PGM1 – Congenital Disorder of Glycosylation

Phosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose-1-phosphate and glucose-6-phosphate, linking glycogen metabolism to nucleotide-sugar biosynthesis. Biallelic pathogenic variants in PGM1 cause an autosomal recessive congenital disorder of glycosylation (Congenital Disorder of Glycosylation), first described in 2013 and replicated in multiple cohorts over the past decade.

Genetic evidence supports a definitive gene–disease relationship. More than 20 probands across 17 unrelated families have been reported with biallelic PGM1 variants, including both homozygous and compound heterozygous cases (PMID:24499211). Segregation of variants with disease has been demonstrated in consanguineous pedigrees with two or more affected siblings (PMID:31563034). A recurrent missense change, c.1508G>A (p.Arg503Gln), is noted in multiple families and correlates with reduced enzyme activity.

Clinically, PGM1-CDG presents as a multisystem disorder. Common features include hepatopathy, hypoglycemia, myopathy, dilated cardiomyopathy, coagulopathy, cleft palate, bifid uvula, endocrine dysfunction (growth delay, hypogonadotropic hypogonadism, hypothyroidism), dysmorphic features, microcephaly, intellectual disability, obesity, hyperlipidemia, hyperuricemia, and short stature (HP:0001392; HP:0001943; HP:0003198; HP:0001644; HP:0001928; HP:0000175; HP:0000193; HP:0001510; HP:0000044; HP:0000821; HP:0000252; HP:0001256; HP:0001513; HP:0003077; HP:0001081; HP:0004322; HP:0002149).

Functional studies confirm loss of PGM1 activity (<5% of normal) in patient fibroblasts, abnormal N-glycan profiles on transferrin and ApoC-III isofocusing, and rescue of glycosylation with galactose supplementation in vitro and in patients (PMID:24878975; PMID:24499211). Structural and biochemical analyses of missense variants (e.g., p.Gly291Arg, p.Asp263Tyr) reveal enzyme destabilization, impaired catalysis, and induced structural disorder, underpinning pathogenicity (PMID:26972339).

Some variability in response to galactose therapy has been reported, with standard doses (1 g/kg/day) failing to normalize glycosylation in all patients, indicating a need for individualized dosing (PMID:28794993). No studies have refuted the PGM1–CDG association.

Together, these data establish a definitive autosomal recessive association between PGM1 and congenital disorder of glycosylation, supported by robust human genetic and functional evidence. Early recognition via transferrin isoform analysis and PGM1 sequencing enables prompt dietary intervention and multidisciplinary care.

Key Take-home: PGM1-CDG is a treatable multisystem disorder; confirm diagnosis with enzymatic and genetic testing to guide galactose-based therapy.

References

• The New England journal of Medicine • 2014 • Multiple phenotypes in phosphoglucomutase 1 deficiency PMID:24499211
• Neuro endocrinology letters • 2014 • Glycogen storage disease-like phenotype with central nervous system involvement in a PGM1-CDG patient PMID:24878975
• Journal of inherited metabolic disease • 2013 • A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene PMID:22976764
• Forensic science international. Genetics • 2019 • The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood PMID:31563034
• Molecular genetics and metabolism reports • 2017 • Limitations of galactose therapy in phosphoglucomutase 1 deficiency PMID:28794993

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