Study Group Publication List

Bengt Elmerskog, Anne-Grethe Tøssebro, Rebecca Atkinson, Svein Rokne, Barbara Cole, Adam Ockelford, Heather R. Adams (2020).  Overview of advances in educational and social supports for young persons with NCL disorders . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2020 Sep 1.  Children with juvenile-onset Batten disease experience a plateau and decline in cognitive abilities impact their function over time. This article reviews what is known about the pattern of cognitive changes over time, and provides suggestions about an approach to education that emphasizes proactive learning, maintenance of skills, and continued engagement in community life through adaptations and supports in their environment. 

Margaux C Masten, Justin D Williams, Jennifer Vermilion, Heather R Adams, Amy Vierhile, Alyssa Collins, Frederick J Marshall, Erika F Augustine, Jonathan W Mink (2020). The CLN3 Disease Staging System: A New Tool for Clinical Research in Batten Disease. Neurology, 2020 Jun 9;94(23).  We recently developed and tested a clinical staging system for CLN3 disease (CLN3 Staging System; CLN3SS). Because CLN3 disease unfolds more slowly than other forms of Batten disease, division into groups based on discrete and meaningful clinical features is likely to be useful. In the CLN3SS, an individual is in stage 0 if they have genetically confirmed CLN3 disease but have not yet developed symptoms. Once there is evidence of vision loss, an individual enters stage 1. Stage 2 represents individuals who have vision loss and have experienced their first CLN3 disease-related seizure. Stage 3 represents individuals who have lost the ability to walk independently. Our goal is for this staging system to be useful for dividing individuals into groups that will lead to more efficient clinical trials in CLN3 disease. 

Cozart, E., Augustine, E., Mink, J., Thatcher, A., & Adams, H. (2017). Batten disease and parents: marital quality, support, and communication. Journal of the International Child Neurology Association, 0.  This study identified services and support accessed by parents of children with Batten disease and assessed parental marital quality. Twenty-nine parents of 23 Batten-affected children participated in this study.  Results showed that 78% of children received in-home nursing or paraprofessional care.  Parents expressed an interest in and preference for parent-to-parent communication for support and information about Batten disease; over 90% of parents used the internet and social media to learn or talk about Batten disease.  Furthermore, parent marital quality was lower than that reported in studies of the general population or parents of children with chronic, non-neurodegenerative disease. 

Williams RE, Adams HR, Blohm M, Cohen-Pfeffer JL, de Los Reyes E, Denecke J, Drago K, Fairhurst C, Frazier M, Guelbert N, Kiss S, Kofler A, Lawson JA, Lehwald L, Leung MA, Mikhaylova S, Mink JW, Nickel M, Shediac R, Sims K, Specchio N, Topcu M, von Löbbecke I, West A, Zernikow B, Schulz A. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017 Apr;69:102-112.
In this publication, management goals and strategies for CLN2 disease are described. Such goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease.

Ragbeer SN, Augustine EF, Mink JW, Thatcher AR, Vierhile AE, Adams HR. Remote assessment of cognitive function in juvenile neuronal ceroid lipofuscinosis (Batten disease): a pilot study of feasibility and reliability. J Child Neuro. 2016; 31(4):481-487.
This study presents preliminary evidence that telemedicine (remote video conferencing) may be a feasible and reliable way to conduct neuropsychological testing with children who have juvenile Batten disease. The authors suggest that using telemedicine in future research studies might reduce travel burden for families, reduce research costs, and improve access to expert care and/or clinical trials.

Augustine EF, Adams HR, Beck CA, Vierhile A, Kwon J, Rothberg PG, Marshall F, Block R, Dolan J, Mink JW; Batten Study Group. Standardized assessment of seizures in patients with juvenile neuronal ceroid lipofuscinosis. Dev Med Child Neurol 57(4):366-71, 2015.
This study examined seizures in individuals with JNCL using the Unified Batten Disease Rating Scale (UBDRS).  The most common seizures were generalized tonic-clonic seizures.  Seizures began, on average, at the age of 9 years and 7 months and became worse with age.  Seizures typically occurred less than once every 3 months and were managed with one to two medications for most participants.  Valproate and levetiracetam were the most commonly used seizure medications.

Drack AV, Mullins RF, Pfeifer WL, Augustine EF, Stasheff SF, Hong SD. Immunosuppressive Treatment for Retinal Degeneration in Juvenile Neuronal Ceroid Lipofuscinosis (Juvenile Batten Disease). Ophthalmic Genet. 2014 Feb 19. 21:1-6.

In this study, the visual function of an individual with JNCL who is being treated with immunosuppressive therapy is examined over two years.

Adams HR, Rose K, Augustine EF, Kwon JM, Deblieck EA, Marshall FJ, Vierhile A, Mink JW, Nance MA. Experience, knowledge, and opinions about childhood genetic testing in Batten disease. Molecular genetics and metabolism 111(2):197-202, 2014.
This study sought to understand parents’ perspectives, knowledge, and experiences related to genetic testing for Batten disease. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain genetic testing in children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics.

