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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive inheritance HP:0000007

PGM1-CDG results from biallelic pathogenic PGM1 variants. Reported families include homozygous variants segregating in consanguineous kindreds as well as compound heterozygotes; heterozygous parents are unaffected carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:37181075 SUPPORT Human Clinical

"Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme."

States the autosomal recessive mode of inheritance and anchors the entry to OMIM 614921, the phenotype MIM matched by the MONDO:0013968 xref.

PMID:31563034 SUPPORT Human Clinical

"Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease."

Family segregation in this kindred (three homozygous affected sibs, heterozygous unaffected parents) directly demonstrates recessive transmission.

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Subtypes

2

Multisystem form

The classic infantile-onset presentation, comprising congenital malformations (bifid uvula, cleft palate, Pierre Robin sequence) together with hypoglycemia, hepatopathy, coagulation and endocrine abnormalities, myopathy and cardiomyopathy. Liver involvement is essentially universal in this form.

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement."

The consensus guideline contrasts the infantile multisystem presentation with the adult isolated-muscle presentation, the two forms modeled here.

Primary myopathic form

A predominantly muscular presentation that may not become apparent until adolescence or adulthood, with exercise intolerance, fatigability, muscle weakness and recurrent exercise-induced rhabdomyolysis. Hepatic involvement is characteristically absent, which is a practical discriminator from the multisystem form.

Show evidence (2 references)

PMID:32681750 SUPPORT Human Clinical

"some patients present in adulthood with isolated muscle involvement"

Establishes the adult-onset, isolated-muscle presentation as a recognized distinct form.

PMID:28882528 SUPPORT Human Clinical

"We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis."

A worked example of the muscle-dominant presentation studied by exercise physiology in an adolescent/young adult.

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Mechanistic Hypotheses

1

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

galactose_resistant_cardiomyopathy EMERGING

Evidence balance 4 support

D-galactose reliably corrects transferrin glycosylation, liver enzymes and coagulation factors, yet consistently fails to improve cardiac function. Two non-exclusive explanations are under active investigation: (a) the cardiomyopathy is driven principally by a mitochondrial/energetic defect that nucleotide-sugar repletion cannot address, paralleling the galactose-resistant respiratory deficit demonstrated in PGM1-null muscle cells; or (b) it is driven by hypoglycosylation of sarcolemmal and extracellular-matrix glycoproteins (laminin-211) in a compartment that oral galactose does not adequately reach or reverse once structural remodeling is established. A third arm (c) was added in 2026: PGM1 binds the Z-disk protein LDB3 (ZASP/Cypher), and patient-derived iPSC-cardiomyocytes lose Z-disk components together with mitochondrial proteins, implying a structural role for PGM1 that is independent of its enzymatic output altogether. Arm (c) is not a competitor to arm (a) so much as a candidate cause of it - the proposal is that Z-disk destabilization uncouples the sarcomere from mitochondrial metabolism. The distinction matters because it determines whether cardiac-directed therapy should target energetics, sarcomeric integrity, or PGM1 protein restoration (e.g. AAV9-PGM1 gene replacement); only the last addresses all three arms, and it is the only one of the three arms so far evidenced in human patient cardiomyocytes rather than mouse heart or skeletal-muscle surrogates.

Pathograph links

Impaired Glycogen Synthesis and Glycogenolysis -> Cardiomyocyte Energetic and Mitochondrial Failure DIRECT The same inability to route glycogen-derived carbon into glycolysis compromises cardiomyocyte energy supply. This is arm (a) of the galactose-resistant-cardiomyopathy hypothesis.

Mixed Type I and Type II Protein Hypoglycosylation -> Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation DIRECT Sarcolemmal and extracellular-matrix glycoproteins, notably laminin subunits, are hypoglycosylated in the myocardium. This is arm (b) of the galactose-resistant-cardiomyopathy hypothesis.

Cardiomyocyte Energetic and Mitochondrial Failure -> Dilated Cardiomyopathy and Progressive Heart Failure DIRECT

Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation -> Dilated Cardiomyopathy and Progressive Heart Failure DIRECT

Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction -> Cardiomyocyte Energetic and Mitochondrial Failure INDIRECT UNKNOWN INTERMEDIATES Loss of Z-disk-mitochondrial coupling is the proposed route from sarcomeric destabilization to the energetic failure of the myocyte.

Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction -> Dilated Cardiomyopathy and Progressive Heart Failure DIRECT Impaired contractility and prolonged contraction kinetics in PGM1-deficient cardiomyocytes are the cellular correlate of the clinical cardiomyopathy.

Show evidence (4 references)

PMID:37175952 SUPPORT In Vitro

"In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity."

Supports arm (a): a galactose-resistant energetic deficit exists in PGM1-deficient striated muscle cells.

PMID:36709920 SUPPORT Model Organism

"a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses"

Supports arm (b): a specific sarcolemmal glycosylation lesion in the PGM1-deficient myocardium.

PMID:41723528 SUPPORT In Vitro

"Although galactose therapy corrects glycosylation defects, cardiac dysfunction typically persists, suggesting a glycosylation-independent mechanism."

States the premise the whole hypothesis group rests on, and motivates arm (c) specifically as a glycosylation-independent route.

+ 1 more reference

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Discussions and Knowledge Gaps

2

By what mechanism does PGM1 deficiency cause bifid uvula, cleft palate and Pierre Robin sequence, and why is this the only manifestation present at birth?

KNOWLEDGE GAP OPEN pgm1_craniofacial_mechanism_gap

Attached to

pathophysiology#Multisystem Glycoprotein Dysfunction

Midline palatal malformation is the earliest and one of the most consistent features of PGM1-CDG, and is the clinical clue that most often triggers diagnosis, yet no specific glycoprotein client or developmental pathway has been linked to it. Palatal shelf fusion depends on glycosylated extracellular matrix and adhesion molecules, but this remains an inference rather than a demonstrated mechanism in PGM1-CDG.

Proposed experiments

Tissue-restricted Pgm2 knockout in cranial neural crest or palatal shelf mesenchyme

exp_pgm1_conditional_neural_crest_knockout

Because the constitutive knockout is embryonic lethal before E9.5 and yields no live homozygotes, palatal development must be studied with a conditional allele restricted to cranial neural crest or palatal shelf mesenchyme, assessing shelf elevation and fusion together with matrix glycoprotein glycosylation.

Glycoproteomic profiling of palatal tissue and craniofacial organoids

exp_pgm1_palatal_glycoproteomics

Profile palatal shelf tissue or patient-derived craniofacial organoids to identify which adhesion and extracellular-matrix client glycoproteins are hypoglycosylated, in order to nominate a specific developmental mechanism.

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"We did not attempt to show experimentally the mechanisms that account for the clinical phenotypes of phosphoglucomutase 1 deficiency."

The landmark study explicitly declines to establish phenotype-specific mechanisms, and its three proposed mechanisms cover glucose metabolism, glycosylation and cardiomyopathy but not the craniofacial malformation.

Does the AAV9-PGM1 rescue of dilated cardiomyopathy in the cardiomyocyte-specific Pgm2 knockout mouse predict benefit in human PGM1-CDG cardiomyopathy?

HUMAN MODEL MISMATCH OPEN pgm1_aav_cardiac_model_mismatch

Attached to

pathophysiology#Cardiomyocyte Energetic and Mitochondrial Failure pathophysiology#Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation pathophysiology#Dilated Cardiomyopathy and Progressive Heart Failure

The constitutive Pgm2 knockout is embryonic lethal before E9.5 and produces no live homozygotes, so the only tractable in vivo cardiac model is a tamoxifen-inducible cardiomyocyte-restricted knockout in an otherwise PGM1-sufficient animal. That model necessarily lacks the systemic hypoglycemia, hepatic, endocrine and craniofacial disease of human PGM1-CDG, and the acute post-natal onset of the lesion differs from the lifelong hypomorphic state of human patients, most of whom carry missense alleles with residual activity rather than a null. Whether the striking AAV9 rescue translates to human hearts that have remodeled over years is therefore an open translational question, not an established result.

Proposed experiments

Genotype-stratified longitudinal cardiac natural history study

exp_pgm1_cardiac_natural_history

Track cardiac structure and function longitudinally in genotype-stratified human PGM1-CDG cohorts to define the window before ventricular remodeling becomes irreversible, which determines whether a gene-replacement approach could plausibly benefit already-affected hearts.

AAV9-PGM1 in a hypomorphic knock-in mouse with established cardiomyopathy

exp_pgm1_hypomorphic_aav_trial

Test AAV9-PGM1 in a missense knock-in (hypomorphic) rather than null model, and after cardiomyopathy is already established rather than preemptively, to better match the human therapeutic setting.

Show evidence (2 references)

PMID:31077402 SUPPORT Model Organism

"In this study, we demonstrated that homozygosity for Pgm2-KO mutations leads to embryonic lethality in mice"

Establishes why no constitutive null mouse exists and why cardiac conclusions rest on a conditional, tissue-restricted model.

