Smith Magenis Syndrome and Autism Spectrum Disorders (SMS/TSA)

Chronobiological Characterization of Smith Magenis Syndrome and Autism Spectrum Disorders in Paediatric Age

Autism Spectrum Disorders (ASD) are a neurodevelopmental disorder. Their prevalence is estimated at around 0.4% of the general population worldwide. Their early onset and chronic nature make them a disabling disorder, all the more so as there is a high prevalence of sleep disorders in these populations, estimated at between 50 and 80%, with many complaints of insomnia in particular. These sleep disorders may result from biological, psychological, social, environmental and family factors.

Smith Magenis Syndrome (SMS) is a complex disorder characterized by severe neurological, psychological and behavioral disorders including sleep-wake rhythm disorders. It is a rare disease with a prevalence of 1/25 000.

These sleep disorders observed could be the consequence of a general dysregulation of the circadian system, since SMS patients show an inversion of the melatonin secretion profile (with a totally abnormal diurnal peak) and in patients with autism spectrum disorders, an overall reduction in melatonin secretion.

These sleep-wake disturbances cycle could play a significant role in learning deficits and in the frequency and severity of behavioral abnormalities observed in SMS and ASD.

In this project, investigators propose to study the mechanisms involved in the sleep-wake cycle disorders observed in Smith Magenis and Autism Spectrum children, in particular by evaluating the quality of the pupillary reflex using a pupillometer. The pupillary reflex is a simple and non-invasive method to test light sensitivity and the photobiological mechanisms involved.

In this way, investigators want to evaluate the diurnal profile of the pupillary reflex in children with Smith Magenis syndrome and with Autism Spectrum Disorders in relation to the diurnal melatonin profile.

Investigators will complete this study by determining the chronobiological profile of these patients by measuring different variables:

• Diurnal cortisol and amylase profile
• 24h body temperature and heart rate profile
• Urinary cortisol and 6-sulfatoxymelatonin (major metabolite of melatonin) profiles
• Daytime sleepiness profile measured subjectively by questionnaire and objectively via a waking EEG recording.
• Actimetry at home
• Polysomnography
• A neurocognitive and behavioural assessment

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder; Smith-Magenis Syndrome
• Intervention / Treatment: Other: Assessment

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Patricia FRANCO, PhD; Phone Number: +33 0427856052; Email: patricia.franco@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69677
    • Recruiting
    • Service Épilepsie-Sommeil-Explorations Fonctionnelles Neurologiques Pédiatriques Hôpital Femme-Mère-Enfant HCL
    • Contact: Patricia FRANCO, Pr; Phone Number: +33 0427856052; Email: patricia.franco@chu-lyon.fr
    • Principal Investigator: Patricia FRANCO, Pr
  • Bron, France, 69678
    • Recruiting
    • GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier and EDR-Psy Q19 Team (Centre National de la Recherche Scientifique & Lyon 1 Claude Bernard University)
    • Contact: Pr Caroline Demily Dr Alice POISSON; Phone Number: caroline.DEMILY@ch-le-vinatier; Email: alice.POISSON@-le-vinatier.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genetically confirmed Smith Magenis syndrome (microdeletion of the short arm of chromosome 17 or mutation of the RAI1 gene; obtained by FISH, CGH-array or molecular biology) and children with neuropsychologically confirmed autism spectrum disorder, with no genetic pathology found.
• Aged 5-12 years
• Consent form signed by the parent(s)
• Requiring a sleep assessment in the Hopital Femme Mère Enfant paediatric sleep unit of Pr Franco
• Affiliation to a social security system.

Exclusion Criteria:

• Associated ophthalmological disorders that do not allow the photomotor reflex to be studied: optic neuritis, glaucoma and retinitis pigmentosa.
• Algic child (risk of measurement bias: when a patient is in pain his pupils dilate and we observe a greater amplitude in the photomotor reflex), defined by a score on the FPS-R Face Scale >4/10.

Only for SMS patients:

- Dyschromatopsia detected in consultation with a rapid Ishihara test adapted to the child's cognitive level, if necessary supplemented by a test performed by ophthalmologists.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Children with Smith Magenis Syndrome	Other: Assessment; Pupil reflex and melatonin profile, circadian profile assessment
Other: Children with Autism Spectrum Disorders	Other: Assessment; Pupil reflex and melatonin profile, circadian profile assessment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of the percentage change between pupil diameter at the end of light exposure and before exposure	This measurement will allow to evaluate the diurnal profile of the pupillary reflex and will be measured by a NeuroLight pupillometer (IDMed). This measurement will be done every 2 hours from 8am to 8pm, for one day	One day
Measurement of salivary melatonin levels	This measurement will allow to evaluate the diurnal melatonin profile and will be evaluated using saliva samples. This measurement will be done every 2 hours from 8am to 8pm, for one day	One day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the chronobiological profile : Salivary cortisol levels	Salivary cortisol levels will be evaluated using saliva samples	Every 2 hours from 8am to 8pm, for one day
Determination of the chronobiological profile : Amylase levels	Amylase levels will be evaluated using saliva samples	Every 2 hours from 8am to 8pm, for one day
Determination of the chronobiological profile : Urinary 6-sulfatoxymelatonin level	Urinary 6-sulfatoxymelatonin level will be evaluated using urinary samples	over 24hours
Determination of the chronobiological profile : Urinary cortisol level	Urinary cortisol level will be evaluated using urinary samples	over 24hours
Determination of the chronobiological profile : Variations in body temperature in degrees	Body temperature will be measured by ibuttonR placed on the surface of the skin	over 24hours
Determination of the chronobiological profile : Assessment of sleepiness by questionnaire (numerical score)	The Karolinska questionnaire will be carried out at the time of salivary sampling and pupil diameter measurement and the score obtained will be compared with the salivary melatonin level.	Every 2 hours from 8am to 8pm, for one day
Determination of the chronobiological profile : Assessment of sleepiness by spectral analysis (EEG)	Somnolence will be evaluated by calculating power spectrum in several frequency bands.	Every 2 hours from 8am to 8pm, for one day
Determination of the chronobiological profile : Sleep assessment by actimetry	Home activity monitor during an outpatient recording with a watch in order to assess the sleep wake rhythm at home	2 weeks
Determination of the chronobiological profile :Sleep assessment by Polysomnography	Polysomnography during hospitalization in order to assess the structure of sleep	24 hours
Neuropsychological assessment	WISC +/- Vineland	One day

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Patricia FRANCO, PhD, Service Épilepsie-Sommeil-Explorations Fonctionnelles Neurologiques Pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2022
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: October 21, 2021
• First Submitted That Met QC Criteria: November 2, 2021
• First Posted (Actual): November 11, 2021

Study Record Updates

• Last Update Posted (Actual): June 6, 2024
• Last Update Submitted That Met QC Criteria: June 4, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; Sleep disorders; Autism Spectrum Disorder; Circadian rhythm; Paediatrics; Chronobiology; Smith Magenis Syndrome; Pupillary reflex
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodevelopmental Disorders; Abnormalities, Multiple; Chromosome Disorders; Chronobiology Disorders; Syndrome; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Smith-Magenis Syndrome
• Other Study ID Numbers: 69HCL20_0682

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No