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Phosphoglucomutase 1 (PGM1; HGNC:8905) deficiency is an autosomal recessive multisystem disorder combining congenital disorder of glycosylation and glycogen storage disease features in PGM1-congenital disorder of glycosylation. Affected individuals present with endocrine, hepatic, cardiac and muscular manifestations due to loss of PGM1 enzymatic activity.
Genetic studies have identified biallelic PGM1 variants in 19 probands (PMID:26768186) from multiple families, including segregation of homozygous c.112A>T (p.Asn38Tyr) in six additional affected relatives in a consanguineous pedigree (PMID:26768186). Case reports and series document compound heterozygous splice (c.1145-222G>T) and missense (c.1264C>T (p.Arg422Trp); p.Gln530Ter) variants in unrelated patients, fulfilling autosomal recessive inheritance. Based on replication across cohorts, family segregation, and concordant biochemical phenotypes, the gene–disease relationship is classified as Strong.
Inheritance is autosomal recessive. Segregation of homozygous c.112A>T (p.Asn38Tyr) in six additional relatives supports linkage (PMID:26768186). Across published reports, at least 19 probands harbor combinations of missense (e.g., c.112A>T (p.Asn38Tyr)), nonsense (p.Gln530Ter), splicing (c.1145-222G>T), and frameshift variants. The spectrum includes 13 distinct missense alleles, recurrent founder or hotspot mutations (p.Gly291Arg: NM_002633.3:c.871G>C and c.871G>A), and deep-intronic splice defects. Variant c.112A>T (p.Asn38Tyr) is reported homozygously in multiple siblings (PMID:26768186).
Biochemical characterization of recombinant PGM1 missense mutants reveals two major classes: variants with severe catalytic impairment (kcat/Km <1.5% of wild-type for p.Gly291Arg) and variants prone to misfolding and aggregation (p.Asp263Tyr, p.Arg422Gln) (PMID:25288802; PMID:28117557; PMID:32057119). Structural studies demonstrate induced disorder at active-site loops and disruption of key salt bridges, correlating with loss of enzymatic activity and reduced protein stability. Cellular assays confirm absence or severe reduction of PGM1 protein and activity in patient fibroblasts.
PGM1 deficiency is a well-established autosomal recessive disorder with strong clinical validity. Loss-of-function variants lead to impaired interconversion of glucose-1-phosphate and glucose-6-phosphate, causing combined glycosylation and glycogen storage defects manifesting as hypoglycemia, elevated transaminases, cardiomyopathy, muscle weakness, exercise intolerance, rhabdomyolysis, and structural malformations (cleft palate). Functional assays and structural analyses consistently support a loss-of-function mechanism. Early and continuous galactose supplementation improves glycosylation but does not fully prevent cardiac complications, underscoring the need for multidisciplinary management.
Key Take-home: Biallelic PGM1 variants cause a strong autosomal recessive PGM1-CDG phenotype; genetic testing and early galactose therapy with cardiac surveillance enable optimized patient care.
Gene–Disease AssociationStrong19 probands with biallelic PGM1 variants, segregation in multiple families, concordant biochemical phenotypes Genetic EvidenceStrongMultiple unrelated probands (n=19)[PMID:26768186], autosomal recessive segregation, diverse variant classes Functional EvidenceModerateBiochemical and structural studies demonstrate catalytic impairment and instability across multiple PGM1 missense variants |