Beta-Propeller Protein-Associated Neurodegeneration (BPAN) Without Evidence of Iron Deposition on Initial Neuroimaging: A Systematic Review of Clinical and Neuroimaging Characteristics

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked dominant disorder caused by de novo pathogenic variants in WDR45, and is among the most common subtypes of neurodegeneration with brain iron accumulation (NBIA). BPAN follows a recognised biphasic disease course: a static encephalopathy phase in childhood characterised by developmental delay, intellectual disability, and epilepsy, followed by rapid-onset parkinsonism and dementia in early adulthood. Iron deposition in the substantia nigra and globus pallidus — the neuroimaging hallmark of BPAN — typically becomes evident during the neurodegenerative phase. However, a substantial proportion of patients are imaged during the childhood phase, when iron is absent or undetectable, and the diagnosis is consequently delayed or missed entirely. While this phenomenon has been acknowledged in individual case series and narrative reviews, the frequency of iron-absent presentations, the duration of the pre-iron phase, the neuroimaging characteristics before iron deposition, and the consequences of omitting iron-sensitive sequences have not been systematically characterised across the published literature. This systematic review aims to fill that gap.