Locus Coeruleus and CCHS (Congenital Central Hypoventilation Syndrome)

Not yet recruiting

• Conditions: Ondine Syndrome (Congenital Central Hypoventilation Syndrome)

• Registration Number: NCT07081464
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

This study investigates whether cognitive dysfunction in young patients with congenital central hypoventilation syndrome (Ondine Syndrome) is related to the severity of the disease and dysfunction of the locus coeruleus (a brainstem structure involved in autonomic control and cognition). The investigators will assess cognitive evoked potentials (P300 wave) using high-resolution EEG during attention tasks, pupillometry, brain MRI, neuropsychological tests, and heart rate variability. Patients with different severities of PHOX2B gene mutation (alanine expansions \<27 vs. ≥27) will be compared.

Detailed Description

Ondine Syndrome (congenital central hypoventilation syndrome) is a rare autosomal dominant genetic disorder caused by mutations in PHOX2B. Patients require lifelong nocturnal ventilation and often have cognitive impairments. The cause of cognitive deficits is uncertain: possible hypoxic brain injury or direct effects of PHOX2B mutations on brain regions like the locus coeruleus.

This cross-sectional study includes 21 patients aged 7-20 years with Ondine Syndrome and PARM-type (polyalanine repeat mutation) PHOX2B mutations, divided into moderate (\<27 alanine expansions) and severe (≥27 expansions) groups. During routine hospitalization, participants undergo:

High-resolution EEG with evoked potentials during auditory and visual attention tasks to measure P300 wave amplitude.

Pupillometry during the same tasks to assess locus coeruleus function.

3T (3 Tesla magnetic resonance imaging) MRI (anatomical and diffusion imaging) without sedation.

Neuropsychological assessment with the Vineland test.

Holter ECG to analyze heart rate variability.

The goal is to link locus coeruleus dysfunction to disease severity and explore its impact on cognition, autonomic balance, and sleep."

Study Timeline

• Status Verified: 2025-07
• Study First Submitted: 2025-07-07
• Study First Submitted QC: 2025-07-22
• Last Update Submitted: 2025-07-22
• Study First Posted: 2025-07-23
• Last Update Posted: 2025-07-23
• Study Start: 2025-10-15
• Primary Completion: 2027-10-15
• Study Completion: 2027-10-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

• Neonatal diagnosis of Ondine Syndrome.
• PARM-type PHOX2B mutation.
• Age 7 to 20 years.
• Receiving nocturnal ventilation.
• Consent obtained. Affiliated with social security.

Exclusion Criteria

• Severe autism spectrum disorder preventing test completion.
• Legal guardianship or curatorship.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Amplitude of the P300 wave (peak-to-baseline) recorded by high-resolution EEG during visual and auditory attention tasks.	24 hours	Measurement of cognitive evoked potential P300 amplitude using a 64-electrode EEG system during Flanker and oddball paradigms to assess locus coeruleus function.

Secondary Outcome Measures

Name	Time	Method
Functional connectivity parameters of the locus coeruleus measured by high-resolution EEG and 3T brain MRI diffusion imaging.	24 hours
Ratio of maximal pupil diameter during attention tasks to resting pupil diameter measured by pupillometry.	24 hours
Heart rate variability parameters from Holter ECG monitoring.	24 hours
Structural connectivity parameters of the locus coeruleus measured by high-resolution EEG and 3T brain MRI diffusion imaging.	24 hours
Scores of socio-adaptive behavior from the Vineland neuropsychological test (Vineland Adaptative Behavior Scales II, with scores ranging from 20 to 160; higher scores indicating better functioning).	24 hours	Vineland Adaptative Behavior Scales II, with scores ranging from 20 to 160; higher scores indicating better functioning.

Trial Locations

Locations (1)

Robert Debré Hospital; 🇫🇷 Paris, Ap-hp / DRCI, France