A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.

Abstract

POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2. The proband, a 5-week-old female infant, presented with seizures and acute liver failure. Extensive metabolic workup, including untargeted metabolomics analysis and elevated plasma growth differentiation factor 15, was suggestive of mitochondrial dysfunction. Rapid trio genome sequencing identified compound heterozygous variants, a likely pathogenic variant and a variant of uncertain significance in POLG2. This case expands the clinical phenotype associated with POLG2-related mitochondrial disease to include a severe hepatocerebral syndrome manifesting in early childhood. This case underscores the utility of integrated genomic and metabolomic analyses in diagnosing rare and complex mitochondrial disorders. These findings also emphasize the importance of considering POLG2-related mitochondrial disease in the differential diagnosis of infants presenting with liver failure and neurological symptoms and enhance our understanding of the phenotypic spectrum associated with this disorder.