We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration: NCT03173300.

• Keywords
• PMM2, congenital disorders of glycosylation, genetic variations, genotype/phenotype correlations, inherited metabolic disorders, natural history, phosphomannomutase 2-CDG,
• MeSH
• Child MeSH
• Adult MeSH
• Phenotype MeSH
• Phosphotransferases (Phosphomutases) * genetics   chemistry   MeSH
• Genetic Association Studies * MeSH
• Genotype MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Congenital Disorders of Glycosylation * genetics   diagnosis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Names of Substances
• Phosphotransferases (Phosphomutases) * MeSH
• phosphomannomutase 2, human MeSH Browser

Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.

• Keywords
• N-glycosylation, congenital disorders of glycosylation, dolichal, dolichol, lipid droplets, polyisoprenoids, polyprenal, polyprenol, pseudoautosomal region,
• MeSH
• 3-Oxo-5-alpha-Steroid 4-Dehydrogenase metabolism   genetics   MeSH
• Dolichols * metabolism   biosynthesis   MeSH
• Glycosylation MeSH
• Humans MeSH
• Membrane Proteins metabolism   genetics   MeSH
• Mutation, Missense MeSH
• Congenital Disorders of Glycosylation metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3-Oxo-5-alpha-Steroid 4-Dehydrogenase MeSH
• Dolichols * MeSH
• Membrane Proteins MeSH
• SRD5A3 protein, human MeSH Browser

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

• Keywords
• ACTH, CDG, Cortisol, Glycosylation, Inborn errors of metabolism, PMM2-CDG, Phosphomannomutase 2-CDG,
• MeSH
• Adrenal Insufficiency diagnosis   etiology   physiopathology   MeSH
• Child MeSH
• Adult MeSH
• Phosphotransferases (Phosphomutases) blood   genetics   MeSH
• Glycosylation MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Pituitary-Adrenal System physiology   MeSH
• Congenital Disorders of Glycosylation MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Phosphotransferases (Phosphomutases) MeSH
• phosphomannomutase MeSH Browser