P066: Treatment of BOLA3-associated multiple mitochondrial dysfunctions syndrome 2 with a mitochondrial cocktail

Introduction: Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder characterized by neurodevelopmental abnormalities, microcephaly, myoclonic epilepsy, and other types of seizure.COXPD35 is caused by pathogenic variants in the TRIT1.There are only 14 patients with COXPD35 have been reported in the literature.Aim & Method: To define the clinical and molecular findings of two unrelated patients with COXPD35, bringing the total number of patients reported to 16 patients.Case Presentation: Patient 1: A 7-year-old male with intermittent tremors, global developmental delay, feeding difficulties, axial hypotonia, and peripheral hypertonia with hyperreflexia noted since infancy.He developed generalized tonic-clonic seizures at 4 years, which was warranted to start levetiracetam but stopped shortly.The patient stayed clinically seizure-free.At 5 years of age, he was diagnosed with ADHD and acquired frequent stereotypical movements and insomnia.He is currently in a multiple disabilities classroom.He speaks using 2-3-word sentences.He has a wide-based ataxic gait, facial dysmorphism, and a growth curve below the 5th percentile but no microcephaly.Patient 2: A 5-year-old male presented with daily spells of twitching and jerking movements of the head at 6 months, diagnosed as myoclonic seizures.By 12 months, he had severe global developmental delay.He had an electroencephalogram (EEG) which was consistent with epileptic encephalopathy.Epilepsy was refractory to multiple medications, leading to considering medications that are not often used.He also has ADHD and insomnia.On physical examination, he was able to walk independently with an ataxic gait.He had axial hypotonia with lower limb hypertonia and spasticity.He eats independently and has learned 20-30 words.Facial dysmorphism and microcephaly were noted.Diagnostic Workup: Patient 1: Brain MRI showed left optic nerve hypoplasia.Biochemical investigations showed a slight decrease in total glutathione, whereas plasma amino acid (PAA) acylcarnitine profiles (ACP) and lactate were normal.Exome sequencing revealed a de-novo TRIT1 variant c.702A>C (p.Ala234Ala) and a paternally inherited TRIT1 variant c.22C>T (p.Arg8Ter).Patient 2: Brain MRI showed bilateral reduced white matter and diffusely thin corpus callosum.Lactate levels have been normal.ACP was normal, and PAA was notable for intermittent elevation of alanine.Exome sequencing revealed compound heterozygous variants in TRIT1: c.