Pathophysiology, biological models and new therapeutic approaches in β-Propeller Associated Neurodegeneration

Neurodegeneration with brain iron accumulation (NBIA) encompasses a set of rare disorders that present a diagnostic challenge due to their genetic and clinical diversity, with treatment options currently limited to symptom alleviation. One subtype, β-Propeller Associated Neurodegeneration (BPAN), results from pathogenic variants in the WDR45 gene on the X chromosome. This condition is marked by iron accumulation in the globus pallidus and substantia nigra, alongside early onset developmental delays, seizures, and motor impairments. The WDR45 gene produces the WDR45 protein, which plays a key role in the creation and maturation of autophagosomes-crucial components of the autophagy process, a cellular mechanism vital to the organism's proper function. In BPAN, reduced autophagy correlates with mitochondrial dysfunction, impaired antioxidant defenses, elevated lipid peroxidation, buildup of lipofuscin granules, and disrupted iron metabolism. However, the precise relationships between these pathological issues remain unclear. There is no curative treatment for BPAN, therefore care focuses on palliation and symptom management through a multidisciplinary approach. Nonetheless, research into various therapeutic strategies is ongoing, including gene therapy to correct the genetic anomaly and methods to influence pathological pathways like autophagy deficiency, lipid peroxidation, and iron accumulation. A novel approach has recently been suggested, aimed at reactivating the inactive X chromosome in females with BPAN.