Brain Iron in Beta-Propeller Protein Associated Neurodegeneration (BPAN)

Neurodegeneration with Brain Iron Accumulation (NBIA) comprises a group of rare disorders characterized by progressive neurodegeneration and abnormal iron deposition in the brain. Among these, BPAN, caused by pathogenic variants in the WDR45 gene, is the most frequent subtype and follows a biphasic clinical course, with developmental delay, epilepsy and intellectual disability in childhood and progressive motor and cognitive decline in adolescence or early adulthood.

Conventional MRI allows detection of iron deposition but remains limited to qualitative assessment and lacks sensitivity at early stages. Quantitative Susceptibility Mapping (QSM) is an advanced MRI technique that enables non-invasive, in vivo quantification of magnetic susceptibility changes associated with iron deposition. Although QSM has been validated in other neurodegenerative disorders, its application in BPAN remains limited, with no longitudinal data available to date.

This study addresses the lack of quantitative biomarkers in BPAN and aims to better characterize the natural history of iron accumulation.

Participants will undergo standardized brain MRI including specific sequences usable for QSM at baseline and at 18 months. Clinical assessments, including motor and adaptive behavior scales, will be performed concurrently. No contrast agent will be used.

Each participant will be followed for 18 months, with two main study visits (baseline and 18 months). Clinical and imaging data will be collected at each visit as part of routine care and study procedures. Additional visits may occur if clinically indicated. The total study will last 24 months, including a 6-month inclusion period

• Standardized brain MRI including specific sequences usable for Quantitative Susceptibility Mapping (QSM) (Other): All participants will undergo standardized study procedures at two time points (baseline and 18 months), including brain MRI acquisition and clinical assessments. Brain MRI will be performed using a standardized protocol, including conventional sequences and additional sequences required for Quantitative Susceptibility Mapping (QSM), such as multi-echo gradient-echo acquisitions sensitive to magnetic susceptibility variations. No contrast agent will be administered. QSM maps will be reconstructed using validated post-processing methods, and quantitative analyses will be conducted in predefined regions of interest (e.g., substantia nigra, globus pallidus) to estimate intracerebral iron load. At each visit, participants will undergo clinical evaluations, including neurological examination and assessment of motor and adaptive functions using validated scales. All procedures will be repeated at 18 months under similar conditions to enable longitudinal intra-individual comparisons.

Primary outcomes

• Brain Iron [Baseline (T0), month 18 (T18).]: Quantitative change on intracerebral iron levels using QSM technology in BPAN patients between baseline (Day 0) and 18 months

Secondary outcomes

• Correlation between intracerebral iron levels and clinical symptom severity [Baseline (T0), month 18 (T18).]: To evaluate the potential association between quantitative intracerebral iron levels in the different regions of interest (ROIs) and clinical symptom severity, as assessed by the clinical test scores.

Sex: All, ages: 5 Years to 18 Years

Inclusion Criteria:

* Affiliation to a social security system
* French-speaking participants
* Age between 5 and 18 years
* Genetically confirmed BPAN (WDR45 mutation)
* Written and free informed consent from at least one parent (e.g., in single-parent families) or the holder(s) of parental responsibility.

Exclusion Criteria:

* Patient-specific exclusion criteria :

  o Participation in an interventional clinical trial that could interfere with our study or that includes an ongoing exclusion period
* Contraindications to brain MRI :

  * Presence of a pacemaker, neurostimulator, or implantable defibrillator (risk of temporary or permanent damage to the device, deprogramming, or heating of metal components)
  * Presence of cochlear implants (risk of demagnetization, electrode overheating, and artifacts)
  * Presence of ferromagnetic foreign bodies in the eye or brain near nerve structures (risk of displacement and complications such as brain injury or blindness)
  * Presence of metal prostheses, particularly orthodontic braces
  * Presence of a ventriculoperitoneal shunt
* Contraindications related to anesthesia:

  * Known allergy to one or more products used for anesthesia

• Chloé ANGELINI, MD, Principal investigator, University Hospital, Bordeaux