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Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts., Competing Interests: Declaration of competing interest Adeline Vanderver and Laura Adang have received research support from IONIS pharmaceuticals, Takeda, Sanofi, Eli Lilly, Boehringer Ingelheim, Affinia and Orchard Therapeutics. In addition, Dr. Vanderver has received research support from Illumina, Sana, Passage Bio, Homology and PMD foundation. Dr. Adang from Biogen, MSD Foundation, Don't Forget Morgan, Legacy of Angels and Orphan Disease Center. Dr. Vanderver and Dr. Adang hold the license for the AGS Severity Scale and Dr. Vanderver the patent of ASO in TUBB4A. Dr. Vanderver participates on the advisory board of ELA and United Leukodystrophy Foundation. Dr. Adang is the scientific advisor for CureMLD, MLD Foundation, Don't Forget Morgan, Yaya Foundation and MLDi. Dr. Vanderver is a site Principal Investigator (PI) for Takeda Pharmaceutical's clinical trial for Metachromatic Leukodystrophy NCT03771898 and is an advisor to Passagebio. Dr. Adang also serves as an advisor to Biogen. Dr. Vanderver, Dr. Adang, Dr. Fatemi, Dr. Eichler, Dr. Bonkowsky, Dr. Fraser, Dr. Keller, Dr. Emrick and Dr. Van Haren are recipients of NIH funding through the NINDS (National Institute of Neurological Disorders and Stroke) and/or NCATS (National Center for Advancing Translational Sciences). Dr. Eichler is a recipient of grants through Kennedy Krieger Institute Inc. and Children's Hospital Corporation dba Boston Children's Hospital, and has <1% equity in Swan Bio, and royalties from AAV9 license for AMN. Dr. Eichler receives consulting fees from Leal Therapeutics, Swan Bio, Ionis, Minoryx, UptoDate, Origen, Takeda Therapeutics and Third Rock Ventures. Dr. Eichler is the founder and consultant of Swan Bio, is the ALD connect chair, and serves on the chair on the advisory board of European Leukodystrophy Association, board member at United Leukodystrophy Foundation, and as a scientific advisor for National Tay Sachs and Allied Diseases Association. Dr. Fatemi is a PI for Viking Therapeutics and Minoryx Therapeutics and receives research support from CureLBSL, Brian's Hope Foundation, SwanBio, Autobahn Therapeutics, Poxel Therapeutics, Vertex Pharmaceuticals, and Maryland Stem Cell Research Fund. Also, Dr. Fatemi was former Data and Safety Monitoring Board (DSMB) member for BlueBird Bio, and serves as the ALD Connect Board member. Dr. Fatemi co-invented a patent currently licensed to Ashvattha. All other authors have no conflicts of interest. Dr. Bonkowsky receives research support through grant from European Leukodystrophy Association, and consults for Ionis, Sanofi, Autobahn, Denali, Passage Bio, Bluebird, Calico. He also serves on the ALD connect board. Dr. Keller is the site PI for Ionis Pharmaceuticals Alexander Disease trial and Biomarin Pharmaceuticals Brineura extension study. Dr. Keller consults for Veristat and serves on United Leukodystrophy Foundation and Leukodystrophy Care Network Certified Center. Dr. Emrick serves on the advisory board for Ionis pharmaceuticals. Dr. Van Haren receives research support from United Leukodystrophy Foundation and Stanford MCHRI. He consults for Bluebird Bio, Poxel, Autobahn Therapeutics and Viking, and has participated in the Calico Board. He also serves in the leadership capacity at ALD connect, United Leukodystrophy Foundation and Global Leukodystrophy Alliance. All other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)