Abstract
BACKGROUND AND OBJECTIVES: There is limited published evidence to guide the diagnosis and management of LMNB1-related autosomal dominant leukodystrophy (ADLD), an adult-onset progressive neurodegenerative genetic disorder caused by pathogenic variants in LMNB1. METHODS: We used a modified Delphi process to systematically combine literature evidence with international experts' recommendations to determine best-practice clinical care guidelines in the areas of diagnosis, genetic testing, surveillance, and management. RESULTS: Diagnosis: The diagnosis of ADLD should be considered in an individual with characteristic brain MRI findings and/or clinical symptoms of autonomic dysfunction, with or without a positive family history of autosomal dominant inheritance. The typical disease onset is insidious, followed by progression of manifestations.Genetic testing: The diagnosis of ADLD should be considered established in an individual with suggestive clinical and MRI findings, positive family history, and either a heterozygous pathogenic LMNB1 duplication or deletion upstream of the LMNB1 promoter identified on genetic testing. Single-gene testing that can identify LMNB1 structural variants (duplications/deletions) at a high resolution is currently the optimal means of confirming a genetic diagnosis. Exome sequencing is not recommended as a first-tier test.Surveillance: Careful physical examination, tilt table testing, brain and cervical spinal cord MRI, and neuropsychometric assessment should be conducted at first presentation, with follow-up evaluations determined by baseline findings and the clinical course. Symptoms localizing to other segments of the spinal cord may necessitate additional neuroimaging.Management: Specialists in neurology, physiotherapy, and genetics/genetic counseling are key to providing optimal care. Other specialists whose input will be valuable for some affected individuals include urologists, mental health specialists, physical medicine and rehabilitation physicians, and dieticians. For the management of myelopathy, a stepwise approach should be considered, beginning with oral antispasticity medications, followed by botulinum toxin injections, and, if needed, progressing to intrathecal baclofen therapy. All individuals with ADLD and those at risk who wish to conceive should be offered prenatal genetic counseling. DISCUSSION: Our consensus-based approach allowed us to formulate guideline recommendations in the setting of limited scientific evidence. Our analysis highlights the need for rigorous, collaborative studies on ADLD, including natural history studies, outcome assessments, and biomarker development, to improve our understanding and care of this devastating rare condition.