TWNK gene pathogenic variant and Perrault syndrome

Perrault syndrome is a rare autosomal recessive genetic disorder characterized primarily by sensorineural hearing loss and ovarian dysfunction in females, often accompanied by neurological and other systemic abnormalities. The disease exhibits significant clinical heterogeneity, and its pathogenesis involves pathogenic variants in multiple genes, among which pathogenic variants in the TWNK gene represent an important cause. The TWNK gene encodes the Twinkle, a mitochondrial DNA (mtDNA) helicase that plays a crucial role in the replication and maintenance of mtDNA stability. Due to the variability in mtDNA copy numbers across different tissues, TWNK gene pathogenic variants result in a wide spectrum of clinical manifestations with notable heterogeneity. In particular, the high sensitivity of the nervous system to energy metabolism disturbances may exacerbate the associated symptoms. The complex genetic background of Perrault syndrome poses challenges for clinical treatment, making it essential to further investigate its molecular and genetic basis to enhance diagnosis, treatment, and genetic counseling. This review summarizes the clinical features, molecular pathogenesis, diagnostic techniques, therapeutic approaches, and genetic counseling strategies related to Perrault syndrome caused by TWNK pathogenic variants, providing a scientific basis for its clinical management.