Researchers have identified guanylate kinase 1 deficiency as a newly recognized genetic cause of mitochondrial DNA depletion syndrome, which may respond to targeted pharmacological therapies, according to a recent study.

The report, published in Annals of Neurology, identified guanylate kinase 1 (GUK1) deficiency as a novel and potentially treatable cause of mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS). The research, which examined four patients across three families, uncovered biallelic pathogenic variants in GUK1, an enzyme previously thought to be exclusively cytosolic. Affected patients presented with ptosis, ophthalmoparesis, and proximal limb weakness, alongside hepatopathy and T-lymphocyte abnormalities not commonly seen in other forms of MDDS.

GUK1 has two isoforms: a mitochondrial long isoform and a cytosolic short isoform. The study found that GUK1 deficiency disrupts mitochondrial deoxynucleoside triphosphate pools, resulting in mtDNA depletion. Muscle biopsies revealed mtDNA depletion and deletions, along with impaired mitochondrial respiratory chain activity.

Treatment of patient-derived fibroblasts with deoxyguanosine and forodesine, a purine phosphatase inhibitor, demonstrated restoration of mtDNA levels, indicating that GUK1 deficiency may respond to pharmacological intervention. This suggests potential therapeutic strategies for patients with this form of MDDS.

Full disclosures can be found in the published study.