PMID:36709920 SUPPORT Model Organism

"To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model."

Confirms the model is cardiomyocyte-restricted and conditional, which is the source of the translational mismatch. Marked PARTIAL because the paper supports the rescue result but not its human generalizability.

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Pathophysiology

14

Biallelic PGM1 Loss of Function

Biallelic pathogenic variants in PGM1 (1p31.3) abolish or severely reduce phosphoglucomutase-1 activity. PGM1 supplies the large majority of phosphoglucomutase activity in most tissues, and residual activity in patient fibroblasts or leukocytes is severely reduced (the 2021 consensus guideline, PMID:32681750, reports a range from undetectable to 20% of controls). Most reported alleles are missense and act by loss of function, often through catalytic impairment or local structural destabilization of the enzyme.

PGM1 hgnc:8905

phosphoglucomutase activity GO:0004614 ↓ DECREASED

Downstream

Impaired Glucose-1-Phosphate and Glucose-6-Phosphate Interconversion Loss of enzyme activity directly removes the catalytic step that interconverts the two hexose phosphates.

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients."

The landmark cohort establishes that PGM1 variants cause a measurable enzymatic loss of function in affected individuals.

PMID:28882528 SUPPORT Human Clinical

"Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot."

Confirms loss of PGM1 protein and activity in patient muscle and fibroblasts, supporting a loss-of-function mechanism.

Impaired Glucose-1-Phosphate and Glucose-6-Phosphate Interconversion

Phosphoglucomutase-1 reversibly interconverts glucose-1-phosphate and glucose-6-phosphate, the metabolic node that connects glycogen (via glucose-1-phosphate) to glycolysis and to the hexose-phosphate pool used for nucleotide-sugar synthesis. When this step is blocked, flux is disrupted in both directions: glucose-6-phosphate generated from a dietary glucose load cannot be routed into glycogen, and glucose-1-phosphate released from glycogen cannot enter glycolysis or gluconeogenic output.

glucose metabolic process GO:0006006 ⚠ ABNORMAL

Downstream

Impaired Glycogen Synthesis and Glycogenolysis Glycogen can neither be built from glucose-6-phosphate nor mobilized into glycolysis, because both routes require the PGM1 step.

UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly Reduced glucose-1-phosphate availability limits UDP-glucose synthesis, the donor pool feeding endoplasmic-reticulum glycan assembly.

UDP-Galactose Depletion and Impaired Golgi Galactosylation The Leloir pathway is functionally stalled, lowering the UDP-galactose pool needed for Golgi galactosylation.

Show evidence (2 references)

PMID:37175952 SUPPORT In Vitro

"Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate."

Defines the enzymatic reaction that is lost and places it at the glycogen / glycolysis junction.

PMID:24499211 SUPPORT In Vitro

"Analyses of sugar metabolites in fibroblasts from patients revealed increased concentrations of galactose-1-phosphate and glucose-1 phosphate, as compared with fibroblasts from controls."

Direct metabolite measurement in patient fibroblasts showing accumulation upstream of the enzymatic block.

Impaired Glycogen Synthesis and Glycogenolysis

Loss of the PGM1 step blocks both arms of glycogen handling. In liver, stored glycogen cannot be converted to glucose during fasting; in skeletal muscle, glycogen cannot be rapidly mobilized for anaerobic glycolysis during exertion. The muscle physiology closely mimics McArdle disease, including a flat lactate response to ischemic forearm exercise and a second-wind phenomenon.

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

Hepatocyte CL:0000182 Skeletal muscle cell CL:0000188

glycogen catabolic process GO:0005980 ↓ DECREASED glycogen biosynthetic process GO:0005978 ↓ DECREASED glycolytic process GO:0006096 ↓ DECREASED

Downstream

Fasting Hypoglycemia and Hepatic Metabolic Stress

Skeletal Muscle Energy Failure

Cardiomyocyte Energetic and Mitochondrial Failure The same inability to route glycogen-derived carbon into glycolysis compromises cardiomyocyte energy supply. This is arm (a) of the galactose-resistant-cardiomyopathy hypothesis.

Show evidence (2 references)

PMID:28882528 SUPPORT Human Clinical

"We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder."

Direct in vivo exercise physiology in a patient demonstrating a blocked muscle glycogenolysis. Note the authors hedge the synthesis arm ("may also limit glycogen synthesis"), so the biosynthetic half of this node is the weaker of the two claims.

PMID:24499211 SUPPORT Human Clinical

"During fasting, liver glycogen cannot be converted into glucose via glucose-6-phosphate, and hypoglycemia may occur."

States the hepatic arm of the glycogen block and its link to fasting hypoglycemia.

UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly

This is the type I (endoplasmic-reticulum) arm of the mixed glycosylation defect. Reduced glucose-1-phosphate limits UDP-glucose, the donor used for glucosylation of the dolichol-linked oligosaccharide precursor and for calnexin/calreticulin quality control. Patient fibroblasts show an abnormal lipid-linked oligosaccharide profile, and truncated or incompletely transferred precursors leave N-glycosylation sequons unoccupied - detected in serum as whole missing transferrin glycans. Unlike the canonical type I CDG, the deficient element is not a glycosyltransferase of the assembly line but the nucleotide-sugar donor supply upstream of it.

dolichol-linked oligosaccharide biosynthetic process GO:0006488 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

Mixed Type I and Type II Protein Hypoglycosylation Incompletely assembled precursors produce whole missing N-glycans, the type I component of the transferrin pattern.

Show evidence (2 references)

PMID:28617415 SUPPORT In Vitro

"In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts."

Demonstrates the ER lipid-linked oligosaccharide abnormality and the underlying nucleotide-sugar disturbance in PGM1-CDG fibroblasts, the disorder-specific substitution for the module's type I trigger.

PMID:28617415 SUPPORT In Vitro

"D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG."

Rescue of the lipid-linked oligosaccharide profile by restoring nucleotide sugars confirms that donor depletion, not a transferase defect, drives the ER arm.

UDP-Galactose Depletion and Impaired Golgi Galactosylation

This is the type II (Golgi) arm. PGM1 deficiency stalls the Leloir pathway and lowers the UDP-galactose available to Golgi galactosyltransferases, so N-glycans that are transferred to protein cannot be completed: they lack terminal galactose and, consequently, the sialic acid that caps it. The UDP-galactose to UDP-glucose ratio is reduced in patient cells, and the resulting glycans are truncated rather than absent. This is the arm that oral D-galactose therapy targets directly.

N-glycan processing GO:0006491 ↓ DECREASED galactose metabolic process GO:0006012 ⚠ ABNORMAL

Golgi apparatus GO:0005794

Downstream

Mixed Type I and Type II Protein Hypoglycosylation Incomplete Golgi galactosylation yields truncated, galactose-deficient glycans, the type II component of the transferrin pattern.

Show evidence (2 references)

PMID:24499211 SUPPORT In Vitro

"The ratio of UDP-galactose to UDP-glucose was decreased, suggesting that UDP-galactose is limiting for N-glycan biosynthesis"

Establishes UDP-galactose as the limiting nucleotide sugar, the mechanistic basis of the galactose-deficient truncated glycans.

PMID:30982613 SUPPORT In Vitro

"replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively"

Tracer metabolomics assigns UDP-glucose to the ER arm and UDP-galactose to the Golgi arm, the two-arm split modeled by this node and its ER sibling.

Mixed Type I and Type II Protein Hypoglycosylation

The two arms converge on the diagnostic hallmark of PGM1-CDG: a mixed glycosylation defect in which serum transferrin simultaneously shows loss of complete N-glycans (type I, reduced site occupancy) and truncated glycans lacking galactose and terminal sialic acid (type II, incomplete processing). Very few CDG produce both patterns in one patient, and this combined signature on intact-transferrin mass spectrometry is the single most useful biochemical clue to the diagnosis. Because glycosylation modifies a large fraction of secreted and membrane proteins, the lesion degrades many unrelated client glycoproteins at once.

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

Hepatocyte CL:0000182 Fibroblast CL:0000057

protein N-linked glycosylation GO:0006487 ↓ DECREASED protein O-linked glycosylation GO:0006493 ↓ DECREASED

Downstream

Multisystem Glycoprotein Dysfunction

Coagulation Factor Hypoglycosylation and Antithrombin Deficiency

Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation Sarcolemmal and extracellular-matrix glycoproteins, notably laminin subunits, are hypoglycosylated in the myocardium. This is arm (b) of the galactose-resistant-cardiomyopathy hypothesis.

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose."

The defining mixed pattern: missing whole glycans (type I) together with galactose-deficient truncated glycans (type II).

