Novel mutations in RMND1 presenting with dystonia and seizures (P4.168)

Objective: To describe a 3 year-old boy who presented at age 7 months with seizures and dystonia, in the setting of fever with novel compound heterozygous RMND1 mutations. Background: Mutations in RMND1 , encoding RMND1 (required for nuclear meiosis division-1), a mitochondrial protein of unknown function, have been reported in 20 patients presenting with early onset encephaloneuromyopathy, seizures, hearing impairment, nephropathy and early mortality. Laboratory studies have demonstrated decreased biochemical activities and levels of mitochondrial respiratory chain enzymes due to impaired mitochondrial protein synthesis. Design/Methods: This child of non-consanguineous parents developed normally until age 5 months, when he began to lose weight. At age 7 months, following DTAP, he developed a focal seizure with left arm and leg jerking and secondary generalization. Brain MRI showed focal diffusion restriction in the right frontotemporal regions. He was treated for presumed viral encephalitis. He had recurrent seizures, including infantile spasms, on multiple anti-epileptic drugs and developed dystonia of the right leg. He also manifested psychomotor retardation. Hearing and renal functions have been normal, but he developed hyponatremia. Results: Whole exome sequencing in the patient revealed two novel mutations in RMND1 : the missense mutation c.1316A>T (p.E439V) and the splice site mutation (c.614-2T>C). The parents each carried one mutation. Sequencing of the cDNA from the patient skin fibroblasts uncovered an alternative transcript containing an in-frame deletion of 6 nucleotides, resulting in the lack of two amino acids in the protein (D205_A206del). The patient fibroblasts showed biochemical defects of the mitochondrial complex I, III and IV and defect of mitochondrial protein synthesis. Conclusions: Although our patient’s fibroblasts manifested molecular and biochemical defects similar to those of other children with mutations in RMND1 , the boy’s clinical presentation differed from reported cases. This report confirms the clinical heterogeneity of RMND1 mutations and its importance in mitochondrial protein synthesis. Disclosure: Dr. Sanchez-Quintero has nothing to disclose. Dr. Lopez Gomez has nothing to disclose. Dr. Lichter-konecki has nothing to disclose. Dr. Pisani has nothing to disclose. Dr. Rivello has received personal compensation for activities with Best Doctors. Dr. Riviello9s spouse has received personal compensation in an editorial capacity for Up To Date. Dr. Hirano has received (royalty or license fee or contractual rights) payments from MitoRainbow Therapeutics, Inc. Dr. Quinzii Hirano has nothing to disclose.