We have evaluated over 80 individuals with genetically confirmed JNCL using the UBDRS, and more than half have been evaluated on multiple occasions. This is the largest cohort of patients with JNCL followed clinically over time using a disease-specific rating scale. However, our cohort may diverge in some ways from the greater population of patients with JNCL. Anecdotal evidence and our own clinical experience suggest that the function of the subjects who participated in our study was representative of patients with JNCL as a whole.
Despite limitations in controlling for ascertainment bias, our data show the value of the UBDRS in quantifying JNCL progression. Correlation analyses show that Physical Impairment and Capability show quantifiable changes that appear to meaningfully reflect clinical morbidity. In our analyses, we focused on the Physical Impairment scores though we note its high correlation with Capability scores and that both domains demonstrate clinical worsening over time ().
Physical Impairment is the one domain in the UBDRS that requires an experienced examiner to collect data by performing a physical examination. Other domains are based on caregiver reports in face-to-face interviews with these same examiners. The advantage of the Physical Impairment domain is that it does not rely on parents or guardians to provide history and information. The high correlation with Capability demonstrates convergent validity with this domain in evaluating patients with JNCL.
Statistical analyses allow some generalizations about the rate of worsening physical impairment over time. Based on this cohort, we predict that an individual's Physical Impairment scores would increase approximately 3 points each year, suggesting that changes could be detected in clinical assessments performed every 6–12 months. However, there is much variability between individuals that is not well explained. The Physical Impairment domain is still influenced by the emotional and behavioral state of the subject at the time of testing, for example. Some of these qualities are assessed in other UBDRS domains not presented here.
We used fairly simple models to evaluate the variation in the Physical Impairment scores with age. Yet these models are robust in supporting our conclusions that UBDRS Physical Impairment deteriorates over time. Some subjects decline more rapidly than others, but this effect is not clearly dependent on genotype or gender. Although we highlight a single exception (subject A), patients who are homozygous for the common deletion are generally not distinguishable from compound heterozygotes based on their clinical histories and the UBDRS.
The idea that genotype might explain some of the clinical variability in JNCL has been suggested since the first description of the CLN3
Yet some patients homozygous for the common deletion can have very slow progression, mimicking a protracted course.8
The R334H mutation, often seen with a common deletion mutation, has been noted in some individuals with slower disease progression. This is similar to our subject A, who had later onset of physical impairment. In our cohort we follow 2 other individuals, one a compound heterozygote for the R334H mutation, and another homozygous for this mutation; their Physical Impairment scores do not show a protective effect and it is known that R334H is not consistently associated with a protracted clinical course.8
In the course of genetically characterizing our subjects, we have identified 3 novel variants (). The c.207G>A variant does not change the amino acid (Ser69) and is not predicted to create or destroy a splice site. Segregation studies show that it is in trans with the common deletion. We have been unable to obtain a fresh specimen to fully evaluate potential splicing effects such as disruption of a splicing enhancer binding site.15
The c.240delG mutation causes a frameshift starting at Pro81. The Leu384Pro mutation is in a position conserved in all reported CLN3
sequences in GenBank, except in the yeast Schizosaccharomyces pombe
instead of Leu
). Thus, the evidence supports a pathogenic role for c.240delG and L384P.
These analyses demonstrate the utility of the UBDRS Physical Impairment domain in quantifying disease progression in patients with JNCL. Further modeling and incorporation of other UBDRS domains may help account for the intersubject variability seen in UBDRS Physical Impairment and Capability domains. Our ability to quantify disease progression despite this variability compares favorably with scales used in other neurodegenerative conditions, such as in Niemann-Pick type C,16
and Huntington disease.20,21
Results from this study suggest that the UBDRS is a valid, reliable, and sensitive tool for assessment of clinical change over time and will have utility in the evaluation of therapies for JNCL.