PMID:31077402 SUPPORT Other

"PGM1 deficiency is increasingly recognized as a congenital disorder of glycosylation (CDG), where reduced N-linked glycosylation in the endoplasmic reticulum (ER) and Golgi is observed, resulting in both missing and truncated glycans (mixed type I and type II glycosylation defects)"

Explicitly names the mixed type I plus type II classification and localizes the two arms to ER and Golgi. Tagged OTHER because this is the review framing in the paper's introduction rather than its own experimental result.

Multisystem Glycoprotein Dysfunction

Simultaneous hypoglycosylation of many secreted and membrane glycoproteins produces the characteristic multisystem outflow: hepatic dysfunction with transaminase elevation, endocrine deficits (hypogonadotropic hypogonadism, secondary adrenal insufficiency, growth failure), craniofacial malformation, and variable neurologic involvement, in addition to the coagulation and cardiac arms modeled separately.

Hepatocyte CL:0000182

protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL

Show evidence (2 references)

PMID:35562242 SUPPORT Other

"Symptoms typically start in infancy and most frequently include hypoglycemia (possibly leading to seizures), cleft palate/bifid uvula (which can lead to feeding difficulties), elevated liver enzymes, coagulopathy, muscle weakness and exercise intolerance (often with rhabdomyolysis), and, in some..."

Enumerates the multisystem consequence set downstream of hypoglycosylation. Tagged OTHER because this is an expert review summarizing the phenotype rather than reporting primary data.

PMID:26768186 SUPPORT Human Clinical

"Four out of seven patients have deteriorating adrenal function with abnormally low cortisol and ACTH levels during hypoglycemia and subnormal response of cortisol to low dose ACTH test"

Documents the endocrine (ACTH/cortisol axis) component of the multisystem glycoprotein dysfunction.

Coagulation Factor Hypoglycosylation and Antithrombin Deficiency

Coagulation and anticoagulation proteins are heavily glycosylated and are among the most sensitive readouts of hypoglycosylation in CDG. In PGM1-CDG antithrombin is the most commonly and most severely affected factor, with prolonged aPTT and reductions in factors XI, IX and VII also reported; a minority of patients suffer major thrombotic events. These abnormalities improve on D-galactose, making antithrombin activity a candidate treatment biomarker and trial endpoint.

blood coagulation GO:0007596 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:38968673 SUPPORT Human Clinical

"The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %) deficiency. Four individuals had major thrombotic events."

Identifies antithrombin as the dominant coagulation abnormality and documents clinically significant thrombosis.

Fasting Hypoglycemia and Hepatic Metabolic Stress

Because hepatic glycogen cannot be released as glucose through the PGM1 step, fasting, intercurrent illness, or vomiting precipitate ketotic hypoglycemia, frequently the presenting problem in infancy. Conversely, after a glucose load, accumulating glucose-6-phosphate that cannot be stored as glycogen is diverted toward lactate and lipogenesis, contributing to transaminase elevation and hepatic steatosis. In young patients, hypoglycemia is primarily hyperinsulinemic, whereas starvation- or febrile-illness-associated ketotic hypoglycemia is also reported and becomes more relevant at other ages. Secondary ACTH/cortisol deficiency can further compound the hypoglycemia.

Hepatocyte CL:0000182

glucose homeostasis GO:0042593 ⚠ ABNORMAL

Show evidence (3 references)

PMID:24499211 SUPPORT Human Clinical

"After a dietary glucose load, large amounts of glucose-6-phosphate are generated, which cannot be converted into glycogen."

Explains the postprandial diversion of hexose phosphate that accompanies the fasting-intolerance phenotype.

PMID:26768186 SUPPORT Human Clinical

"Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients."

Quantifies the fasting hypoglycemia phenotype within a single well characterized family.

PMID:32681750 SUPPORT Human Clinical

"Hypoglycemia was primarily due to hyperinsulinism in young patients."

The international guideline establishes hyperinsulinism as the primary route to hypoglycemia in young patients, correcting a prior description that treated it as only an unspecified subset finding.

Skeletal Muscle Energy Failure

Skeletal muscle cannot mobilize glycogen for rapid anaerobic ATP production, so exercise depends abnormally on fat oxidation and carbohydrate oxidation is blocked; forearm exercise produces no lactate rise but an exaggerated ammonia rise, and patients show the McArdle-like second wind. Beyond the glycogenolytic block, PGM1-null myoblasts and myotubes have reduced basal respiration and reduced mitochondrial ATP-production capacity that D-galactose does not correct, which is the leading explanation for why myopathy and rhabdomyolysis respond less completely to therapy than the glycosylation abnormalities do.

Skeletal muscle cell CL:0000188

ATP biosynthetic process GO:0006754 ↓ DECREASED glycogen catabolic process GO:0005980 ↓ DECREASED

Show evidence (2 references)

PMID:28882528 SUPPORT Human Clinical

"Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture."

Classic physiological signature of a block in muscle glycogenolysis and glycolysis in a PGM1-deficient patient.

PMID:37175952 SUPPORT In Vitro

"Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose."

Establishes a galactose-resistant mitochondrial energetic deficit in PGM1-null muscle cells, distinct from the galactose-responsive glycosylation arm.

Cardiomyocyte Energetic and Mitochondrial Failure

Arm (a) of the galactose-resistant cardiomyopathy hypothesis. In the cardiomyocyte-specific Pgm2 (mouse PGM1 ortholog) knockout heart, glycogen accumulates in excess while mitochondria are swollen and fragmented and mitochondrial function falls, indicating that the failing myocardium has an energy-supply problem and not only a glycosylation problem. The parallel finding in PGM1-null skeletal muscle cells, where D-galactose does not restore respiration or ATP production, is what makes this arm the leading explanation for the treatment resistance of the cardiac phenotype.

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

Cardiomyocyte CL:0000746

ATP biosynthetic process GO:0006754 ↓ DECREASED

Experimental models

PGM1-deficient patient-derived iPSC-cardiomyocytes IPSC DERIVED MODEL Extends the mitochondrial arm from mouse heart and PGM1-null skeletal muscle cells into human cardiomyocytes.

Downstream

Dilated Cardiomyopathy and Progressive Heart Failure

Show evidence (2 references)

PMID:36709920 SUPPORT Model Organism

"Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG."

The cardiomyocyte-specific knockout mouse reproduces the human cardiac ultrastructural pathology, including the mitochondrial injury that defines this node, and matches a human cardiac explant.

PMID:36709920 SUPPORT Model Organism

"In addition, we found decreased mitochondrial function in the heart of KO mice."

Direct functional demonstration of the cardiac mitochondrial deficit.

Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation

Arm (b) of the galactose-resistant cardiomyopathy hypothesis. Cardiac glycoproteomics in the Pgm2 conditional knockout shows broad changes in N-glycosylation concentrated on sarcolemmal and extracellular-matrix proteins, most prominently the laminin-211 subunits that couple the cardiomyocyte membrane to its basement membrane. Loss of this linkage is a recognized route to dilated cardiomyopathy independent of energy supply.

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

Cardiomyocyte CL:0000746

protein N-linked glycosylation GO:0006487 ↓ DECREASED

sarcolemma GO:0042383

Downstream

Dilated Cardiomyopathy and Progressive Heart Failure

Show evidence (1 reference)

PMID:36709920 SUPPORT Model Organism

"a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses"

Identifies sarcolemmal and matrix glycoprotein hypoglycosylation, laminin-211 in particular, as a specific molecular lesion in the PGM1-deficient myocardium.

Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction

Arm (c) of the galactose-resistant cardiomyopathy hypothesis, and the only arm evidenced in human patient-derived cardiomyocytes rather than in mouse or in skeletal-muscle surrogate cells. Untargeted proteomics of iPSC-derived cardiomyocytes from PGM1-deficient patients shows depletion of Z-disk components, LDB3 (ZASP/Cypher) among them, and AlphaFold3 modelling predicts a direct PGM1-LDB3 interaction that was then confirmed in vitro. This places a structural, sarcomeric role for PGM1 alongside its enzymatic one: the protein is not only a metabolic enzyme whose loss starves the myocyte, it is a binding partner whose loss destabilizes the Z-disk. Because the claim is about a protein-protein interaction rather than a nucleotide-sugar pool, no amount of oral galactose addresses it - which is the point of curating it as a separate arm.

Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone

Cardiomyocyte CL:0000746

PGM1 hgnc:8905

sarcomere organization GO:0045214 ↓ DECREASED

Experimental models

PGM1-deficient patient-derived iPSC-cardiomyocytes IPSC DERIVED MODEL The model is where the Z-disk lesion was discovered, so it recapitulates it by construction.

Downstream

Cardiomyocyte Energetic and Mitochondrial Failure Loss of Z-disk-mitochondrial coupling is the proposed route from sarcomeric destabilization to the energetic failure of the myocyte.

Dilated Cardiomyopathy and Progressive Heart Failure Impaired contractility and prolonged contraction kinetics in PGM1-deficient cardiomyocytes are the cellular correlate of the clinical cardiomyopathy.

