A Comprehensive Overview of the Clinical, Electrophysiological, and Neuroimaging Features of BPAN: Insights From a New Case Series.

Background: Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically and clinically heterogeneous group of rare neurological disorders characterized particularly by iron accumulation in the basal ganglia. To date, 15 genes have been associated with NBIA. Among them, WDR45, linked to beta-propeller protein-associated neurodegeneration (BPAN), represents the only X-linked dominant subtype of NBIA. Herein, clinical, electrophysiological, and neuroimaging evaluations were used to broaden the understanding of BPAN in a newly reported case series.

Methods: This study included 10 individuals with BPAN, categorized into three age groups. WDR45 variant data retrieved from next-generation sequencing or Sanger sequencing were reviewed and reassessed. Comprehensive clinical evaluations including magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and video electroencephalographic monitoring were conducted.

Results: The clinical manifestations were highly heterogeneous, with cognitive impairment being a consistent finding among the patients, with variable severity. The associated WDR45 variants are likely to exert loss-of-function effects. Electroencephalogram (EEG) abnormalities included age-dependent background slowing and epileptiform discharges. MRI indicated a characteristic pattern, while two patients lacked these typical findings. FDG-PET imaging demonstrated hypometabolism extending beyond cerebral structures, with predominant cerebellar and pontine involvement in pediatric patients and frontoparietal hypometabolism in adults.

Conclusions: This study contributes further to our understanding of the heterogeneous clinical spectrum of BPAN. Genotype-phenotype correlation in BPAN remains unclear due to the absence of sufficiently large cohorts in the literature, including the present study. Nevertheless, even within this small sample, the phenotypic heterogeneity observed among individuals harboring the same genotype highlights the biological complexity of the disease. Neuroimaging findings may reflect progressive and widespread neurological involvement in an age-dependent pattern, whereas EEG data suggest that epilepsy severity tends to decrease after adolescence.