Our primary aim was to search for associations of genotype with behavioural function in a group of children and young adults with genetically confirmed JNCL. At least 40 disease-causing mutations in CLN3
have been identified (CLN3
mutation database: http://www.ucl.ac.uk/ncl/cln3.shtml
); however, the function of the protein encoded by this gene is unknown. We did not find significant associations between genotype and clinical behavioural phenotype in this cross-sectional examination of the data. Our compound heterozygous participants included individuals with a diverse set of genotypes, some of which have been individually reported to be associated with alternative clinical progression. However, we did not find consistent genotype–phenotype differences using our objective rating scale data. The collective grouping of these compound heterozygotes may partly explain why the findings of the present study are different from those of a previous Finnish investigation that reported phenotypic variability among heterozygotes. However, the difference may also reflect the smaller sample size of the previous investigation and the different methodology for rating motor neurological function.14
Another possibility is that variable progression in individual cases is due to other modifier genes or mutations in CLN3
that are not yet understood. Identification of genotype–phenotype patterns associated with either CLN3
mutations or modifier genes may help further our understanding of genomic and biochemical correlates or modifiers of clinical disease and provide a focus for targeted interventions with respect to both anticipation and management of symptoms, and improved models for future clinical trials.
We also recognize that the use of an ordinal scale can affect the interpretation of clinical ratings of symptom frequency and severity. More work is needed to refine our understanding of what type of numerical score would best describe the clinical state of individuals with JNCL, but to our knowledge no better scoring system yet exists for describing disease and disease progression in this rare disease. The UBDRS was modelled after two other clinical rating scales, also using ordinal rankings, that are criterion standard assessment tools for clinical studies of particular diseases: UHDRS for Huntington disease13
and UPDRS for Parkinson disease15
Our second goal was to examine the validity of the behaviour assessment portion of the UBDRS for evaluation of JNCL. Previous investigations by the URMC Batten Study Group established good reliability of the UBDRS,9
and also established the use of the CBCL for quantifying behavioural problems in this disease.4
Our present study extends and integrates the work of these earlier projects. There was good convergence of the UBDRS behavioural scale and the CBCL – an externally valid, omnibus measure of child behaviour problems. Further, there was evidence of divergence or lack of association between the UBDRS physical scale and the CBCL. In addition, we demonstrated that, within the UBDRS itself, the behavioural and physical scales appear to measure independent constructs. The significant correlations among related items and scales from the UBDRS behavioural scale and the CBCL, and divergence between mood and behavioural symptoms (on both UBDRS and CBCL) and physical manifestations, help support the validity of the UBDRS behavioural construct. Our group has also previously reported that cognitive and physical symptoms are not closely related, particularly in earlier disease stages,5
and this also seems to be the case when considering behavioural and physical symptoms. The finding that physical and psychiatric features are uncorrelated is consistent with findings in Huntington disease, another neurodegenerative disease, but one with onset primarily in adulthood.13,16
A future step of our research will be to examine whether there is differing progression of the longitudinal course of physical versus behavioural symptoms.
The small but significant correlation between aggression and mood symptoms was unexpected. Children and young adults with emotional distress may also have more generalized behavioural problems, as was suggested in this study by significant correlations between total problems scores (on UBDRS and CBCL) and both mood problems and aggressive/externalizing problems (as assessed by either the UBDRS or CBCL). There may also be overlapping features of these symptom clusters (internalizing or mood problems) and aggression, such as an irritable or labile mood that can be accompanied by aggressive outbursts. As noted previously, the ‘aggressive to self’ UBDRS item may overlap with features of the CBCL depressive scales, which contain reference to self-injurious behaviours. Finally, normative data from the CBCL10
also show modest but significant correlations between internalizing (i.e. mood problems) and externalizing (e.g. aggression, defiance) problems. The management of mood and behaviour symptoms in the setting of dementia is challenging at best, and there are no established guidelines for treatment of these dementia-related problems in paediatric groups. Prospective clinical trials of behavioural and pharmacological interventions are needed to establish best practices for improving affected individuals’ symptoms and quality of life. We have also previously acknowledged the challenges of evaluating the relative impacts of seizures, cognitive impairment, and behavioural symptoms in this disease.4
We view each of these symptoms as manifestations of the underlying neurodegenerative disease process, and recognize that further work is needed to establish a disease model clarifying the relationships among these symptoms.
In studying any rare disease, small sample sizes may limit the extent of analyses, but are an unavoidable limitation. Nonetheless, our studies of JNCL involve the largest known group of individuals with this disease. In our longitudinal studies, we will further compile an extensive body of data on within-participant progression of physical and behavioural symptoms (UBDRS, CBCL), other aspects of the disease (seizures, vision loss, and dementia), symptom management, and other relevant medical history and patient and family demographics. In doing so, we will be able to better describe the clinical phenotype and natural history of JNCL within individual participants and subgroups (e.g. by genotype, sex). The relatively smaller number of compound heterozygotes and their wide variety of mutations is also a potential limiting factor in understanding genotype–phenotype relationships. Although the overall percentage of compound heterozygotes as a function of the total sample is not predicted to increase, we expect that continuing enrolment will increase the absolute number as well as the range of compound heterozygotes available for study. Finally, in our sample, all participants were clinically symptomatic at the time of assessment. Consequently, little is known about early and perhaps subtle genotype–phenotype differences that may signal or accompany clinical onset of disease. A future goal is to better understand clinical phenotype–genotype associations across the full range of disease severity and disease duration, including children and young adults with genetically confirmed CLN3 but who are presymptomatic or in very early stages of phenoconversion.
What this paper adds
- Previous reports of genotype and clinical phenotype differences were unsupported in this investigation
- It furthers our understanding of neurobehavioral symptoms in JNCL.
- The validity of a disease-specific rating scale for neurobehavioral symptoms in JNCL is established.
- Neurobehavioral and physical symptoms in JNCL are differentiated.