Show evidence (2 references)

PMID:41723528 SUPPORT In Vitro

"Proteomic analyses revealed depletion of Z-disk components, including LDB3."

Directly reports the Z-disk protein depletion this node represents, in patient-derived cardiomyocytes.

PMID:41723528 SUPPORT In Vitro

"AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro."

Supports a direct PGM1-LDB3 interaction as the structural basis for the node, with in-vitro confirmation of a computational prediction.

Dilated Cardiomyopathy and Progressive Heart Failure

The convergent cardiac consequence and the most life-threatening complication of PGM1-CDG. Ventricular dilation with a falling ejection fraction progresses to heart failure, arrhythmia, cardiac arrest, transplantation or sudden death. It is the one manifestation D-galactose does not correct, which is why it is modeled as a distinct convergence node fed by two competing upstream arms rather than folded into the general multisystem outflow.

Cardiomyocyte CL:0000746

cardiac muscle contraction GO:0060048 ↓ DECREASED

Show evidence (2 references)

PMID:36709920 SUPPORT Model Organism

"Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG."

Establishes the convergent dilated-cardiomyopathy readout and its fidelity to the human phenotype.

PMID:31563034 SUPPORT Human Clinical

"Our findings also suggest that the autosomal recessive PGM1-CDG might be highly associated with life-threatening cardiomyopathy with arrhythmia or sudden cardiac death as the first symptom presenting from childhood and adolescence."

Human evidence that the cardiac arm can be the presenting and fatal manifestation.

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Histopathology

4

Hepatic Steatosis, Cholestasis, or Slight Fibrosis

Liver biopsies in the multisystem form have shown steatosis, cholestasis, and/or slight fibrosis. These findings are supportive but nonspecific and a biopsy is not required to establish PGM1-CDG.

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Liver biopsy, performed in five patients, showed steatosis, cholestasis and/or slight fibrosis."

Directly documents the spectrum of human liver-biopsy findings in five patients.

PAS-Positive Hepatic Glycogen Accumulation FREQUENT

Increased periodic acid-Schiff staining identified hepatic glycogen accumulation in a subset of the biopsied patients.

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Glycogen accumulation, defined by increased PAS-positive staining, was observed in two out of five liver biopsies."

Two of five biopsies (40%) were PAS-positive, supporting FREQUENT within the explicitly scoped biopsy denominator rather than disease-wide.

Myopathic Changes or Fat/Glycogen Accumulation VERY_FREQUENT

Most reported skeletal-muscle biopsies were abnormal, with increased internal nuclei, variation in fiber size, and/or accumulation of fat or glycogen. These findings are nonspecific and muscle biopsy is reserved for research rather than routine diagnosis.

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Muscle biopsy was performed in 12 patients; 10 biopsies were abnormal, showing myopathic changes (increase of internal nuclei or fiber size variation) and/or accumulation of fat or glycogen."

Abnormal findings in 10/12 biopsies (83%) support VERY_FREQUENT within the biopsied cohort.

Intramuscular Fat Accumulation FREQUENT

Fat accumulation was present in a majority of the abnormal skeletal-muscle biopsies.

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"The fat accumulation, indicative for glycogen storage disease, was reported in 6 of these 10 patients."

Fat accumulation in 6/10 abnormal biopsies (60%) supports FREQUENT within that scoped denominator.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

34

Blood 1

Thrombosis OCCASIONAL Abnormal thrombosis HP:0001977

Show evidence (1 reference)

PMID:38968673 SUPPORT Human Clinical

"Four individuals had major thrombotic events."

Four major thrombotic events among 73 reported individuals (about 5%) supports the OCCASIONAL band.

Cardiovascular 3

Dilated Cardiomyopathy OCCASIONAL HP:0001644

Course: PROGRESSIVE

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Dilated cardiomyopathy, cardiac arrest, or both occurred in six patients; three patients were listed for heart transplantation."

6/19 patients (about 32%) had dilated cardiomyopathy and/or cardiac arrest; the dilated cardiomyopathy subset alone is below that, supporting a conservative OCCASIONAL band.

PMID:32681750 SUPPORT Human Clinical

"Some patients develop life-threatening cardiomyopathy."

International consensus confirms the cardiomyopathy risk and its life-threatening character.

Sudden Cardiac Death HP:0001645

Show evidence (1 reference)

PMID:31563034 SUPPORT Human Clinical

"During follow-up one of the brothers died unexpectedly after physical exertion during daily life at the age of twelve years."

Documents exertion-associated sudden death in a molecularly confirmed PGM1-CDG sibling.

Abnormal Heart Valve Morphology VERY_RARE HP:0001654

Onset: CONGENITAL

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Other echocardiogram abnormalities include mild left ventricular enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n = 2)."

Valvular defects in 2/57 patients (4%) support the VERY_RARE band.

Digestive 2

Anal Atresia HP:0002023

Onset: CONGENITAL

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"anal atresia, and a missing lumbar vertebra."

The guideline's review of molecularly confirmed human cases directly lists anal atresia among the less common congenital findings.

Acute Hepatic Failure OCCASIONAL HP:0006554

Temporal: ACUTE

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Episodes of acute hepatic failure were described in five patients, however, without details concerning the circumstances or the extent of presentation."

Five of the 57 molecularly confirmed patients reviewed by the guideline falls in the OCCASIONAL band.

Endocrine 3

Growth Hormone-IGF Axis Deficiency OCCASIONAL Secondary growth hormone deficiency HP:0008240

Show evidence (2 references)

PMID:32681750 SUPPORT Human Clinical

"Decreased levels of growth hormone or IGF1 was reported in 12 patients"

The combined growth-hormone/IGF-1 count is 12/57 (21%), supporting the OCCASIONAL band for axis deficiency. Marked PARTIAL because the source does not report how many of those patients met the narrower definition of secondary growth-hormone deficiency.

PMID:32681750 SUPPORT Human Clinical

"9 patients showed decreased serum insulin-like growth factor-binding protein 3 (IGFBP-3)"

Adds direct evidence for the IGFBP-3 component of the growth-hormone/IGF axis; marked PARTIAL for the same mapping limitation.

Hypogonadotropic Hypogonadism OCCASIONAL HP:0000044

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Two girls had hypogonadotropic hypogonadism with delayed puberty."

2/19 patients (about 11%) maps to the OCCASIONAL band.

Adrenal Insufficiency OCCASIONAL HP:0000846

Show evidence (1 reference)

PMID:26768186 SUPPORT Human Clinical

"ACTH deficiency should be considered in any PGM1 deficient patient with hypoglycemia."

Recommends screening for ACTH deficiency. The OCCASIONAL band is set conservatively because 4/7 in a single consanguineous family is not generalizable to the wider PGM1-CDG population.

Eye 3

Abnormal Eye Movement VERY_RARE Abnormality of eye movement HP:0000496

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"The most commonly reported ophthalmologic abnormalities were unspecified abnormal eye movements (n = 2)8,10 and strabismus (n = 2).10 Less common findings were nasolacrimal duct obstruction and epiphoria (n = 1).11"

Abnormal eye movements in 2/57 patients (4%) support the VERY_RARE band.

Strabismus VERY_RARE HP:0000486

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"The most commonly reported ophthalmologic abnormalities were unspecified abnormal eye movements (n = 2)8,10 and strabismus (n = 2).10 Less common findings were nasolacrimal duct obstruction and epiphoria (n = 1).11"

Strabismus in 2/57 patients (4%) supports the VERY_RARE band.

Epiphora VERY_RARE HP:0009926

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Less common findings were nasolacrimal duct obstruction and epiphoria (n = 1)."

A single reported case among 57 patients supports the VERY_RARE band; the source spells the finding "epiphoria," mapped here to the canonical HPO term Epiphora.

Head and Neck 2

Bifid Uvula FREQUENT HP:0000193

Onset: CONGENITAL

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Although all the patients had multisystem disease at the time of the study, the only apparent clinical feature at birth was a bifid uvula (in 16 of the 19 patients)."

Establishes bifid uvula as the sole congenital sign in this cohort. The band is deliberately set to FREQUENT rather than to the 16/19 (84%) figure this snippet supports, because that cohort was ascertained partly through the craniofacial finding; the later 57-patient consensus review reports bifid uvula in a lower proportion.

PMID:31077402 SUPPORT Other

"At birth, affected patients have frequent malformations in the spectrum of bifid uvula, cleft palate, and Pierre-Robin sequence."

Independent framing of the congenital craniofacial spectrum as "frequent", consistent with the FREQUENT band. Tagged OTHER because this is the review background of a mouse-model paper, not its own experimental result.

Cleft Palate FREQUENT HP:0000175

Onset: CONGENITAL

Show evidence (2 references)

PMID:32681750 SUPPORT Human Clinical

"Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement."

International consensus describes cleft palate as a typical infantile presenting feature; "most patients present as infants with cleft palate" maps to the FREQUENT band.

