grid.239560.b, Center for Genetic Medicine, Children’s Research Institute, Children’s National Health System, ; Washington, DC USA

[6 ]ISNI 0000 0004 1757 3470, GRID grid.5608.b, Department of Neurosciences, , University of Padova, ; Padova, Italy

Author information

Eli F. Kelley http://orcid.org/0000-0001-8337-2253

Article

Publisher ID: 1200

DOI: 10.1186/s12931-019-1200-1

PMC ID: 6796481

PubMed ID: 31619245

SO-VID: 665c3737-d218-45be-8c74-7c516be06173

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 August 2019

Date accepted : 25 September 2019

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ScienceOpen disciplines: Respiratory medicine

Keywords: duchenne muscular dystrophy,beta2-adrenergic receptor,genotype,respiratory,nocturnal ventilation,risk

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ScienceOpen disciplines: Respiratory medicine

Keywords: duchenne muscular dystrophy, beta2-adrenergic receptor, genotype, respiratory, nocturnal ventilation, risk

Influence of β ₂ adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy

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European Respiratory Society: COVID-19

Most cited references 48

Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy.

Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database

Technical report: diagnosis and management of childhood obstructive sleep apnea syndrome.

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