Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN)

Abstract

Background: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes.

Methods: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2.

Results: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests.

Conclusion: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Keywords: BPAN; Clinical assessment tools; NBIA; WDR45.

Fig. 1.

Late onset of symptoms of BPAN is associated with ambulation and gain of spoken language. The gain of developmental skills was compared across the sub-cohorts of BPAN based on age of onset (black line, onset ≤0.5 years old; grey dotted line, onset>0.5 years old). Late onset disease was associated with improved gain of ambulation (A; log-rank test p = 0.0015; n = 27) and gain of first word (B; log-rank test p = 0.0015; n = 26; age of first word was missing for one subject). There was no difference in age at seizure onset by age at initial symptom onset (C; log-rank test p = 0.8823; n = 27).

Fig. 2.

Neurologic severity and trajectory in our BPAN cohort. A. Neurologic severity was assigned using summed scores from neurologic severity scores within the BPAN cohort. At the time of the last clinical assessment, functional assessment scales were applied to assign neurologic severity: GMFCS (gross motor), MACS (fine motor), and communication (CFCS). Higher scores represent greater impairments. B. The age at which key events occurred for each subject are represented in a graphical timeline (n = 27). This includes age at clinical presentation (solid black circle), age at diagnosis (grey circle), independent ambulation (red open triangle), and onset of seizures (black X) overlayed on a grey bar representing the duration of available medical records. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3.

Motor performance in the BPAN population. Left panel, GMFM-66-IS performance was assessed in a subgroup of individuals (n = 11). Scores are expressed in percentage. Middle and right panels, Peabody-2 performance in a subgroup of subjects (n = 5) was used to assess fine motor skills (Grasping and Visual Motor Integration-VMI). Peabody is presented as age equivalence. Individuals with early onset disease are shown by open triangle, while individuals with late onset disease are represented with a closed circle.

Fig. 4.

Cognitive non-verbal and adaptive behavior performance in the BPAN population. A. Performance on the Leiter-3 showed as Intelligence Quotient (IQ) and subscore percentiles. (B–D) VABS-3 performance is presented as percentages (B), standard scores (C), and subdomains are presented as v-scores (D). In all panels, individuals with early onset disease are shown by open triangle/white bars, while individuals with late onset disease are represented with a closed circle/grey bars. The box and whiskers represents median with interquartile ranges.