PMID:26768186 SUPPORT Human Clinical

"All patients have an abnormal palatine structure (cleft palate, bifid uvula) and elevated serum transaminases"

Independent family series confirming universal palatal abnormality.

Metabolism 3

Elevated Hepatic Transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Signs of hepatopathy with moderately elevated serum aminotransferase levels developed in all patients."

"in all patients" in the 19-patient landmark cohort supports the VERY_FREQUENT band.

Hypoglycemia FREQUENT HP:0001943

Temporal: RECURRENT

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Hypoglycemia was common, especially in childhood, requiring treatment with frequent meals, complex carbohydrates, or overnight tube feeding."

"common" maps to the FREQUENT band per the project frequency-mapping table.

PMID:26768186 SUPPORT Human Clinical

"Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients."

Documents the recurrent, ketotic character of the hypoglycemia.

Malignant Hyperthermia OCCASIONAL HP:0002047

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Malignant hyperthermia with severe rhabdomyolysis occurred in two patients after the administration of general anesthesia."

2/19 patients (about 11%) maps to the OCCASIONAL band (5-29%).

Musculoskeletal 3

Abnormal Vertebral Morphology HP:0003468

Onset: CONGENITAL

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"anal atresia, and a missing lumbar vertebra."

The missing lumbar vertebra is direct human evidence for an abnormal vertebral morphology association.

Rhabdomyolysis OCCASIONAL HP:0003201

Temporal: RECURRENT

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Attacks of rhabdomyolysis were studied in 43 patients and occurred in 25% of patients (11/43)."

The guideline's phenotype-specific denominator places rhabdomyolysis at 25%, supporting OCCASIONAL and superseding the earlier over-read of a compound sentence about muscle symptoms overall.

Muscle Weakness FREQUENT HP:0001324

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"The majority of the patients had muscle symptoms, including exercise intolerance, muscle weakness, and rhabdomyolysis."

Muscle weakness is one of the muscle symptoms present in the majority of the landmark cohort, supporting the FREQUENT band.

Nervous System 3

Intellectual Disability OCCASIONAL HP:0001249

Show evidence (2 references)

PMID:32681750 SUPPORT Human Clinical

"Cognitive impairments were noted in 14 patients, intellectual disability in 8, learning disabilities in 11 and speech delay in 2."

Intellectual disability in 8/57 patients (14%) supports the OCCASIONAL band and replaces an overly general neurologic HPO association.

PMID:30262252 SUPPORT Human Clinical

"We detected 17 patients out of the 41 reported PGM1-CDG cases with significant neurologic involvement."

Preserves the broader human systematic-review context but is marked PARTIAL because it does not provide an intellectual-disability-specific numerator.

Motor Delay OCCASIONAL HP:0001270

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Motor delay was described in four patients."

Motor delay in 4/57 patients (7%) supports the OCCASIONAL band.

Seizure OCCASIONAL HP:0001250

Temporal: RECURRENT

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Epileptic seizures have been reported in three patients with developmental delay, with an abnormal EEG detected in one patient."

Seizures in 3/57 patients (5.3%) support the OCCASIONAL band and provide a specific HPO association in place of the prior neurologic umbrella term.

Constitutional 1

Exercise Intolerance FREQUENT HP:0003546

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"The majority of the patients had muscle symptoms, including exercise intolerance, muscle weakness, and rhabdomyolysis."

"The majority of the patients" maps to the FREQUENT band (30-79%).

Growth 2

Short Stature FREQUENT HP:0004322

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Growth retardation was reported in all but four patients."

15/19 patients (about 79%) reported with growth retardation, at the top of the FREQUENT band.

PMID:26768186 SUPPORT Human Clinical

"4/7 have short stature (<-2 SDS) and one was diagnosed with growth hormone deficiency"

Independent series quantifying short stature specifically (rather than "growth retardation") at 4/7, and documenting growth hormone deficiency as one contributing mechanism.

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:38968673 SUPPORT Human Clinical

"The most common clinical presentations include muscle involvement, failure to thrive, cleft palate, and cardiac involvement."

Lists failure to thrive among the most common presenting features across 73 reported individuals.

Other 8

Pierre Robin Sequence OCCASIONAL HP:0000201

Onset: CONGENITAL

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Of 57 patients with PGM1-CDG reported to date, cleft palate was the most commonly reported anomaly (n = 28), followed by bifid uvula (n = 25) and Pierre-Robin sequence (n = 15)."

Direct human evidence identifies Pierre-Robin sequence in 15/57 reported patients (26%), supporting the OCCASIONAL band without relying on review background from a mouse-model paper.

Hyperinsulinemic Hypoglycemia HP:0000825

Temporal: RECURRENT Onset: INFANTILE

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Hypoglycemia was primarily due to hyperinsulinism in young patients."

Directly supports the age-dependent hyperinsulinemic phenotype while avoiding an unsupported whole-disease frequency estimate.

Electrocardiographic Abnormality OCCASIONAL Abnormal EKG HP:0003115

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Electrocardiogram (ECG) abnormalities including long QT interval, ST wave elevation, T wave inversion, sinus tachycardia, and minor incomplete intraventricular conduction disturbance were observed in five patients."

Five of 57 reviewed patients (9%) had ECG or conduction abnormalities, supporting the OCCASIONAL band.

Left Ventricular Dilatation OCCASIONAL HP:4000141

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Other echocardiogram abnormalities include mild left ventricular enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n = 2)."

Three of 57 patients (5.3%) had mild left-ventricular enlargement, supporting the OCCASIONAL band.

Abnormal Cardiac Septum Morphology VERY_RARE HP:0001671

Onset: CONGENITAL

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Other echocardiogram abnormalities include mild left ventricular enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n = 2)."

Septal defects in 2/57 patients (4%) support the VERY_RARE band.

Reduced Antithrombin III Activity FREQUENT HP:0001976

Show evidence (1 reference)

PMID:38968673 SUPPORT Human Clinical

"Coagulation information was available for only 58.9 % of the reported individuals, out of which 67.4 % of PGM1-CDG individuals were reported to have abnormalities. The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %) deficiency."

Among the 58.9% of reported individuals for whom coagulation data existed, 67.4% had abnormalities and antithrombin was the most frequent. The band is therefore stated on the tested denominator, not the whole reported cohort; the 67.4% figure covers any coagulation abnormality rather than antithrombin deficiency specifically, so FREQUENT is the most that this evidence supports.

Elevated Circulating TSH OCCASIONAL Elevated circulating thyroid-stimulating hormone concentration HP:0002925

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"High levels of serum thyroid-stimulating hormone (TSH) were reported in three patients and decreased levels of thyroxin-binding globulin (TBG) in six."

Elevated TSH in 3/57 patients (5.3%) supports the OCCASIONAL band.

Nasolacrimal Duct Obstruction VERY_RARE HP:0000579

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Less common findings were nasolacrimal duct obstruction and epiphoria (n = 1)."

A single reported case among 57 patients supports the VERY_RARE band.

🧬

Genetic Associations

1

PGM1

Gene: PGM1 hgnc:8905 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"We identified 21 different mutations in PGM1 in 19 patients."

Establishes PGM1 as the causal gene and documents substantial allelic heterogeneity.

PMID:27206562 SUPPORT Human Clinical

"Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score."

Supports the absence of a usable genotype-phenotype correlation in PGM1-CDG.

💊

Medical Actions

13

Oral D-Galactose Supplementation

Action: oral monosaccharide (D-galactose) supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: D-galactose CHEBI:12936

The disease-directed therapy and the feature that makes PGM1-CDG unusual among the CDG. Oral D-galactose enters the Leloir pathway downstream of the PGM1 block and directly replenishes UDP-galactose and UDP-glucose, restoring the nucleotide-sugar donors required for both ER and Golgi glycosylation. Recommended dosing is approximately 1.0 to 1.5 g/kg/day (younger patients may require up to 3.0 g/kg/day), maximum 50 g/day, given in divided doses with gradual titration to avoid gastrointestinal effects. Transferrin glycosylation, transaminases, antithrombin III and hypoglycemia improve; exercise intolerance and rhabdomyolysis improve in some. Cardiomyopathy does NOT improve, so galactose therapy must not create false reassurance about cardiac risk and lifelong cardiac surveillance remains mandatory. Monitoring should include ALT/AST, CK, coagulation factors including antithrombin III, intact transferrin or N-glycan analysis, serum galactose-1-phosphate and urine galactitol.

Mechanism Target:

INHIBITS UDP-Galactose Depletion and Impaired Golgi Galactosylation — D-galactose bypasses the PGM1 block via the Leloir pathway and replenishes the depleted UDP-galactose pool, reversing the Golgi galactosylation defect that produces the truncated type II glycans.

INHIBITS UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly — Galactose loading also raises UDP-glucose and improves the lipid-linked oligosaccharide profile, partially correcting the ER (type I) arm.

