A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study

PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants in the PMM2 gene, leading to impaired glycosylation of proteins. Our objective was to provide a detailed clinical characterization and define the mutational spectrum of PMM2-CDG in the Tunisian population. We conducted a retrospective study on patients with genetically confirmed PMM2-CDG, followed between 2005 and 2024. Ten patients from six unrelated Tunisian families were enrolled. All presented with neurological symptoms, including psychomotor delay (10/10), cerebellar ataxia (9/10) and strabismus (9/10). Brain MRI revealed cerebellar atrophy in all patients. Dysmorphic features were common including almond-shaped eyes (9/10), large mouth (6/10), and thin upper lip (6/10). Skeletal anomalies were observed in 9/10 patients. Peripheral neuropathy was confirmed in 6/7 patients. Laboratory analyses revealed elevated transaminases (6/10), hypocholesterolemia (7/10), elevated LDH (7/10), hypoalbuminemia (2/6), and IgA deficiency (3/5). Renal anomalies included hyperechogenicity (2/9) and a duplicated collecting system (1/9). Genetic analysis revealed a homozygous variant NM_000303.3(PMM2): c.395 T > C; p.(Ile132Thr) in all patients. Haplotype analysis of the PMM2 locus showed that all 6 families shared an identical allele. In conclusion, this is the first study to characterize the clinical and genetic profile of PMM2-CDG in the Tunisian population. Despite a shared genotype, patients exhibited moderate neurological phenotypes with inter- and intrafamilial variability. The recurrent homozygous c.395 T > C; p.(Ile132Thr) variant and identical haplotype confirm a founder effect in the Tunisian population.