To explore the benefits of mTOR inhibition in two patients with mitochondrial disease using a rapamycin analogue, Everolimus: Patient A has Leigh syndrome due to a NDUSF4 mutation, and Patient B has mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to MT-TL1, m.3243 A>G mutation.

Childhood onset mitochondrial disease causes severe morbidity and mortality and is untreatable. Rapamycin dramatically attenuated disease progression in NDUFS4 knockout model mice simulating Leigh Syndrome. This study encouraged us to treat two children with mitochondrial disease using a rapamycin analogue, Everolimus.

Patient A was diagnosed at age 13 months with Leigh syndrome (homozygous NDUSF4 missense mutation). At age 24 months, she had significant motor and speech delay, was unable to stand or walk, and dependent on tracheostomy and gastrostomy.

Patient B was diagnosed at age 4 years with MELAS syndrome (MT-TL1, m.3243A>G.) At age 5-1/2, he was hypotonic, lethargic, epileptic and dependent on gastrostomy.

Both patients were started on Everolimus (4.5 mg/m2/d) using the FDA approved protocol for the treatment of patients with tuberous sclerosis and subependymal giant cell astrocytomas.

Patient A showed remarkable response to treatment. After 20 months of treatment, she was walking independently with an ataxic gait, speaking in sentences, and no longer dependent on tracheostomy or gastrostomy. The Gross Motor Function Measure-88 had improved from 48.8% at age 2 years to 83.75% at age 3.8 years. Repeat brain MRI showed significant improvement.

The condition of Patient B, in contrast, continued to deteriorate until his death at age 6.7 years. Brain MRI studies also worsened reflecting this clinical deterioration.