Show evidence (5 references)

PMID:28617415 SUPPORT Human Clinical

"Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole..."

Prospective nine-patient pilot trial establishing efficacy on liver, coagulation and glycosylation endpoints.

PMID:28617415 SUPPORT Human Clinical

"Oral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study."

Safety and efficacy conclusion of the prospective pilot study.

PMID:35562242 SUPPORT Other

"The maximum safe dose that has been well tolerated without adverse effects is 50 g/day"

Source for the maximum tolerated daily dose in the dosing recommendation. Tagged OTHER because this is an expert review synthesizing dosing practice.

+ 2 more references

Fasting Avoidance and Complex Carbohydrate Feeding

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Prevention of hypoglycemia by frequent complex-carbohydrate meals and snacks, overnight enteral feeding where needed, and a written emergency plan for intercurrent illness. Uncooked cornstarch before bedtime can be introduced after six months of age, and modified cornstarch (Glycosade) can be used after three years. Stabilizing glucose homeostasis by dietary means remains standard care alongside D-galactose.

Mechanism Target:

INHIBITS Fasting Hypoglycemia and Hepatic Metabolic Stress — Continuous exogenous carbohydrate supply substitutes for the unavailable hepatic glycogen output.

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"supplementation with complex carbohydrates stabilizes blood glucose"

The landmark study's own conclusion supporting complex-carbohydrate management of the hypoglycemia.

PMID:32681750 SUPPORT Human Clinical

"The oral administration of uncooked corn starch before bedtime can be initiated over the age of 6 months. Modified cornstarch (Glycosade) can be used in children over 3 years."

Provides guideline-backed age thresholds for uncooked and modified cornstarch rather than leaving complex-carbohydrate feeding as prose only.

Diazoxide for Hyperinsulinemic Hypoglycemia

Action: Pharmacotherapy NCIT:C15986

Agent: diazoxide CHEBI:4495

Oral diazoxide should be considered when hypoglycemia is hyperinsulinemic, particularly in young patients, alongside frequent feeding, complex carbohydrates and D-galactose.

Target Phenotypes: Hyperinsulinemic hypoglycemia HP:0000825

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Oral diazoxide therapy should be considered for hyperinsulinemic hypoglycemia."

The international guideline directly recommends diazoxide for the hyperinsulinemic hypoglycemia phenotype.

Avoidance of Hepatotoxic Medications

Category: Therapeutic Action: medication avoidance and supportive care Ontology label: Supportive Care NCIT:C15747

Avoid hepatotoxic medications where alternatives exist because the multisystem form has chronic hepatopathy and a documented risk of acute hepatic failure.

Target Phenotypes: Acute hepatic failure HP:0006554

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Hepatotoxic medication should be avoided."

Captures the guideline's explicit medication-avoidance recommendation as a structured preventive action.

Cardiac Surveillance

Category: Monitoring Action: cardiac surveillance Ontology label: Supportive Care NCIT:C15747

Because D-galactose does not correct the cardiomyopathy, cardiac surveillance must continue lifelong in every patient regardless of biochemical response. Baseline assessment at diagnosis and periodic echocardiography and ECG (with Holter monitoring, cardiac MRI or exercise testing where indicated) are the practical implementation, and screening of at-risk first-degree relatives is warranted once a proband is identified.

Show evidence (2 references)

PMID:35562242 SUPPORT Other

"However, it does not treat the cardiomyopathy observed in some patients"

Establishes the rationale for cardiac management independent of D-galactose. Tagged OTHER because this is an expert review.

PMID:31563034 SUPPORT Human Clinical

"All first-degree relatives underwent clinical examination including cardiac ultrasound, Holter-ECG, exercise stress test and biochemistry panel."

Documents the concrete cardiac screening protocol applied to a PGM1-CDG family, which detected affected siblings.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Refractory dilated cardiomyopathy may require heart transplantation, which has been performed successfully as early as 12 months of age in PGM1-CDG. Transplantation addresses only the cardiac arm; D-galactose is continued for the systemic disease.

Mechanism Target:

INHIBITS Dilated Cardiomyopathy and Progressive Heart Failure — Transplantation replaces the failing PGM1-deficient myocardium; it does not address the systemic disorder, which still requires D-galactose.

Show evidence (2 references)

PMID:36873091 SUPPORT Human Clinical

"Cardiac function was stable in the first 18 months of follow-up, and hematologic, hepatic, and endocrine laboratory findings improved during D-galactose therapy."

Documents a successful infant heart transplant with concurrent D-galactose therapy for the systemic disease.

PMID:36873091 SUPPORT Human Clinical

"The latter therapy improves several systemic symptoms and biochemical abnormalities in PGM1-CDG but does not correct the heart failure related to cardiomyopathy."

States the division of labour between D-galactose and transplantation.

Perioperative and Anesthetic Precautions

Action: perioperative supportive care Ontology label: Supportive Care NCIT:C15747

PGM1-CDG carries two distinct perioperative hazards that should be planned for before any surgery. Malignant hyperthermia with severe rhabdomyolysis has occurred after general anesthesia, and the coagulation abnormalities (notably antithrombin deficiency, but also reduced procoagulant factors) create both thrombotic and hemorrhagic risk, so a hemostasis panel should be reviewed preoperatively.

Show evidence (2 references)

PMID:24499211 SUPPORT Human Clinical

"Malignant hyperthermia with severe rhabdomyolysis occurred in two patients after the administration of general anesthesia."

Documents the anesthetic hazard that motivates pre-anesthetic evaluation.

PMID:38968673 SUPPORT Human Clinical

"We recommend coagulation parameters should be routinely checked in individuals with PGM1-CDG or suspected of having PGM1-CDG."

Supports routine coagulation assessment, which in the perioperative setting is the actionable form of that recommendation.

Hydrocortisone Replacement for Secondary Adrenal Insufficiency

Action: Pharmacotherapy NCIT:C15986

Agent: hydrocortisone CHEBI:17650

Patients with documented ACTH/cortisol deficiency benefit from hydrocortisone replacement, which reduces but does not entirely eliminate hypoglycemic episodes. Morning cortisol and ACTH should be checked at least annually in patients with hypoglycemia.

Show evidence (1 reference)

PMID:26768186 SUPPORT Human Clinical

"Hydrocortisone replacement therapy improved, but not entirely eliminated hypoglycemic episodes."

Directly reports the effect of hydrocortisone replacement on hypoglycemia in PGM1-deficient patients.

L-Thyroxine for Clinical Hypothyroidism

Action: Pharmacotherapy NCIT:C15986

Agent: L-thyroxine CHEBI:18332

Treat clinical hypothyroidism with L-thyroxine. Thyroid-axis surveillance is warranted because elevated TSH and reduced thyroxine-binding globulin are reported in PGM1-CDG.

Target Phenotypes: Elevated circulating thyroid-stimulating hormone concentration HP:0002925

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Therapy with L-thyroxine is indicated for clinical hypothyroidism treatment."

Direct guideline recommendation for thyroid-hormone replacement.

Growth Hormone Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin CHEBI:749556

Growth hormone can be used for documented growth impairment associated with growth-hormone-axis deficiency, although response is variable and not all patients improve.

Target Phenotypes: Growth hormone-IGF axis deficiency HP:0008240 Short stature HP:0004322

Show evidence (1 reference)

PMID:32681750 SUPPORT Human Clinical

"Growth impairment can be managed with growth hormone therapy, although not all patients respond to this treatment."

Captures both the guideline recommendation and the explicitly stated response limitation.

Cleft Palate Repair and Craniofacial Care

Action: cleft palate repair Ontology label: Surgical Procedure NCIT:C15329

Surgical repair of cleft palate with multidisciplinary craniofacial, airway, feeding, dental and speech support. Bifid uvula alone generally requires no surgical intervention but is the diagnostic clue that should prompt biochemical testing.

Show evidence (1 reference)

PMID:31077402 SUPPORT Other

"At birth, affected patients have frequent malformations in the spectrum of bifid uvula, cleft palate, and Pierre-Robin sequence."

Establishes the craniofacial malformations that require repair and multidisciplinary care. Marked PARTIAL because it documents the indication rather than the intervention; there is no PGM1-specific craniofacial surgical protocol, and management follows standard cleft/Pierre Robin care.

AAV9-PGM1 Gene Replacement Therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Experimental, preclinical only. AAV9-delivered PGM1 gene replacement both prevented and halted progression of dilated cardiomyopathy in the cardiomyocyte-specific Pgm2 knockout mouse. This is the most promising candidate for the galactose-resistant cardiac phenotype, but no human safety or efficacy data exist.

Mechanism Target:

INHIBITS Biallelic PGM1 Loss of Function — Gene replacement restores PGM1 protein and enzymatic activity at the level of the primary lesion rather than downstream of it.

Show evidence (1 reference)

PMID:36709920 SUPPORT Model Organism

"Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype."

Preclinical proof of concept in the cardiac conditional knockout mouse. This is model-organism evidence only; no human data exist.

