Objective: To assess the utility of PKAN-DRS as an outcome measure for monitoring disease progression in PKAN .

Background: The PKAN-DRS assess multiple domains affected by PKAN. To date, its longitudinal validation has not been assessed.

Method: PKAN-DRS was performed on patients with PKAN from 2 referral centres, during clinical visits from 2014-2023. Statistical analyses were performed using R (v.4.3.2). Correlation between clinical scores was assessed using Pearson correlation coefficients, Holm correction was used for multiple comparisons. Time-to-event analysis was performed on Kaplan-Meier cumulative incidence curves.

Results: 64 PKAN-DRS assessments were performed on 30 patients. 11 patients had 3 or more assessments, 14 had 2 assessments and 5 had a single assessment. For the 25 patients who had longitudinal assessments, the median time between assessments was 2.5y. Age at assessment ranged from 2.6-59 years, with a median of 23.6 (IQR 13.4-31 years). PKAN-DRS total scores ranged from 3-104 (median 51, mean 51.9, and SD 28.0). Subscales focussed on disability, parkinsonism, and dystonia all correlate closely with each other and the overall score (Pearson correlation coefficients 0.68-0.97) (Fig.1). Considering the mean slope of the 25 patients with longitudinal testing, there is a 6.1 points/year increase (95% CI 2.8-9.5) (Fig.2). This slope is steeper in classical (8.8 points-per-year; 95% CI 0.76-16.8) compared to atypical patients (5.1 points-per-year; 95% CI 1.2-9.0). Using a mixed effects model with binary covariates for sex and classical status, the fixed effect of age at assessment is 1.53 points/year and is statistically significant (p<0.0001). By including the age of onset of symptoms, both age at assessment (now 1.79 points/year, p=0.0009) and age at onset have fixed effects on the predicted DRS score. The effect of age at disease onset is negative (-2.9 points per year, p=0.002), meaning that the earlier age at onset, the more rapid is the progression.

Conclusion: The PKAN-DRS score increases with age, as confirmed by 3 different analyses, with the mixed effects model best accounting for patient variability. Our study provides longitudinal validation of the PKAN-DRS, strengthening  its use in clinical trials. The scale also captured differences among phenotypes, with children having a classic phenotype showing a more rapid progression.

Figure 1: PKAN-DRS inter-section graphs

Figure 2: PKAN-DRS score increases with age

References: Darling, A., Tello, C., Martí, M. J., Garrido, C., Aguilera‐Albesa, S., Tomás Vila, M., … & Pérez Dueñas, B. (2017). Clinical rating scale for pantothenate kinase‐associated neurodegeneration: a pilot study. Movement Disorders, 32(11), 1620-1630.
Darling, A., Decio, A., Serrano, M., Albesa, S. A., Zubimendi, I. G., Vila, M. T., … & Pérez-Dueñas, B. (2015). OP61–2294: Pantotenate kinase associated neurodegeneration: Clinical assessment and genetic characterization by means of a Spanish multi-centre research network. European Journal of Paediatric Neurology, 19, S19-S20.
Marshall, R. D., Collins, A., Escolar, M. L., Jinnah, H. A., Klopstock, T., Kruer, M. C., … & Lenderking, W. R. (2019). A scale to assess activities of daily living in pantothenate kinase‐associated neurodegeneration. Movement disorders clinical practice, 6(2), 139-149.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-monitoring-through-the-pkan-disease-rating-scale-pkan-drs-in-pantothenate-kinase-associated-neurodegeneration-pkan/