Phosphoglucomutase 1 deficiency (PGM1-CDG, formerly glycogen storage disease XIV) is a rare autosomal recessive disorder in which the PGM1 enzyme that interconverts glucose-1-phosphate and glucose-6-phosphate is deficient, simultaneously impairing glycogen metabolism, glycolysis, and protein glycosylation. Oral D-galactose has become standard of care because it corrects the glycosylation defect and improves liver, endocrine, and coagulation abnormalities. Whether it improves the skeletal muscle phenotype — exercise intolerance, exertional contractures, and recurrent rhabdomyolysis — remains unresolved: a single-patient report found marked improvement in walking capacity, while later case series, in-vitro muscle models, and clinical observations report persistent myopathy, persistent rhabdomyolysis, and no recovery of muscle energy-producing capacity on galactose; no controlled trial has been completed (the first randomized placebo-controlled crossover trial was still not recruiting as of August 2026). The mechanistic basis and tissue specificity of impaired glycogen and energy metabolism (direct glucose-1-phosphate supply blockade versus tissue-specific compensation versus secondary systemic effects versus glycosylation-independent structural and mitochondrial roles of the PGM1 protein), and the relationship between residual PGM1 activity and the spectrum from isolated myopathy to multisystem disease, likewise remain open.

Background

Phosphoglucomutase 1 (PGM1) is a ubiquitously expressed enzyme that interconverts glucose-1-phosphate (G1P) and glucose-6-phosphate (G6P), and therefore sits at the junction of glycogen metabolism (glycogen synthesis and breakdown both proceed through G1P), glycolysis (which starts from G6P), and protein glycosylation (the sugar-nucleotide donors UDP-glucose and UDP-galactose are made from G1P). Biallelic pathogenic variants in PGM1 cause PGM1 deficiency, historically classified as glycogen storage disease type XIV and now grouped with the congenital disorders of glycosylation (CDG, a family of inherited defects in the attachment of sugar chains to proteins) as PGM1-CDG. The clinical spectrum is broad: cleft palate, liver dysfunction, hypoglycemia, endocrine and coagulation abnormalities, dilated cardiomyopathy, and — central to this problem — exercise intolerance with exertional muscle pain, contractures, and episodes of rhabdomyolysis (acute breakdown of muscle fibers releasing creatine kinase and myoglobin into blood). A key insight from the source study came from exercise testing: because muscle glycogenolysis is blocked at PGM1, the disorder biochemically mimics McArdle disease (GSD V, deficiency of muscle glycogen phosphorylase), including the 'second wind' phenomenon, a spontaneous improvement of exercise tolerance as the body shifts to fat oxidation and blood-borne fuels. Unlike McArdle disease, however, in which muscle glycogen accumulates behind the blocked enzyme, muscle glycogen in PGM1 deficiency can be low or normal, suggesting the defect may also limit glycogen synthesis — plausibly because G1P supply to UDP-glucose and to glycogen synthase (the enzyme that extends the glycogen polymer using UDP-glucose) is itself compromised.

Dietary D-galactose became the therapy of choice after 2017. The biochemical rationale is specific: galactose enters metabolism via the Leloir pathway, which converts it to G1P, bypassing PGM1 to replenish the UDP-sugar pools used for glycosylation. But galactose-derived G1P cannot become G6P — and thus cannot directly feed glycolysis — without PGM1 itself. This is why galactose can correct glycosylation markers (the transferrin glycoform pattern, the standard blood test for sugar-chain attachment defects, plus antithrombin III, transaminases, and coagulation) while its benefit for muscle energy metabolism is mechanistically uncertain. The source study (a detailed single-patient exercise-metabolism investigation of a severely affected compound-heterozygous woman — one PGM1 allele carrying the missense change R422W, the other the truncating change Q530X) showed that intravenous glucose and oral sucrose acutely lowered exercise heart rate and perceived exertion, and its discussion framed the still-unsettled questions that define this problem. Standard background on PGM1-CDG and the broader glycogen storage disease field can be found in the international consensus guidelines (Altassan et al. 2021) and the glycogen storage diseases primer (Hannah et al. 2023).

Problem Statement

The problem, as raised by the source study and still open, is to establish effective, mechanism-based management of the skeletal muscle phenotype of PGM1 deficiency, comprising four linked unresolved questions: (1) To what extent does dietary D-galactose supplementation improve muscle energy metabolism and exercise capacity in PGM1 deficiency — published reports being limited and inconsistent (one single-patient exercise study showing improvement; later case series and models showing persistent myopathy), and galactose-derived glucose-1-phosphate not being directly convertible to the glucose-6-phosphate required for glycolysis — and what do the available reports indicate about the magnitude of benefit, the optimal dose, and the characteristics of responders? (2) What is the mechanistic basis and tissue specificity of impaired glycogen synthesis in PGM1 deficiency — is the low or normal muscle glycogen (in contrast to the accumulation seen in McArdle disease) due to direct blockade of glucose-1-phosphate supply for UDP-glucose and glycogen synthase flux, tissue-specific compensation, secondary effects of systemic metabolic derangement, or glycosylation-independent, non-catalytic structural and mitochondrial roles of the PGM1 protein (for example, the reduced mitochondrial ATP-production capacity of PGM1-deficient muscle cells, or PGM1-protein interactions such as the LDB3 Z-disk interaction reported in cardiomyocytes) — this list of candidate mechanisms being illustrative rather than exhaustive? (3) How does measured residual PGM1 activity (in fibroblasts versus muscle) relate to the full spectrum of clinical severity, from isolated exercise-induced myopathy to multisystem congenital-disorder-of-glycosylation manifestations — and can residual-activity thresholds that predict dynamic exercise symptoms, chronic myopathy, and systemic features be derived from the available activity measurements? (4) Do chronic therapeutic strategies (long-term glucose management, sucrose timing around exercise, or continued galactose supplementation) reduce exercise-induced rhabdomyolysis and improve long-term outcomes, with what safety profile and metabolic trade-offs (for example, weight gain from increased carbohydrate use)?

All four questions are jointly constitutive of the problem. Because no controlled trial and no large genotype-phenotype cohort have been reported, the clinical evidence available for (1), (3), and (4) is limited to small uncontrolled case series, in-vitro models, and registry data. (1)'s responder characteristics and (3)'s predictive thresholds concern the same relationship, approached from the clinical and the biochemical side; and (4) is the long-term extension of (1)'s efficacy question, adding safety and sustainability.

References

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  17. ClinicalTrials.gov record NCT05402332 (accessed 2026-08-27): A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-Controlled, Crossover Trial Assessing the Efficacy, Safety, and Tolerability of AVTX-801 (D-galactose) in Subjects With Phosphoglucomutase 1 Deficiency Related Congenital Disorders of Glycosylation (PGM1-CDG); status not yet recruiting, estimated start 2026-10-01. https://clinicaltrials.gov/study/NCT05402332
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