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Abstract Details

MTOR Inhibition, a Potential Treatment for Leigh Syndrome? Report of Three Cases.
Child Neurology and Developmental Neurology
P10 - Poster Session 10 (5:00 PM-6:00 PM)
6-002
To explore the use of everolimus in Leigh syndrome (LS).
LS is a neurodegenerative disorder due to mitochondrial dysfunction, characterized by developmental delay/regression and symmetrical lesions in the central nervous system. No treatment is currently available. Studies in animal models of LS suggest that inhibition of the mTOR signaling pathway can delay onset and progression of symptoms. Previously, treatment of two children with mitochondrial disorders led to disparate responses, with improvement in the patient with LS.

Medical records of three genetically confirmed patients with LS treated with everolimus were reviewed. All were treated with everolimus targeting trough levels of 5-15ng/ml.

Patient A is a 9 year-old girl with a homozygous pathogenic variant in NDUFS4. Onset was at age 11 months with loss of milestones, hypotonia, and seizures. Everolimus treatment was started at age 2 years. After initial clinical improvement, her condition stabilized, but subsequently progressed. She is still alive. Patient B is a 16 year-old boy with compound heterozygous variants in NDUFAF6. Symptoms started at age 3 years with speech and motor regression, and dystonia. He started everolimus at age 14 years and has been stable for 2 years. Patient C is an 11 year-old boy with the m.8344 A>G mutation in MT-TK gene (95% heteroplasmy in blood). His complex clinical syndrome includes: upper cervical/medullary lesions causing hypoventilation and dysphagia, myoclonic epilepsy, myopathy, cardiac hypertrophy, optic neuropathy, and hearing loss. Symptom onset was at age 7 years, when optic atrophy was noted. Everolimus was started at age 10 years. His symptoms initially improved, but subsequent follow-up revealed clinical worsening at time of infections and onset of diabetes mellitus.
Everolimus may slow progression of LS, with acceptable side-effects, but response has been variable and partial. This preliminary experience justifies a prospective trial examining safety and effectiveness of everolimus treatment.
Authors/Disclosures
Michio Hirano, MD, FAAN (Columbia University Medical Center)
PRESENTER 		Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Biopharma SRL. 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 $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Biopharma SRL. Dr. Hirano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apollo Communication. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Envision Communications. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for 好色先生. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Cure SMA. Dr. Hirano has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Muscular Dystrophy Association. The institution of Dr. Hirano has received research support from UCB. The institution of Dr. Hirano has received research support from Cyclerion. The institution of Dr. Hirano has received research support from Astellas. The institution of Dr. Hirano has received research support from Tisento Therapeutics. The institution of Dr. Hirano has received research support from Stealth Biotherapeutics. The institution of Dr. Hirano has received research support from Abliva. 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.
Valentina Emmanuele, MD, PhD (NYP at CUIMC) Dr. Emmanuele has nothing to disclose.
Alexander Goldberg, PhD Dr. Goldberg has nothing to disclose.
Kristin Engelstad No disclosure on file
Linn E. Katus, DO (Neurological Institute of New York, Columbia University Medical Center) The institution of Dr. Katus has received research support from Parkinson's Foundation.
Jennifer Bain, MD, PhD (Columbia Doctors) Dr. Bain has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Consulting. Dr. Bain has received personal compensation in the range of $0-$499 for serving as a Consultant for M3 Consulting. Dr. Bain has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Legal Company . Dr. Bain has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Grin Therapeutics. The institution of Dr. Bain has received research support from Yellow Brick Road Project.
James Garvin (Columbia University Irving Medical Center) No disclosure on file
Darryl C. De Vivo, MD, FAAN (Columbia University) Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen and Novartis. Dr. De Vivo has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aspa Therapeutics.