A clinical rating scale for Batten disease - Reliable and relevant for clinical trials

University of Rochester School of Medicine and Dentistry, 1351 Mt. Hope Ave., Suite 223, Rochester, NY 14620, USA.
Neurology (Impact Factor: 8.29). 08/2005; 65(2):275-9. DOI: 10.1212/01.wnl.0000169019.41332.8a
Source: PubMed


Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions.
To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL.
A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted kappa statistics.
Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 +/- 1.6 years, and the mean duration of illness was 9.0 +/- 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85.
The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

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    • "JNCL patients also often suffer from psychiatric symptoms, including depression, anxiety and auditory and/or visual hallucinations [41], [54], [55]. Pain assessment and PPI testing of JNCL patients may be warranted, as these tests, if revealing of phenotypes, could be a useful means of further monitoring disease progression, alongside other already established clinical tests [56], [57]. "
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    ABSTRACT: Cln3(Δex7/8) mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Δex7/8) mice. Homozygous Cln3(Δex7/8) mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 weeks of age. Homozygous Cln3(Δex7/8) mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12-13 week old homozygous Cln3(Δex7/8) mice, which were also seen to a lesser extent in heterozygous Cln3(Δex7/8) mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15-16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3(Δ) (ex7/8) mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3(Δ) (ex7/8) neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3(Δ) (ex7/8) mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Δ) (ex7/8) mice that merit further study for JNCL biomarker development.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "To obtain a best estimate of age at first symptom onset, we limited this analysis to subjects whose parents reported vision loss as the first symptom. Vision loss is the most common first symptom that is most clearly linked to JNCL disease (Marshall et al 2005). Some subjects with multiple assessments had slight variation in the estimated age at onset from year to year. "
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    ABSTRACT: Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.
    Full-text · Article · Dec 2011 · Journal of Inherited Metabolic Disease
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    • "We have developed a clinical rating instrument for JNCL, the Unified Batten Disease Rating Scale (UBDRS) (Marshall et al. 2005). The UBDRS is a reliable and valid tool that quantitatively assesses five aspects of JNCL: physical ability, seizure activity, behavioral problems, functional capability, and global clinical impression of disease. "
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    ABSTRACT: Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood that typically presents at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. No therapy has been shown to slow the progression of disease in JNCL patients, and all current treatments are symptomatic. Flupirtine has been shown in vitro to reduce apoptosis in CLN3 lymphocytes. Based on that preclinical study, several children with JNCL were given flupirtine by their parents. The purpose of this study was to determine if there was evidence of attenuated disease progression in any JNCL symptom domain. We administered a survey to parents of JNCL children to qualitatively assess flupirtine efficacy. We used the Unified Batten Disease Rating Scale (UBDRS) to determine specific aspects of disease progression and investigated three age-related factors: loss of independent ambulation, loss of intelligible speech, and loss of ability to perform independent activities of daily living. The median scores for the UBDRS physical, behavior, and capability subscales were determined in flupirtine-exposed subjects and compared to age-, sex-, and genotype-matched subjects who had never taken flupirtine. Twenty-one percent of survey responders reported administering flupirtine to their JNCL child, and 56% of these families perceived beneficial changes that they attributed to flupirtine. However, our quantitative, prospectively obtained data did not show any change in JNCL disease progression that could be attributed to flupirtine. This study highlights the need for prospective experimental therapeutic research.
    Full-text · Article · May 2011 · Journal of Inherited Metabolic Disease
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