Functional ability profiles in beta-propeller protein-associated neurodegeneration (BPAN)

Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare neurodevelopmental degenerative disorder caused by pathogenic variants in WDR45 leading to brain iron accumulation. Its rarity and complex clinical course make it difficult to select appropriate clinical outcome assessments (COAs). This study evaluates established COAs for feasibility and effectiveness in capturing BPAN's functional ability profiles exploring cognitive, motor, and behavioral features.

We performed an observational study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We administered the Gross Motor Function Measure-88 (GMFM-88), the Leiter International Performance Scale (Leiter-3), and the Vineland Adaptive Behavior Scale (VABS-3). A Rasch validated version of the GMFM-88, the GMFM-66, was derived from the GMFM-88 data. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Statistical analyses were performed to compare performance across cohorts and assess correlations, with significance defined as p < 0.05.

Fifty-three individuals (43 females, 10 males) with molecularly confirmed BPAN participated. The VABS-3 (n = 53) showed a decline in adaptive skills over time, with significant differences between Communication and Socialization Domain performance (Kruskal-Wallis test with Dunn's correction p < 0.0001). GMFM-88 assessments (n = 32) showed a median performance of 33.4 %. Patient participation/behavior affected data completeness. The more limited GMFM-66 correlated better with the VABS-3 Gross Motor subdomain than the GMFM-88 (r = 0.94, r = 0.73, respectively). The Leiter-3 (n = 36) demonstrated significant non-verbal cognitive impairment, although there were behavioral challenges which impacted implementation. Longitudinal VABS-3 data revealed a median - 2.9 points/year decline in Adaptive Behavior Composite scores, reflecting progressive functional loss.

This study highlights key considerations for selecting COAs in BPAN. The panel of COAs should accommodate the behavioral challenges associated with BPAN that can limit participant compliance with testing. The abbreviated GMFM-66 was a more reliable tool to capture motor skills. Similarly, behavioral difficulties impacted Leiter-3 performance, which demonstrated general impairment in non-verbal cognitive skills. The VABS-3 effectively tracked adaptive function decline, demonstrating feasibility for longitudinal monitoring. Future studies should expand cohort size, refine assessment strategies, and align measures with disease progression to optimize clinical trial readiness.