Incidence and prevalence of phosphomannomutase 2-congenital disorder of glycosylation: Past, present, and future

Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs and is caused by pathogenic variants of the gene encoding PMM2, which catalyzes an essential early step in N-linked glycosylation. Efforts to derive an accurate prevalence estimate for this often life-threatening disorder, for which there are currently no approved therapies, are hampered by the wide spectrum of clinical manifestations, the rarity of the disease, and the lack of a central global patient registry. Here, we calculated new estimates of PMM2-CDG incidence and prevalence in North America and Europe based on the frequency of disease-causing alleles using the Hardy–Weinberg equation. Allele frequencies were obtained from the Genome Aggregation Database (gnomAD v4.0) and the likelihood of specific allele combinations resulting in a live birth was adjusted based on the occurrence of genotypes in patient datasets and the expected consequences for protein function. New incidence and prevalence estimates were then calculated in the context of historical ethnicity and birth data from national statistical databases, combined with estimated patient mortality rates. The calculated new incidence estimate was 1 in 33,576 for North America and Europe combined (1 in 40,375 and 29,043, respectively), which predicts an average of 303 live births per year for both regions combined since 1980. The new prevalence estimate was 1 in 63,694 (1 in 76,183 and 57,022 in North America and Europe, respectively), which translates to a total of 14,154 patients living with PMM2-CDG in North America and Europe. Notably, this prevalence is more than 5-fold higher than the current estimate of 2447 diagnosed cases combined, and 10-fold higher than the worldwide prevalence most frequently quoted in the literature. These striking differences highlight the underdiagnosis of the disease and the critical need for improved diagnostic and therapeutic strategies for PMM2-CDG.