Clinical trial NCT05954494: Protection Response to Cellular Stress in BPAN's Patient Study
Official title: Protection Response to Cellular Stress in BPAN's Patient Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Children and Adults with BPAN Carrying Pathogenic Variants of WDR45
Keywords: BPAN
WDR45
Stress protection
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2023-07-20
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Community sample of patients, organized with patient's associations and major reference centers. As this is a rare genetic disorder with no treatment, we conduct this research at the request of the above-mentioned patient associations.

At present, about twenty patients are followed for this pathology in France and 2 to 3 patients are diagnosed on average each year. Assuming a refusal rate of 5% (knowing that this study is based on the wishes of the patients' families), we plan to include a total of 20 patients.

Brief summary: BPAN (beta-propeller associated neurodegeneration) is caused by mutations in the autophagy gene WDR45, also known as WIPI4, located on the X chromosome. Mutations in WDR45 result in neurodevelopmental impairment in girls and early-onset epileptic encephalopathy in boys, followed by neurodegeneration in adults (SENDA). This condition is a subtype of neurodegeneration with brain iron overload (NBIA). BPAN is the most recently identified subtype of NBIA and it is important to understand how mutations in WDR45, present in patients∙e∙s, cause cell death.

Autophagy is a cell survival mechanism responsible for the degradation and recycling of cell contents. It has been proposed that autophagy becomes less efficient during normal aging, which could cause neuronal death and thus lead to neurodegeneration.

Reduced autophagic activity has been observed in lymphoblastic cells of BPAN patients and in brains of KO mice for WDR45. The current hypothesis to explain the pathology associated with WDR45 mutations is that a defect in autophagy leads to neurodegeneration. However, we do not know if the autophagy defect is causal or if other deregulations of cellular responses contribute to neurodegeneration. Preliminary results from Pr. Bertrand Mollereau's team suggest that a global deregulation of cellular stress responses may be induced in patient cells. This includes in particular the endoplasmic reticulum response to stress (UPR response) as well as lipid storage mechanisms.

The investigators hypothesize that cells from patients carrying pathogenic variants of WDR45 will exhibit deregulation of cellular stress response pathways.


Eligibility criteria: Inclusion Criteria:

* Weight ≥ 12.5kg
* Presence of WDR45 pathogenic variant gene
* Children or adults (no upper limit for age)
* Patient under guardianship could be included if they are assisted by their guardian/adviser in compliance with article L1122-2 of the Public Health Code by virtue of the protection of vulnerable populations

Exclusion Criteria:

- According to the order of 12/04/2018 of the Public Health Code : Weight ≤ 12.5 kg for a 10mL sample or For 2 male and 2 female Lyon patients : Weight ≤ 25 kg for a 20mL sample

* No French Social Insurance Regimen
* Refusal of participation by the legal representative of the patient

Primary outcomes:
measure: Autophagic capacity of BPAN cells as marker of cellular stress response
timeFrame: At study completion in an average of 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Bron
country: France
facility: Groupement hospitalier est
city: Bron
country: France
facility: Service de génétique - Laboratoire de Biologie Médicale Multi-Site (LBMMS) Groupement Hospitalier Est - Hospices Civils de Lyon
Study officials:
References: