Acute Choreoathetosis and Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With a Novel Homozygous MDH2 Variant

Abstract

A 3-year-old boy with speech delay presented with fever and choreoathetosis, progressing to cardiogenic shock and respiratory failure. He met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C) and improved with treatment, which included intravenous immune globulin (IVIG), methylprednisolone, and anakinra per hospital protocol. Following sedation weaning, choreoathetosis recurred. Repeat brain MRI revealed new symmetric T2 hyperintensity and restricted diffusion in the globi pallidi. He was discharged with persistent developmental regression, hypotonia, and choreoathetosis. Four months later, he was readmitted with respiratory failure from a human metapneumovirus infection and died from refractory cardiogenic shock and multiorgan failure. Posthumous exome sequencing identified a homozygous variant of unknown significance in MDH2 (malate dehydrogenase 2). A sibling with chronic encephalopathy and myocarditis shared this genotype. MDH2 deficiency is associated with movement disorders and cardiomyopathy. MIS-C plausibly triggered clinical decompensation in our patient. Genetic or metabolic causes should be considered in children with a history of developmental delay, acute neurologic symptoms, and symmetric basal ganglia lesions.