POLG-related disorders: Clinical and molecular Spectrum in the Saudi population

Background POLG-related disorders are a group of mitochondrial diseases caused by variants in the POLG gene, which is essential for mitochondrial DNA replication and repair. These disorders encompass a wide spectrum of clinical manifestations, ranging from severe, early-onset conditions to milder, adult-onset syndromes. Methods We conducted a retrospective study of 19 molecularly confirmed cases with POLG-related disorders from 16 unrelated families in six different referral centers. Clinical, radiological, and molecular analysis were performed following standard methods. Results Most of the patients in this study presented with variable neurological symptoms before the age of 12 years (80%); commonly, these symptoms included developmental delay and encephalopathy (63%), seizures (58%), ataxia and dysphagia (42% each). Molecular analysis revealed eight different disease-causing variants in the POLG gene. The most frequently observed variant was c.3286C > T; p.(Arg1096Cys). Notably, the POLG c.1957G > A; p.(Glu653Lys) variant has not been reported in the literature previously, and might impact protein folding and stability. Conclusion Despite the management of these conditions remaining largely supportive, advances in understanding the molecular mechanisms of POLG-related disorders offer promise for future therapeutic strategies targeting mitochondrial function and stability. This study highlights the complexity of POLG-related disorders and underscores the need for continued research into their pathophysiology and treatment.