Every rare disease tells a story. Understanding how one unfolds — how it develops and evolves — is often the first step toward treating it. A small genetic error, a malfunctioning cell or a breakdown in a biological process can set disease in motion. But for many rare conditions, the course of progression remains unwritten. 

A groundbreaking natural history study led by researchers at Mayo Clinic's Center for Individualized Medicine and Department of Clinical Genomics aims to change that, advancing research for one rare disease with the potential to benefit many others. 

At the center of this effort is autosomal dominant leukodystrophy, a rare, hereditary neurodegenerative disorder. It is driven by a single genetic variant that causes an abnormal buildup of a protein. This disrupts nerve cell function and the brain's signaling network. Over time, this damage leads to a slow decline in movement, balance and essential body functions. 

A road map for research and treatment

This extensive study will track the disease from its earliest stages to advanced progression in patients from around the world. By analyzing patient medical records, brain imaging scans, genetic data, neurological assessments and more, researchers will develop a comprehensive dataset to identify key biological markers in people with the disease.  

These insights will serve as a foundation for future clinical trials. 

"Genetic therapies are increasingly becoming a reality for rare diseases, providing hope of a treatment that can address the root cause of the disease," says Margot Cousin, Ph.D., the study's lead investigator and director of the Center for Individualized Medicine's N-of-1 Therapeutics program. "We need to have systems in place to study these disorders so we can bring these therapies into clinical practice efficiently." 

What makes this disease so challenging?

Autosomal dominant leukodystrophy is classified as an ultra-rare disease, meaning it affects a small number of people worldwide. Fewer than 50 families have been identified, but researchers believe many cases go undiagnosed due to its similarities to other neurological conditions and limited access to genetic testing.  

Because it is so rare, most clinicians will never encounter a patient with autosomal dominant leukodystrophy (ADLD). When they do, the disease can be difficult to recognize, as its symptoms resemble other neurological disorders that affect the brain's protective nerve coating. This often leads to misdiagnosis and delays in care. 

Further, the type of genetic alteration that causes autosomal dominant leukodystrophy may not be detected using some common genetic testing methodologies, putting even more importance on the clinical recognition of the disease. Researchers emphasize the need to increase awareness of the disease among neurologists to help patients receive an accurate diagnosis sooner. 

How the study works

This natural history study is a collaboration with Children's Hospital of Philadelphia through the Global Leukodystrophy Initiative. This initiative has extensive expertise and infrastructure needed to capture and analyze data on autosomal dominant leukodystrophy at depth. 

Mayo Clinic researchers are working within this collaboration to improve how the disease is studied and to ensure data collection meets the highest clinical research standards.  

This study is also supported by the ADLD Center, a patient advocacy group, whose mission is to support research on the disease's pathology and therapy. The center provides patients, caregivers and families with essential resources and a strong support network.  

Improving diagnosis and clinical care

Alongside this natural history study, Mayo Clinic has established the Autosomal Dominant Leukodystrophy Clinical Care Center, dedicated to diagnosing and managing this disease. The center is led by Radhika Dhamija, M.B.B.S., a neurologist and medical geneticist in the Mayo Clinic Department of Clinical Genomics. This clinical care center coordinates care across neurology, urology, radiology, genomics and other specialties to provide the highest level of care for patients. 

"We are creating a dedicated clinical and research infrastructure for identifying patients earlier so they can receive the highest level of multidisciplinary care," says Dr. Dhamija. "This is about transforming the future of how we approach rare neurogenetic diseases." 

A model for future rare disease research

Mayo Clinic researchers see this natural history study on autosomal dominant leukodystrophy as a model for accelerating research in other ultra-rare conditions that remain understudied due to small patient populations. 

"We're building a framework that brings scientific clarity to diseases that have remained long overlooked," Dr. Cousin says.  

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