Case Report: Two cases of pediatric neurodevelopmental disorders associated with the DPYD c.1905+1G>A genetic variant

Dihydropyrimidine dehydrogenase (DPD, gene: DPYD ) catalyzes the first step of pyrimidine catabolism. DPD deficiency contributes to a rare inborn error of metabolism associated with pediatric neurological manifestations that show wide variability in clinical presentation with incomplete penetrance (OMIM #274270). Common symptoms include autism spectrum disorder-like behaviors, ataxia, and global developmental delay, with variable involvement of seizures. In this report, we present one case of pediatric DPD deficiency accompanied by epilepsy-like syndromes, and a second case presenting with ataxia and dystonia in carriers of the deleterious DPYD c.1905+1G>A variant (rs3918290, DPYD*2A , ClinVar #432). One subject also carried a variant in the KMT2B gene (c.3014G>A; ClinVar #1333975) that was predicted to be deleterious, which likely contributed to dystonia (OMIM #617284) independently of DPD deficiency. In Subject 1, treatments with anti-epileptic therapies were insufficient for controlling seizures. The two subjects reported herein demonstrate the heterogeneity in clinical presentation associated with pediatric DPD deficiency. Further studies are needed to determine how loss of DPD function can negatively impact neurodevelopment in some individuals, while others who carry the same genetic variants are unaffected by the pediatric condition.