Mink JW, Augustine EF, Adams HR, Marshall FJ, and Kwon JM. Classification and Natural History of the Neuronal Ceroid Lipofuscinoses. J Child Neurol 28: 1101-1105, 2013.
There are several forms of Batten disease that vary in age of onset, specific neurologic phenotype, and rate of progression. We describe 9 major forms and present a classification scheme. Understanding the age of onset, clinical features, and natural history can inform rational diagnostics. Better knowledge of the natural histories of these disorders is necessary to shed light on the underlying pathobiology and to develop new therapies.

Dolisca SB, Mehta M, Pearce DA, Mink JW, and Maria BL. Batten Disease: Clinical Aspects, Molecular Mechanisms, Translational Science, and Future Directions. J Child Neurol 28: 1074-1100, 2013.
This publication outlines the 2012 Neurobiology of Disease in Children Symposium, which discussed the classification and natural history of Batten disease, disease pathology, molecular mechanisms that lead to pathology, and strategies that are being developed as potential therapeutics.

de Blieck EA, Augustine EF, Marshall FJ, Adams H, Cialone J, Dure L, Kwon JM, Newhouse N, Rose K, Rothberg PG, Vierhile A, and Mink JW. Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemp Clin Trials 35: 48-54, 2013.
This publication describes ways in which we have been able to carry out studies related to Batten disease. We created a registry where families can elect to enroll if they wish to be contacted about research studies. Currently, 198 families are enrolled, representing 237 children with Batten disease. Furthermore, the BDSRA has referred participants, and the annual BDSRA meetings have allowed us to enroll participants and complete studies.

Augustine EF, Adams HR, and Mink JW. Clinical Trials in Rare Disease: Challenges and Opportunities. J Child Neurol 28: 1142-1150, 2013.
This publication discusses challenges to conducting clinical trials in Batten disease, such as limited resources to conduct a trial, problems recruiting participants, unknowns related to the natural history of the disease, and ways to accurately measure change.  Authors propose solutions to these barriers, including multicenter collaboration, partnership with patient organizations, training new researchers, and using existing resources effectively.

Adams HR, Mink JW, and Group UoRBCS. Neurobehavioral Features and Natural History of Juvenile Neuronal Ceroid Lipofuscinosis (Batten Disease). J Child Neurol 28: 1128-1136, 2013.
This paper reviews the neurobehavioral features of JNCL.  The relevance of neurobehavioral studies is discussed to better understand the clinical phenotype of JNCL and potential targets for intervention.

Cialone J, Adams H, Augustine EF, Marshall FJ, Kwon JM, Newhouse N, Vierhile A, Levy E, Dure LS, Rose KR, Ramirez-Montealegre D, de Blieck EA, and Mink JW. Females experience a more severe disease course in Batten disease. J Inherit Metab Dis 35: 549-555, 2012.
We investigated differences between males and females with JNCL. Using data from the UBDRS, the BDSRA database, and a quality of life questionnaire (PedsQL), we found that JNCL symptoms began, on average, one year later in females than in males. Furthermore, female age at death was one year earlier than males. Overall, affected females had lower functional abilities, earlier loss of independent function, and lower physical quality of life than males.

Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, and Mink JW. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology 77: 1801-1807, 2011.
In this study, the UBDRS was used to measure the rate of physical and functional decline in individuals with JNCL. Physical impairment and functional capability worsened over time at an even rate following the initial symptom onset. The rate of decline did not depend on specific types of CLN3 mutations. The UBDRS is a reliable and valid instrument that measures symptom progression in JNCL.

Dickson PI, Pariser AR, Groft SC, Ishihara RW, McNeil DE, Tagle D, Griebel DJ, Kaler SG, Mink JW, Shapiro EG, Bjoraker KJ, Krivitzky L, Provenzale JM, Gropman A, Orchard P, Raymond G, Cohen BH, Steiner RD, Goldkind SF, Nelson RM, Kakkis E, and Patterson MC. Research challenges in central nervous system manifestations of inborn errors of metabolism. Mol Genet Metab 102: 326-338, 2011.

Cialone J, Augustine EF, Newhouse N, Vierhile A, Marshall FJ, and Mink JW. Quantitative telemedicine ratings in Batten disease: implications for rare disease research. Neurology 77: 1808-1811, 2011.
The purpose of this study was to determine if the Physical Impairment section of the UBDRS could be feasibly and reliably administered remotely using live video. Two trained raters scored the same exams using live video. The UBDRS Physical Impairment section is reliable when administered with telemedicine methods.

Cialone J, Augustine EF, Newhouse N, Adams H, Vierhile A, Marshall FJ, de Blieck EA, Kwon J, Rothberg PG, and Mink JW. Parent-reported benefits of flupirtine in juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) are not supported by quantitative data. J Inherit Metab Dis 34: 1075-1081, 2011.
We used the UBDRS to investigate the impact of flupirtine on disease progression in JNCL. The age of loss of independent walking, understandable speech, and the ability to perform independent activities of daily living was examined. Although many families perceived flupirtine to be helpful, our data showed that flupirtine had no effect on disease progression.

