Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE ‐Like Features

ABSTRACT Background Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene ( TYMP ), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP . Methods We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo‐obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP ‐related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo‐obstruction. This patient later suffered from a catastrophic stroke‐like episode, resulting in massive cerebral edema and brain death at the age of 38. Results Next‐generation sequencing (NGS) using a custom‐targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis , and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real‐time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long‐range PCR and Nanopore sequencing. Conclusions These cases showed a very distinctive POLG phenotype, with some MNGIE‐like features, expanding the clinical and genetic spectrum of the POLG ‐related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.