Genetic Counseling and Family Testing

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive counseling with a 25% recurrence risk per pregnancy for carrier couples, and cascade testing of siblings, who may have mild or late-onset disease and in reported families have been identified only after an index event. Prenatal and preimplantation genetic testing are available once the familial variants are known.

Show evidence (2 references)

PMID:31563034 SUPPORT Human Clinical

"Our findings suggest that there is a need of multidisciplinary discussion and genetic testing after unexpected cardiac death in the young."

Supports family-level genetic testing, which in this kindred identified two additional affected siblings after the index sudden death.

PMID:31563034 SUPPORT Human Clinical

"Both parents and three other siblings were found to be heterozygous gene carriers without risk for the disease."

Demonstrates the carrier-testing outcome that recessive counseling delivers: unaffected heterozygous relatives can be reassured while affected homozygotes are identified.

🔬

Biochemical Markers

3

Mixed type I and type II serum transferrin isoform pattern (ABNORMAL)

Context: The diagnostic biochemical signature. Intact-transferrin mass spectrometry (MALDI-TOF, ESI-MS/QTOF or LC-MS) shows both loss of complete N-glycans (the type I component) and truncated glycans lacking galactose and terminal sialic acid (the type II component). Transferrin isoelectric focusing, HPLC or capillary electrophoresis can screen for carbohydrate-deficient transferrin but resolve the mixed structural signature less well. Transferrin glycosylation normalizes substantially on D-galactose and is used as a treatment-response readout.

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Mass spectrometry revealed the presence of a variety of transferrin glycoforms, including forms lacking one or both glycans as well as forms with truncated glycans"

Describes the coexistence of missing and truncated glycoforms that defines the mixed pattern.

Creatine kinase (INCREASED)

Context: Creatine kinase is elevated during and between rhabdomyolysis episodes and is part of the recommended monitoring panel; it improved on D-galactose in a subset of treated patients.

Show evidence (1 reference)

PMID:37181075 SUPPORT Human Clinical

"there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two"

Confirms CK as an abnormal, treatment-responsive analyte in PGM1-CDG.

PGM1 enzyme activity in fibroblasts or leukocytes (DECREASED)

Context: Direct enzymatic assay in cultured fibroblasts or leukocytes shows severely reduced activity (the 2021 consensus guideline, PMID:32681750, reports a range from undetectable to 20% of controls; red blood cells cannot be used because PGM1 is absent there). It is supportive but not independently definitive, and residual activity does not correlate reliably with clinical severity, so the final diagnosis rests on molecular testing.

Show evidence (1 reference)

PMID:27206562 SUPPORT Human Clinical

"Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score."

Establishes the important caveat that residual enzyme activity does not predict disease severity.

🔬

Diagnosis

3

Intact Transferrin Mass Spectrometry

First-line biochemical screen and the test that best resolves the characteristic mixed type I / type II signature. Transferrin isoelectric focusing, HPLC or capillary electrophoresis may be used as an initial carbohydrate-deficient-transferrin screen but resolve the structural pattern less well.

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Analysis of serum transferrin by means of isoelectric focusing was performed to screen for congenital disorders of glycosylation."

Documents transferrin analysis as the screening entry point that first identified the disorder.

PGM1 Molecular Genetic Testing

Confirmatory testing identifies two pathogenic or likely pathogenic PGM1 variants, with phase established where possible. Targeted PGM1 sequencing plus deletion/duplication analysis, CDG or metabolic-myopathy gene panels including PGM1, or exome/genome sequencing are all appropriate routes depending on the presentation.

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings."

Illustrates the genomic route to molecular confirmation.

Tulane PGM1-CDG Rating Scale

A clinical severity scoring system (TPCRS) that stratifies patients into phenotypic groups from clinical history and examination. Five variables predict severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth; two of these can be assessed on physical examination alone, allowing rapid triage.

Show evidence (1 reference)

PMID:27206562 SUPPORT Human Clinical

"Principal component analysis identified 5 variables that contributed to 54% variance in the cohort and are predictive of disease severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth."

Defines the severity predictors underlying the TPCRS scoring instrument.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

More than 60 patients reported in the literature as of 2023; population prevalence and incidence remain unknown. PGM1-CDG is nonetheless described as the third most common N-linked CDG.

Show evidence (2 references)

PMID:37181075 SUPPORT Human Clinical

"So far, more than 60 patients have been reported."

Provides the cumulative reported-case count; no population-based prevalence estimate exists.

PMID:36709920 SUPPORT Other

"Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most common N-linked congenital disorders of glycosylation (CDG) in humans."

Places PGM1-CDG in relative rank among the N-linked CDG despite the absence of an absolute prevalence figure.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from PGM1-congenital disorder of glycosylation:

McArdle disease

Overlapping Features Myophosphorylase (PYGM) deficiency produces an almost identical muscle physiology, including a flat lactate response to ischemic forearm exercise and the second-wind phenomenon, which was long considered pathognomonic for McArdle disease. PGM1-CDG is distinguished by the multisystem features (palatal malformation, hepatopathy, coagulopathy, cardiomyopathy) and the abnormal transferrin glycosylation.

Show evidence (1 reference)

PMID:28882528 SUPPORT Human Clinical

"The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency."

Explicitly establishes the diagnostic overlap that makes McArdle disease a key differential.

Glycogen storage disease type I

Overlapping Features Glucose-6-phosphatase deficiency shares fasting hypoglycemia, lactic acidosis, hepatomegaly and exercise intolerance with PGM1-CDG because both disorders obstruct hepatic glucose output at adjacent steps, but GSD I lacks the glycosylation abnormality and the craniofacial and cardiac features.

Show evidence (1 reference)

PMID:24499211 SUPPORT Human Clinical

"These characteristics are also seen with glycogen storage disease Ia, in which there is a defect in hepatic glucose-6-phosphatase."

The landmark paper itself draws the comparison with GSD Ia for the hypoglycemia and exercise-intolerance phenotype.

MPI-congenital disorder of glycosylation

Overlapping Features MPI-CDG is the other classically treatable CDG (with oral D-mannose) and likewise presents with hypoglycemia, hyperinsulinism and hepatopathy, but it causes protein-losing enteropathy and hepatic fibrosis rather than craniofacial malformation, myopathy or cardiomyopathy, and it produces a pure type I transferrin pattern.

Show evidence (1 reference)

PMID:35562242 SUPPORT Other

"This is especially true for MPI-CDG; which almost always presents with hypoglycemia and hyperinsulinism"

Documents the shared hypoglycemia/hyperinsulinism presentation that makes MPI-CDG a differential. Marked PARTIAL because it supports the shared feature rather than the full discriminating comparison.

🔬

Clinical Trials

2

NCT05402332 PHASE_II NOT_RECRUITING

A Phase 2b multicenter, randomized, double-blind, placebo-controlled crossover trial of AVTX-801 (D-galactose) in adults with PGM1-CDG already taking D-galactose, evaluating efficacy, safety and tolerability. The registry lists a future estimated start date, so the trial had not begun enrolling at the time of curation.

Target Phenotypes: Rhabdomyolysis HP:0003201 Elevated hepatic transaminases HP:0002910

Show evidence (1 reference)

clinicaltrials:NCT05402332 SUPPORT Human Clinical

"This is a clinical trial to evaluate the efficacy of AVTX-801 (D-galactose) on the clinical manifestations of PGM1-CDG in participants currently taking D-galactose."

Registered randomized crossover trial formally testing the D-galactose treatment arm curated in this entry.

NCT03404856 UNKNOWN

A single-group Phase 1/2 pediatric study of ORL-1G (D-galactose), registered under the disorder's former name glycogen storage disease type 14, with liver-enzyme reduction as the primary endpoint and transferrin-glycosylation improvement as a secondary endpoint. Registry information is stale, so the current status should not be inferred from the record. The phase slot is left unset because the registry records a combined Phase 1/2 design that the dismech phase enum cannot express.

Target Phenotypes: Elevated hepatic transaminases HP:0002910

Show evidence (1 reference)

clinicaltrials:NCT03404856 SUPPORT Human Clinical

"Study of ORL-1G in Patients With Glycogen Storage Disease Type 14"

Registry record for the pediatric D-galactose study; the GSD type 14 title reflects the disorder's former name.

🧫

Experimental Models

1

PGM1-deficient patient-derived iPSC-cardiomyocytes IPSC_DERIVED_MODEL

Induced pluripotent stem cell-derived cardiomyocytes reprogrammed from PGM1-deficient patient fibroblasts, characterized by multielectrode-array recording, untargeted (glyco)proteomics, tracer metabolomics, and mitochondrial respiration assays. This is the first human cardiomyocyte model of PGM1-CDG; the cardiac arm of the disease had previously been studied in cardiomyocyte-specific Pgm2 knockout mice and in PGM1-null skeletal-muscle cells, neither of which is a human cardiomyocyte.