Adams HR, Beck CA, Levy E, Jordan R, Kwon JM, Marshall FJ, Vierhile A, Augustine EF, de Blieck EA, Pearce DA, and Mink JW. Genotype does not predict severity of behavioural phenotype in juvenile neuronal ceroid lipofuscinosis (Batten disease). Dev Med Child Neurol 52: 637-643, 2010.
This study examined the relationship between genotype and behavior problems in individuals with JNCL.  Authors found that behavior problems did not differ between individuals who were homozygous and heterozygous for the CLN3 deletion.  Authors also found that the Child behavior Checklist (CBCL), a widely used questionnaire that measures behavior problems, can be used with individuals who have JNCL and cross-validates well with the UBDRS.

Getty AL, Rothberg PG, and Pearce DA. Diagnosis of neuronal ceroid lipofuscinosis: mutation detection strategies. Expert Opin Med Diagn 1: 351-362, 2007.

Adams HR, Kwon J, Marshall FJ, de Blieck EA, Pearce DA, and Mink JW. Neuropsychological symptoms of juvenile-onset batten disease: experiences from 2 studies. J Child Neurol 22: 621-627, 2007.
This paper describes two studies of cognitive skills in children with juvenile Batten Disease. 1. 15 children with JNCL completed a brief test of their ability to pay attention. Their attention performances were lower than expected for their age, when compared to non-Batten affected groups.. 2. 18 children with Batten disease completed more detailed cognitive testing.  Compared to healthy, same-age peers, their scores were significantly lower on tests of attention, memory, verbal fluency, and general verbal reasoning skills. There were no significant differences between males and females. Cognitive skills were lower among children with a history of seizures. However, this study cannot tell us if seizures contributed to worse cognitive performance, or if some other factor influenced both seizures and cognitive skills.

Leman AR, Polochock S, Mole SE, Pearce DA, and Rothberg PG. Homogeneous PCR nucleobase quenching assays to detect four mutations that cause neuronal ceroid lipofuscinosis: T75P and R151X in CLN1, and IVS5-1G>C and R208X in CLN2. J Neurosci Methods 157: 124-131, 2006.

Adams H, de Blieck EA, Mink JW, Marshall FJ, Kwon J, Dure L, Rothberg PG, Ramirez-Montealegre D, and Pearce DA. Standardized assessment of behavior and adaptive living skills in juvenile neuronal ceroid lipofuscinosis. Dev Med Child Neurol 48: 259-264, 2006.
We examined behavior and adaptive living skills in children and young adults with Juvenile Batten Disease (JNCL). We found that behavioral and psychiatric symptoms were both frequent and severe in more than half of the study participants. The frequency of these problems did not differ in males and females. Compared to healthy same-age peers, children with JNCL had limitations in their adaptive living skills, such as self-care, hygiene, socialization, and other age-expected, everyday tasks.

Ramirez-Montealegre D, Chattopadhyay S, Curran TM, Wasserfall C, Pritchard L, Schatz D, Petitto J, Hopkins D, She JX, Rothberg PG, Atkinson M, and Pearce DA. Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Neurology 64: 743-745, 2005.

McClaskey JH, Leman AR, and Rothberg PG. Homogeneous amplification nucleobase quenching assay to detect the E474Q LCHAD deficiency mutation. Genet Test 9: 1-5, 2005.

Marshall FJ, de Blieck EA, Mink JW, Dure L, Adams H, Messing S, Rothberg PG, Levy E, McDonough T, DeYoung J, Wang M, Ramirez-Montealegre D, Kwon JM, and Pearce DA. A clinical rating scale for Batten disease: reliable and relevant for clinical trials. Neurology 65: 275-279, 2005.
We developed the UBDRS clinical rating scale to assess the physical-, seizure-, and behavior-related impairment and the functional abilities of individuals with JNCL. We found that the UBDRS is a reliable instrument that can be used to effectively monitor symptoms in individuals with Batten disease.

Leman AR, Pearce DA, and Rothberg PG. Gene symbol: CLN3. Disease: juvenile neuronal ceroid lipofuscinosis (Batten disease). Hum Genet 116: 236, 2005.

Kwon JM, Rothberg PG, Leman AR, Weimer JM, Mink JW, and Pearce DA. Novel CLN3 mutation predicted to cause complete loss of protein function does not modify the classical JNCL phenotype. Neurosci Lett 387: 111-114, 2005.
Much can be learned about the function of a protein and how it causes disease by analyzing the effects of mutations. This paper reports a case of JNCL with a unique mutation that causes a stop signal very close to the beginning of the CLN3 protein. The patient had a clinical course that did not differ from JNCL patients with other mutations.

Rothberg PG, Ramirez-Montealegre D, Frazier SD, and Pearce DA. Homogeneous polymerase chain reaction nucleobase quenching assay to detect the 1-kbp deletion in CLN3 that causes Batten disease. J Mol Diagn 6: 260-263, 2004.