Abstract Details

Title Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 11-017

Background 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.

Objective 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

Design/Methods 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.

Results

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.

Conclusions 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.

Authors/Disclosures
Emanuele Barca, MD, PhD (Columbia University) PRESENTER	Dr. Barca has nothing to disclose.
Adam Kroopnick, MD (NYP)	Dr. Kroopnick has nothing to disclose.
Alexander Houck, MD (Columbia University Irving Medical Center)	Dr. Houck has nothing to disclose.
Kiran Thakur, MD, FAAN (Columbia University College of Physicians and Surgeons)	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.
Rachelle Dugue, MD, PhD	Dr. Dugue has nothing to disclose.
Zarazuela Zolkipli-Cunningham, MBChB (The Children's Hospital of Philadelphia, Human Genetics)	Dr. Zolkipli-Cunningham has nothing to disclose.
Marni Falk	No disclosure on file
Amy Goldstein (CHOP)	No disclosure on file
Matthew Demczko (Children's Hospital of Philadelphia)	No disclosure on file
Ralitza H. Gavrilova, MD (Mayo Clinic)	Dr. Gavrilova has nothing to disclose.
Austin Larson	No disclosure on file
Johan Van Hove	No disclosure on file
Russell P. Saneto, DO, PhD (Seattle Childrens Hospital)	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.
Richard Buchsbaum	No disclosure on file
John L. Thompson, PhD (Columbia Univ School of Public Health)	The institution of Dr. Thompson has received research support from NIH.
Michio Hirano, MD, FAAN (Columbia University Medical Center)	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 $500-$4,999 for serving as a Consultant for Precision Biosciences. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Platform Q Health. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for UCB. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Stealth Biotherapeutics. 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 research support from Reneo Pharmaceuticals. The institution of Dr. Hirano has received research support from Astellas. Dr. Hirano has received intellectual property interests from a discovery or technology relating to health care. 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.