Year: 2025
Type: dissertation
Abstract: This medical thesis establishes a national diagnosis and care protocol (PNDS) for mitochondrial diseases linked to POLG mutations, caused by pathogenic variants of the POLG gene encoding mitochondrial DNA polymerase gamma. Polymerase gamma is responsible for mitochondrial genome replication. POLG deficiency (or POLG) represents the most common cause of mitochondrial diseases, with an estimated prevalence of 1/10 000, but also the most common cause of mitochondrial epilepsy at all ages, 10-25% of cases of progressive external ophthalmoplegia and 1% of cases of genetic ataxia. It constitutes a continuum of phenotypes defined clinically. They are now considered to be a spectrum of overlapping diseases, manifesting from early childhood to adulthood. The seven leading disorders caused by POLG mutations are Alpers–Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myo-cerebro-hepatopathy spectrum, which presents within the first 3 years of life; MNGIE-like disorder; MEMSA syndrome (myoclonic epilepsy myopathy sensory ataxia); SANDO syndrome (sensory ataxia neuropathy dysarthria and ophthalmoplegia); autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. The first POLG mutation was described in 2004. More than 300 pathogenic variants of POLG have been reported, as presented in the Human DNA Polymerase Gamma Mutation Database. PNDS are good practice guidelines for rare diseases. Their aim is to guide optimal diagnostic strategy, therapeutic management and care pathway for a given rare disease. A team of seventy referring physicians from eight paediatric or adult specialties, paramedical health professionals and representatives of patient associations is currently working on this topic throughout the country. The text was discussed at four multidisciplinary meetings in 2025 and reviewed by Carammel and Calisson reference centres, supported by Filnemus network. The discussion allows for the exchange of practices within the territory and the pooling of data concerning this rare disease. Early diagnosis, coordinated care and follow-up by healthcare professionals seem all the more important given that there is currently no effective curative therapy for POLG disorders. This text highlights certain key points for patients with mitochondrial diseases linked to POLG mutations, such as the strict contraindication of treating epileptic seizures with sodium valproate (Depakine® Micropakine®) due to the risk of increased liver failure or even potentially fatal fulminant hepatopathy. Writing of this medical thesis allowed the establishment of French recommendations for the phenotypic spectrum of mitochondrial diseases linked to POLG mutations, from early paediatric forms to late adult forms.
Source: HAL
Author: Rose, Sylvia
Institution: Université Paris Cité
Language: French
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7140003729