Objective:

To explore the use of everolimus in Leigh syndrome (LS).

Background:

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.

Design/Methods:

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.

Results:

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.

Conclusions:

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.