POLG1 mutations in two children with seizures and progressive, fatal encephalopathy

Abnormalities of POLG1 are associated with diverse diseases including male infertility, progressive external ophthalmoplegia (PEO), sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), and Alpers syndrome. We describe two siblings with seizures and compound heterozygous mutations in POLG1 , the gene encoding mitochondrial DNA polymerase gamma. Clinical history in both affected toddlers was marked by progressive seizures with preserved hepatic function. Exons and flanking intron regions of POLG1 of the proband were amplified using PCR and sequenced; subsequent analysis of family members entailed sequencing of exons 6 and 17 and flanking introns only. Compound heterozygous mutations A467T and T914P were detected in both affected siblings. Heterozygous A467T mutation was detected in the mother, heterozygous T914P mutation in the father. Autopsy performed on one of the toddlers showed patchy, marked neuronal loss and astrogliosis within neocortex and dentate gyrus of the hippocampus. The spectrum of neurologic and hepatic findings associated with mutations of POLG1 is broad. While POLG1 mutation A467T is well known, T914P has not been described. Together, these mutations of POLG1 resulted in a fatal neurological syndrome characterized by progressive seizures and preserved liver function.