Expanding the Genetic Spectrum of PPM1K ‐Related Maple Syrup Urine Disease: A Novel Mutation

ABSTRACT Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by impaired catabolism of branched‐chain amino acids (BCAAs). The genes BCKDHA , BCKDHB , DBT , and DLD encode the subunits of the branched‐chain α‐ketoacid dehydrogenase (BCKDH) complex, which is essential for BCAA metabolism. Catalytic subunits are BCKDHA , BCKDHB , DBT , and DLD , whereas the regulator subunits are PPM1K and BCKDK . PPM1K plays a critical role by dephosphorylating and activating this enzyme complex. Pathogenic variants in the PPM1K gene cause an extremely rare, mild form of MSUD. Here, we report an 8‐year‐old male patient with a mild form of MSUD putatively caused by a novel homozygous variant in PPM1K . The patient presented with mild dysmorphic features, delayed speech, relative microcephaly, and overweight, all considered familial phenotypic traits. Laboratory findings revealed mildly elevated plasma branched‐chain amino acids, mild lactic acidemia, and a slight increase in urinary keto acids. Exome sequencing identified a novel homozygous missense variant, c.925A>G p.(Ile309Val), in the PPM1K gene. This case represents the third reported patient with a mild form of MSUD associated with the first reported missense variant in the PPM1K gene in the literature, further expanding the clinical and genetic spectrum of PPM1K‐related disorders.