Article In Brief
The development of various rating scales for neuronal ceroid lipofuscinosis, a group of rare progressive neurodegenerative disorders, has helped investigators cull data that help define the natural history of the disorders.
The best clinical trials depend on rigorously defined and validated outcome measures. But for many extremely rare diseases, there are no such measures, hampering the development of therapy and leaving a gap in the understanding of the disease. For the past 17 years, Jonathan W. Mink, MD, PhD, FAAN, and colleagues at the University of Rochester have devoted themselves to closing that gap for neuronal ceroid lipofuscinosis (NCL), collecting voluminous natural history data and developing a well-validated rating scale for the most common form of the disease, called CLN3, or Batten disease.
A detailed picture of the disease has emerged from that work, which Dr. Mink, professor of pediatric neurology at the University of Rochester in New York, outlined in the H. Houston Merritt Lecture at the Annual Meeting.
The NCLs are a group of progressive neurodegenerative disorders characterized clinically by vision loss, movement disorders, seizures, and dementia, and pathologically by accumulation of a waxy deposit (ceroid lipofuscin) in neurons. They are caused by mutation in any one of at least 13 genes, each of which affects cell metabolism in the lysosome/endosome pathway.
The disorders were initially classified by age of onset, from infantile to adult, “but in the gene era,” Dr. Mink said, “we know that the age of onset doesn't necessarily predict the genetic type of NCL,” and they are now classified by presumed genetic locus.
Some of the genes encode soluble enzymes, and so are more amenable to enzyme replacement therapy; this includes CLN2, for which the Food and Drug Administration has recently approved a treatment. CLN2 is the form of NCL with the highest incidence.
But most of the NCL genes, including CLN3, encode membrane proteins that facilitate lysosomal function, and are not so easily replaced. CLN3 disease is the most prevalent form of NCL, affecting about one in one million people in the United States, and it is that disease for which Dr. Mink and colleagues have labored long to understand the natural history and develop a rating scale.
The Therapeutic Challenges
“This work was motivated by the eventuality of having the opportunity to study interventions,” Dr. Mink said. “Like many of the rare neurodegenerative diseases, CLN3 disease presents some clear experimental therapeutic challenges. First, there is a slow progression over time, and the onset of progression occurs during times of developmental change, so very often the effects of degeneration don't manifest as loss of function, but as a slower attainment, or a loss of developmental improvement.”
Second, he said, is that the signs and symptoms present and evolve at different times over the disease course, for instance with early vision loss and late parkinsonism, “so one can't use only one component of the disease to track progression.” And finally, he noted, there are no established biomarkers.
Developing a Rating Scale
That led University of Rochester's Frederick Marshall, MD, to initiate in 2001 the development of a rating scale, an effort Dr. Mink joined shortly thereafter. Together, they reviewed the clinical literature to identify the salient clinical features, and drafted a rating scale based on the most important features. In 2002, they attended the annual family meeting of the Batten Disease Support and Research Association, “where we evaluated 23 individuals, 23 more than I had ever seen before we started this work,” Dr. Mink said.
They went on to refine the scale based on their experiences in the field, and then conducted formal reliability testing. The instrument reached its final form in 2007, and has demonstrated high levels of face validity, inter-rater reliability, and other measures of reliability.
The Unified Batten Disease Rating Scale (UBDRS) includes quantitative ratings on four subscales: physical assessment (28 items), seizures (12 items), behavior (nine items), and functional capability (five items). It also includes a measure of clinical global impression, and degree of change from the previous evaluation.
Development of the UBDRS, and research on the natural history of the disease that is has facilitated, has been aided by the establishment in 2001 of a registry of known cases, and the creation in 2005 of the Batten Center at the University of Rochester, a comprehensive center for research and clinical care, which allowed the team to bring patients and families to the center for evaluation.
Lessons from Evaluations
To date, Dr. Mink and colleagues have performed 460 evaluations, including 369 evaluations of 123 unique individuals with confirmed mutations in the CLN3 gene. About half have been seen for more than one evaluation. “This gives us the opportunity to do both cross-sectional and longitudinal research,” Dr. Mink said.
Quantitative natural history data are central to testing treatments in rare and lethal conditions such as CLN3, and the UBDRS has allowed the team to collect such data in great depth, and in doing so, to develop a nuanced understanding of the evolution of the disease.
“We've learned that the core disease features present in a characteristic, time-dependent manner, that physical symptoms worsen predictively in a monotonic manner over time, and in much of the course of the disease there is a linear decline,” Dr. Mink said.
“Parkinsonism is the prevalent movement disorder, and cognitive decline occurs earlier than is usually reported by parents and teachers, and progresses over time. And probably most importantly, we've learned that it is the combination of these features that leads to progressive loss of function. We can't attribute that loss to only one feature.”
Seizures are primarily generalized tonic-clonic, and myoclonic seizures are uncommon. “Contrary to what is in the older textbooks, seizures are only moderate in severity in most individuals,” Dr. Mink said.
They have also learned that there is a characteristic order of symptom onset, with vision loss usually first, followed by behavioral problems, cognitive problems, seizures, and motor problems. That predictable order has allowed the development of staging of the disease, which may be useful for stratification for clinical trials.
Cognitive assessment “is a real challenge,” he said, because most validated tools for cognitive assessment depend on vision, which is profoundly impaired early in life. That led team member Heather Adams, PhD, to develop a battery of tests that did not depend on vision. Those tests led to the recognition that verbal ability declines early and worsens with age, until around age 18 or 19, when the tests become insensitive to further change.
The UBDRS “has given us a rich store of prospectively obtained, quantitative, natural history data,” Dr. Mink concluded, which is likely to prove invaluable for future CLN3 trials, and is currently being modified for use in other forms of NCL. Even beyond these diseases, Dr. Mink said, “I like to think we have developed a useful model for doing natural history research in rare neurodegenerative diseases in children.”
“A rating scale in useful on two levels,” commented Ruth Williams, MD, an expert in Batten disease and consultant pediatric neurologist at Evelina Children's Hospital in London. While it can and likely will be used in clinical trials, the quantification of natural history that it allows enables physicians to answer parents' questions. “Because when you give them the awful news about their child's diagnosis,” she said, “they want to know when will the seizures start, or when will their child stop walking. The data from the rating scale allows us to answer these types of questions. It is very simple, but very important.”
Dr. Mink has received research funding from Abeona, Inc. as well as consulting fees from Beyond Batten Disease Foundation and Care Beyond Diagnosis. Dr. Williams had no disclosures.