Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder

Julu, Peter O.O.; Kerr, Alison; Apartopoulos, Flora; Al-Rawas, Sf.S.; Engerström, I Witt; Engerström, Lars; Jamal, G A; Hansen, Stig

doi:10.1136/adc.85.1.29

Cited by 254 publications

(249 citation statements)

References 27 publications

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“…Several reasons could explain the lack of clinically significant effects of DMI on breathing patterns in RTT girls. First, as described by several authors, breathing dysfunction in RTT is very complex and highly variable 5, 6, 7, 8, 22. We monitored the breathing disorders in awake patients at each visit and found similar results on AHI to those reported in two patients with atypical Rett 23.…”

Section: Discussionsupporting

confidence: 57%

“…Among the symptoms of RTT, breathing dysrhythmia may represent a life‐threatening event 3. Breathing disorders are present in 65 to 93% of the patients and characterized by hyperventilation, hypoventilation, breath holds and apneic events 4, 5, 6, 7, 8. Studies in validated mouse models of RTT have shown that Mecp2 null male and heterozygous female mice exhibited breathing disturbances with different level of severity 9, 10, 11.…”

Section: Introductionmentioning

confidence: 99%

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Effect of desipramine on patients with breathing disorders in RETT syndrome

Mancini

Dubus

Jouve

et al. 2017

Ann Clin Transl Neurol

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ObjectiveRett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2‐deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT.MethodsThe trial was a 6‐month, multicenter, randomized, double‐blind, placebo‐controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2–3 mg/kg Desipramine per day (high Desipramine), 1–2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention‐to‐treat analysis was applied.ResultsThe median change in AHI from baseline to 6 months was −31 (IQR: −37 to −11) for the high Desipramine, −17.5 (IQR: −31 to 13) for the low Desipramine, and −13 (IQR:−31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = −0.44; P = 0.0002) was underlined.InterpretationThis first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Effect of desipramine on patients with breathing disorders in RETT syndrome

Mancini

Dubus

Jouve

et al. 2017

Ann Clin Transl Neurol

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“…It is characterized by normal early development followed by regression, leading to loss of spoken language and/or purposeful hand use, gait abnormalities, and development of stereotypic hand movements. Other common features include growth retardation, seizures, breathing abnormalities, vasomotor disturbances, and abnormal behavior 1, 2, 3, 5, 6, 7, 8. The current standard of care is symptomatic management, with no available treatments aimed at ameliorating the cardinal symptoms of the disorder 9, 10, 11…”

Section: Introductionmentioning

confidence: 99%

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

O’Leary

Kaufmann

Barnes

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind crossover study design.MethodsThirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed.ResultsThere were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.InterpretationAs in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

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“…Clinical evidence indicates that RTT patients suffer from reduced cardiac vagal tone that can cause life threatening cardiac arrhythmias (34). To examine heart rate abnormalities in MeCP2 -/y mice and the effect of (1-3)IGF-1 treatment, we monitored real time cardiac pulse rate in nonanesthetized wild-type and MeCP2 -/y animals treated with vehicle or (1-3)IGF-1 (Fig.…”

mentioning

confidence: 99%