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. Neurology The neuronal ceroid lipofuscinoses (NCLs) are degenerative, autosomal recessive storage diseases with common clinical and pathologic features, including blindness, seizures, dementia, motor decline, and lysosomal accumulation of autofluorescent material (ceroid and lipofuscin).1 The NCLs are categorized by genetic etiology. The juvenile form of neuronal ceroid lipofuscinosis (JNCL), also called Batten disease, is the most prevalent NCL. Clinically, JNCL begins with progressive visual loss between 4 and 8 years of age, followed by seizures, then loss of motor coordination and dementia between 10 and 12 years. Death occurs by the third or fourth decade. 1,2 JNCL is due to mutations of the CLN3 3 gene that encodes a ubiquitously expressed protein of unknown function localized to the lysosomal membrane 4,5 ; modeling studies suggest a role in substrate trafficking. 5,6 Most cases of JNCL are caused by an approximately 1-kb deletion in the CLN3 3,7 gene, encompassing exons 7 and 8. Approximately 74% of patients with JNCL are homozygous for this common deletion, and 22% are compound heterozygotes for this deletion and another CLN3 mutation.8 There are no mutations consistently associated with better prognosis. 8 -10 From the University of Rochester (J.M.K., H.A., P.G.R., E. With biological advances, there is hope for rational therapies to prevent, slow, or reverse the course of JNCL. We developed the Unified Batten Disease Rating Scale (UBDRS) to measure disease progression in JNCL.11 We used the UBDRS to evaluate and quantify disease burden in 82 subjects with JNCL from 2002 through 2010...

Future perspectives: Moving towards NCL treatments

“…As candidate treatments for other forms of NCL make their way into clinical trials, the successful efforts for CLN2 will serve as an important model. The first CLN3 human clinical trial is also under way (Phase 2 trial of CellCept, ClinicalTrials.gov NCT01399047) and is aiding in the optimization of an across-site CLN3 rating scale for future analysis of efficacy (15–17). …”

A Case-controlled Investigation of Pain Experience and Sensory Function in Neuronal Ceroid Lipofuscinosis

“…1 The most common form of NCL is Batten disease. These autosomal recessive lysosomal storage diseases are marked by the accumulation of autofluorescent lipopigments in the brain and throughout the body.…”

“…2 NCL is associated with widespread neuron loss, glial activation, and synaptic pathology which contribute to the devastating clinical presentation of the disease (i.e., blindness, epilepsy, dementia) and ultimately death. 1,2 …”

“…3 Unfortunately, diagnosing pain and providing effective treatment can be especially problematic when language abilities are compromised as in the case of individuals with NCL during disease progression. 1,3 …”

“…Considering the degeneration of the central nervous system and the neuronal damage known to occur during the progression of NCL 1 and two prior survey studies, there is ample reason to speculate about sensory problems in relation to the possible pain experienced as the disease progresses. 4 Accordingly, the purpose of this study was to extend the prior survey study findings by 1) further evaluating the use of pain scales developed from work with nonverbal children with developmental disabilities to characterize the pain experience of individuals with NCL, and 2) testing the feasibility of a non-invasive approach for quantifying sensory reactivity among individuals with NCL.…”