A new strategy for assessing the natural history of leukodystrophies

Natural history studies are an important standard in medical research because they analyze demographic, genetic, environmental, and other variables to better understand how diseases develop and their clinical consequences.

Because these studies are typically prospective, identifying targets and following patients to learn about them, they are less ideal for very rare diseases because only a small number of patients with a specific disease are correctly identified.

In a new study, researchers at Children’s Hospital of Philadelphia (CHOP) used a variety of rare leukodystrophies to demonstrate how retrospective studies can integrate real-world data to better capture the trajectory of the disease and provide insights for those Provides important information for future research in patients with rare diseases.

The findings were recently published in the journal Molecular Genetics and Metabolism.

Prospective research into rare diseases (classified as conditions that affect less than 1 in 5 people in the United States) is challenging because many patients are not immediately diagnosed with rare diseases, a process often referred to as ” A Diagnostic Odyssey,” the family spent years waiting for the correct diagnosis.

This delay in diagnosis may be further complicated when the number of patients affected by these diseases is small, both factors limiting the timely collection of natural history data. Without this important information, patients often are not diagnosed before symptoms appear, making it more difficult to draw a complete medical history and potential course.

Leukodystrophies are a group of rare genetic disorders that affect the white matter of the brain. Most leukodystrophies are neurodegenerative, which causes more damage to the white matter and worsens symptoms such as impairments in movement, speech, vision, hearing, and physical and mental development. Developing therapies to treat these diseases has been difficult given the challenges of studying the natural history of leukodystrophies.

The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) is a network of research institutions across the United States working together to address these challenges by mapping the clinical course of different types of leukodystrophy. This provides an important starting point for researchers to collaborate and find new ways to map the natural history of rare diseases.

“By working together, we were able to understand the challenges of studying the natural history of these patients and develop standardized methods that can better utilize the data already in the medical record,” said the study’s lead author Laura Adang, MD, PhD. . D., an attending physician in the Department of Neurology at CHOP, specializes in the care of children with leukodystrophies.

“Using this approach allows us to replicate many features of clinical trials so that we can produce reproducible results to help guide our trial design and accelerate diagnosis for new patients.”

For this study, the researchers developed a series of standard operating procedures that describe the study process and detail a standardized approach to data extraction, including diagnoses, clinical manifestations, and medical events requiring specific interventions. Establish electronic case reports and key variables to collect analyzable data.

To simulate the “blind” research method often used in clinical trials, a blind double-evaluator method was used to perform retrospective evaluation, with a third evaluator reviewing the differences in the scoring methods of the first two evaluators.

The researchers found that this approach successfully used existing medical records to populate key parts of the natural history profile of patients with leukodystrophy.

“Leukodystrophies can vary widely between mutated genes, medical events and clinical manifestations, and often create complex confusion for clinicians trying to make an appropriate diagnosis and for researchers trying to develop new treatments,” the paper said. said Adeline Vanderver, MD, senior author of the study.

“The methods explored in this study provide us with a viable alternative to randomized controlled trials and may help accelerate the design of future clinical trials for treatments for patients with rare diseases.”