Approaches to diagnostic screening for congenital disorders of glycosylation and its prevalence in Japan.

Congenital disorders of glycosylation (CDG) represent an emerging and significant category within the spectrum of inborn errors of metabolism. CDG comprise a heterogeneous group of diseases caused by defects at various stages of the glycosylation pathway. Each year, new types of CDG are identified, and to date, pathogenic variants in 189 genes have been associated with over 200 distinct human glycosylation-related disorders. Each type of CDG exhibits characteristic clinical features. Many of CDG result in multisystem involvement, with the central nervous system being particularly affected. Clinical manifestations are highly variable and may include developmental delays, growth impairment, neurological abnormalities such as ataxia, hepatic dysfunction, cardiac defects, coagulation disorders, and abnormal fat distribution. In patients with unexplained neurological symptoms, it is now standard practice to include CDG in the differential diagnosis. Detection of altered glycosylation patterns in serum proteins is essential in the diagnostic evaluation of CDG. Analytical techniques allow the identification of defects in N-glycosylation, O-glycosylation, and combined glycosylation pathways. Once abnormalities in glycosylation are detected, subsequent genetic analysis is necessary to identify causative variants. Our research institute has contributed to the CDG diagnostic support center in Japan by developing novel analytical methods utilizing mass spectrometry. Through these efforts, we have facilitated the molecular diagnosis of 66 patients with CDG across Japan. In this report, we provide an overview of the current landscape of CDG in Japan, along with a summary of the screening and diagnostic processes.