Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease)

Abstract

Objective: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials.

Methods: We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis.

Results: The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype.

Conclusion: The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials.

Figure. Physical Impairment domain scores worsen over time

(A) Physical Impairment scores at the most recent time of testing for all subjects are shown. The fitted line of predicted values (green dashed line) is based on ordinary linear regression analysis for the entire cohort using the most recent Physical Impairment score with age as the only independent variable. The colored labels indicate the subject's CLN3 genotype (CLN3 deletion homozygotes, filled blue diamond, and other CLN3 genotypes, filled red circle). Subject A is described in the text. (B) Physical Impairment scores of the subset who are homozygous for the common CLN3 deletion (the most common genotype seen). When subjects participated for multiple evaluations, their scores are marked by connected hollow blue diamonds. Those seen for a single visit are marked by a filled blue diamond. The fitted regression line (blue) with 95% confidence interval (CI) reflects the regression estimates for this subset only. The dashed green line is included to show the fitted regression for the entire cohort, discussed in A. (C) Physical Impairment scores of those with other CLN3 genotypes (noncommon deletion homozygotes.) When subjects participated for multiple evaluations, their scores are marked by connected hollow red circles, and those seen for a single visit are marked with a filled red circle. The fitted regression line with 95% CI reflects the regression estimates for this subset only. Subject A is described in the text.