Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database (P3-11.017)

This analysis of Adult-Onset Leigh Syndrome (LS) patients from the North American Mitochondrial Disease Consortium (NAMDC) Registry aims to enhance clinical insights, improve diagnoses, and uncover potential modifiers. LS is a rare syndrome linked to defects in more than one hundred genes. Most LS patients develop subacute neurological deterioration or regression before age two years. The pathological and radiological hallmarks are the subacute necrotizing degeneration of basal ganglia, cerebellum, brainstem, and/or cervical spinal cord, frequently triggered by metabolic stress. A small group of patients develop central nervous system involvement later in life. This retrospective study stemmed from a case of a twenty-five-year-old man with mild developmental delay and sensory-motor neuropathy admitted for worsening weakness. During his hospital stay, he developed a rapidly progressive encephalopathy and classic LS radiological findings. Intrigued by this observation, we interrogated the NAMDC registry to retrieve data from other adult-onset LS individuals. The registry contains demographic, manifestation, genetic, imaging, and biochemistry data from more than 2100 subjects enrolled from 17 centers in North America and Canada. We identified six subjects with onset of CNS manifestations after age 18. Most of the subjects had been involved of other organ systems preceding the CNS lesions. Four probands had pathogenic variants in nuclear-encoded mitochondria metabolism genes, one in mitochondrial DNA-encoded ATP synthase subunit gene, and one patient remained genetically undefined. The disease progression varied among the cohort, with probands harboring nuclear variants experiencing a slower course compared to the individual with a mitochondrial DNA defect, who suffered a rapid, progressive, and fatal deterioration. Our data show that mitochondrial patients with LS experience evolving and progressive phenotypes, and the presence of manifestations in other organs often precedes LS in adults, suggesting that clinicians should carefully avoid metabolic stressors known to precipitate neurodegeneration in subjects with the observed genetic variants. Disclosure: Dr. Barca has nothing to disclose. Dr. Kroopnick has nothing to disclose. Dr. Houck has nothing to disclose. Dr. Thakur has received personal compensation for serving as an employee of World Health Organization. Dr. Thakur has received personal compensation for serving as an employee of Pan American Health Organization. Dr. Thakur has received personal compensation in the range of 10, 000-49, 999 for serving as a Consultant for Delve Bio. The institution of Dr. Thakur has received research support from Center for Disease Control and Prevention. The institution of Dr. Thakur has received research support from National Institute of Health. Dr. Dugue has nothing to disclose. Dr. Zolkipli-Cunningham has nothing to disclose. An immediate family member of Marni Falk has received personal compensation in the range of 5, 000-9, 999 for serving as a Consultant for Lumiere. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Mission Therapeutics. Marni Falk has received personal compensation in the range of 5, 000-9, 999 for serving as a Consultant for Primera Therapeutics. Marni Falk has received personal compensation in the range of 5, 000-9, 999 for serving as a Consultant for Imel Therapeutics. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for MiMo Therapeutics. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for GenoMind. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Autobahn. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Casma Therapeutics. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Mayflower, Inc. . Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Precision Biosciences. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Foresite Labs. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Stealth BioTherapeutics. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Taysha Gene Therapies. Marni Falk has received personal compensation in the range of 10, 000-49, 999 for serving on a Scientific Advisory or Data Safety Monitoring board for Larimar Therapeutics. Marni Falk has received personal compensation in the range of 10, 000-49, 999 for serving on a Scientific Advisory or Data Safety Monitoring board for Khondrion. Marni Falk has received personal compensation in the range of 500-4, 999 for serving as an officer or member of the Board of Directors for United MItochondrial Disease Foundation. Marni Falk has stock in Rarefy Therapeutics. Marni Falk has stock in RiboNova Inc. The institution of Marni Falk has received research support from Merck. The institution of Marni Falk has received research support from Saol Therapeutics. The institution of Marni Falk has received research support from Stealth Biotherapeutics. The institution of Marni Falk has received research support from Astellas. The institution of Marni Falk has received research support from UMDF. The institution of Marni Falk has received research support from CureARS Foundation. The institution of Marni Falk has received research support from Mission Therapeutics. The institution of Marni Falk has received research support from Cyclerion. The institution of Marni Falk has received research support from NIH. The institution of Marni Falk has received research support from DOD. The institution of Marni Falk has received research support from FDA. Marni Falk has received intellectual property interests from a discovery or technology relating to health care. Marni Falk has received publishing royalties from a publication relating to health care. Dr. Goldstein has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Reneo Pharmaceuticals. Dr. Demczko has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Merck Manuals. Dr. Gavrilova has nothing to disclose. Austin Larson has received personal compensation in the range of 5, 000-9, 999 for serving as a Consultant for Illumina. An immediate family member of Austin Larson has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Neurocrine. An immediate family member of Austin Larson has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Ionis. Austin Larson has received personal compensation in the range of 0-499 for serving as a Consultant for Tisento. Austin Larson has received personal compensation in the range of 0-499 for serving as a Consultant for UCB. The institution of Austin Larson has received research support from Stealth Biotherapeutics. The institution of Austin Larson has received research support from Astellas. The institution of Austin Larson has received research support from Entrada. The institution of Austin Larson has received research support from Neuren. The institution of an immediate family member of Austin Larson has received research support from Neurocrine. Johan Van Hove has received intellectual property interests from a discovery or technology relating to health care. Dr. Saneto has received personal compensation in the range of 500-4, 999 for serving on a Scientific Advisory or Data Safety Monitoring board for REATA. Dr. Saneto has received personal compensation in the range of 500-4, 999 for serving on a Speakers Bureau for GW Pharmaceuticals. The institution of Dr. Saneto has received research support from NIH. The institution of Dr. Saneto has received research support from Zogenix. The institution of Dr. Saneto has received research support from GW Pharmaceuticals. The institution of Dr. Thompson has received research support from NIH. Dr. Hirano has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Modis Therapeutics (a subsidiary of Zogenix). Dr. Hirano has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Epirium Bio. Dr. Hirano has received personal compensation in the range of 500-4, 999 for serving as a Consultant for Innovation Specialist. Dr. Hirano has received personal compensation in the range of 5, 000-9, 999 for serving on a Speakers Bureau for Platform Q Health. The institution of Dr. Hirano has received research support from Modis Therapeutics (a subsidiary of Zogenix). The institution of Dr. Hirano has received research support from Cyclerion. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. Dr. Hirano has received personal compensation in the range of 0-499 for serving as a Study Section Reviewer with NIH. Dr. Hirano has a non-compensated relationship as a Research Advisory Board member with Muscular Dystrophy Association that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific and Medical Advisory Board member with United Mitochondrial Disease Foundation that is relevant to AAN interests or activities. Dr. Hirano has a non-compensated relationship as a Scientific Advisory Board member with Barth Syndrome Foundation that is relevant to AAN interests or activities.