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

PMID 42238689 | PMCID PMC13226778 | DOI 10.1016/j.ymgmr.2026.101322 · Molecular genetics and metabolism reports · 2026 · View on PubMed ↗

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.