Organism

human NCBITaxon:9606

Cell source

Fibroblasts from PGM1-deficient patients, reprogrammed to iPSC

Culture

iPSC-derived cardiomyocyte monolayer on multielectrode arrays

Publication

PMID:41723528

Pathograph links

Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction recapitulates fidelity: moderate The model is where the Z-disk lesion was discovered, so it recapitulates it by construction.

Limitations: iPSC-derived cardiomyocytes are immature relative to adult myocardium, with fetal-like sarcomere organization and a glycolytic rather than oxidative metabolic profile - both of which are the very properties this model is used to measure. The PGM1-LDB3 interaction rests on an AlphaFold3 prediction confirmed in vitro, not on structural data from cardiac tissue.

Readouts

Z-disk component abundance, LDB3 included

Direction: DECREASED

Interpretation: Proteomic depletion of Z-disk proteins is the primary measurement behind this node.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"Proteomic analyses revealed depletion of Z-disk components, including LDB3."

Reports the measurement and its direction.

Contractile function by multielectrode array

Direction: DECREASED

Interpretation: Reduced beating frequency and impaired contractility are the functional consequence of the sarcomeric lesion in this model.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics."

Reports the contractile measurements directly.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts."

Establishes that the model is patient-derived and therefore informative for the human cardiac node.

Cardiomyocyte Energetic and Mitochondrial Failure recapitulates fidelity: moderate Extends the mitochondrial arm from mouse heart and PGM1-null skeletal muscle cells into human cardiomyocytes.

Limitations: iPSC-cardiomyocyte metabolism is fetal-like and predominantly glycolytic, so a measured respiration deficit may understate or overstate what an adult myocardium would show. No galactose-rescue arm was reported in this model, so it does not itself test the treatment-resistance claim.

Readouts

Mitochondrial respiration

Direction: DECREASED

Interpretation: Respirometry is the direct functional measurement of the energetic failure node.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration."

Reports the respiration and energy measurements.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"Recent evidence of mitochondrial abnormalities in PGM1-deficient human and murine heart"

Places the model's mitochondrial finding in the context of prior human and mouse cardiac evidence.

Show evidence (1 reference)

PMID:41723528 SUPPORT In Vitro

"Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes."

Describes the model's readout platform.

{ }

Source YAML

click to show

name: PGM1-congenital disorder of glycosylation
creation_date: "2026-08-01T17:30:00Z"
description: >-
  PGM1-congenital disorder of glycosylation (PGM1-CDG, phosphoglucomutase-1
  deficiency; formerly glycogen storage disease type XIV / GSD XIV) is a rare
  autosomal recessive multisystem disorder caused by biallelic pathogenic
  variants in PGM1. Because phosphoglucomutase-1 sits at the junction of
  glycogen metabolism, glycolysis and nucleotide-sugar supply, its deficiency
  simultaneously blocks glycogen synthesis/mobilization and depletes the
  UDP-glucose and UDP-galactose pools required for protein N-glycosylation. The
  result is the archetypal mixed type I plus type II congenital disorder of
  glycosylation: serum transferrin shows both loss of complete N-glycans (type
  I) and truncated, galactose-deficient glycans (type II). Clinically, patients
  present at birth with bifid uvula and/or cleft palate and later develop
  hepatopathy, fasting hypoglycemia, exercise intolerance and rhabdomyolysis,
  coagulation abnormalities (notably antithrombin deficiency), endocrine
  dysfunction, and, most dangerously, dilated cardiomyopathy. Unlike most CDG,
  PGM1-CDG is treatable: oral D-galactose supplementation bypasses the enzymatic
  block, replenishes UDP-galactose, and corrects glycosylation, liver and
  coagulation abnormalities - but it does not rescue the cardiomyopathy.
category: Mendelian
parents:
- hereditary disease
synonyms:
- PGM1-CDG
- PGM1 deficiency
- phosphoglucomutase-1 deficiency
- congenital disorder of glycosylation type It
- CDG-It
- CDG1T
- glycogen storage disease XIV
- GSD XIV
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  icimd_category:
  - classification_value: n_linked_protein_glycosylation
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416) category 18, "Congenital
      disorders of glycosylation", group "Disorders of N-linked protein
      glycosylation". PGM1-CDG produces a mixed type I / type II N-glycosylation
      defect.
  - classification_value: glycogen_metabolism
    notes: >-
      PGM1-CDG was originally described as glycogen storage disease type XIV, and
      the block in glucose-1-phosphate / glucose-6-phosphate interconversion is a
      genuine disorder of glycogen metabolism as well as of glycosylation.
disease_term:
  preferred_term: PGM1-congenital disorder of glycosylation
  term:
    id: MONDO:0013968
    label: PGM1-congenital disorder of glycosylation
has_subtypes:
- name: Multisystem
  display_name: Multisystem form
  description: >-
    The classic infantile-onset presentation, comprising congenital malformations
    (bifid uvula, cleft palate, Pierre Robin sequence) together with
    hypoglycemia, hepatopathy, coagulation and endocrine abnormalities, myopathy
    and cardiomyopathy. Liver involvement is essentially universal in this form.
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients present as infants with cleft palate, liver function
      abnormalities and hypoglycemia, but some patients present in adulthood with
      isolated muscle involvement.
    explanation: >-
      The consensus guideline contrasts the infantile multisystem presentation
      with the adult isolated-muscle presentation, the two forms modeled here.
- name: Myopathic
  display_name: Primary myopathic form
  description: >-
    A predominantly muscular presentation that may not become apparent until
    adolescence or adulthood, with exercise intolerance, fatigability, muscle
    weakness and recurrent exercise-induced rhabdomyolysis. Hepatic involvement
    is characteristically absent, which is a practical discriminator from the
    multisystem form.
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      some patients present in adulthood with isolated muscle involvement
    explanation: >-
      Establishes the adult-onset, isolated-muscle presentation as a recognized
      distinct form.
  - reference: PMID:28882528
    reference_title: "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated metabolism and physiological responses to exercise in an
      18-year-old woman with multiple congenital abnormalities and exertional
      muscle fatigue, tightness, and rhabdomyolysis.
    explanation: >-
      A worked example of the muscle-dominant presentation studied by exercise
      physiology in an adolescent/young adult.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    PGM1-CDG results from biallelic pathogenic PGM1 variants. Reported families
    include homozygous variants segregating in consanguineous kindreds as well as
    compound heterozygotes; heterozygous parents are unaffected carriers.
  evidence:
  - reference: PMID:37181075
    reference_title: "Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM:
      614921) is a rare autosomal recessive inherited metabolic disease caused by
      the deficiency of the PGM1 enzyme.
    explanation: >-
      States the autosomal recessive mode of inheritance and anchors the entry to
      OMIM 614921, the phenotype MIM matched by the MONDO:0013968 xref.
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both parents and three other siblings were found to be heterozygous gene
      carriers without risk for the disease.
    explanation: >-
      Family segregation in this kindred (three homozygous affected sibs,
      heterozygous unaffected parents) directly demonstrates recessive
      transmission.
pathophysiology:
- name: Biallelic PGM1 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Biallelic pathogenic variants in PGM1 (1p31.3) abolish or severely reduce
    phosphoglucomutase-1 activity. PGM1 supplies the large majority of
    phosphoglucomutase activity in most tissues, and residual activity in patient
    fibroblasts or leukocytes is severely reduced (the 2021 consensus guideline,
    PMID:32681750, reports a range from undetectable to 20% of controls). Most
    reported alleles are missense and act by loss of function, often through
    catalytic impairment or local structural destabilization of the enzyme.
  genes:
  - preferred_term: PGM1
    term:
      id: hgnc:8905
      label: PGM1
  molecular_functions:
  - preferred_term: phosphoglucomutase activity
    modifier: DECREASED
    term:
      id: GO:0004614
      label: phosphoglucomutase activity
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphoglucomutase 1 enzyme activity was markedly diminished in all
      patients.
    explanation: >-
      The landmark cohort establishes that PGM1 variants cause a measurable
      enzymatic loss of function in affected individuals.
  - reference: PMID:28882528
    reference_title: "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was
      severely deficient and PGM1 in muscle was undetectable by Western blot.
    explanation: >-
      Confirms loss of PGM1 protein and activity in patient muscle and
      fibroblasts, supporting a loss-of-function mechanism.
  downstream:
  - target: Impaired Glucose-1-Phosphate and Glucose-6-Phosphate Interconversion
    causal_link_type: DIRECT
    description: >-
      Loss of enzyme activity directly removes the catalytic step that
      interconverts the two hexose phosphates.
- name: Impaired Glucose-1-Phosphate and Glucose-6-Phosphate Interconversion
  biological_scale: MOLECULAR
  description: >-
    Phosphoglucomutase-1 reversibly interconverts glucose-1-phosphate and
    glucose-6-phosphate, the metabolic node that connects glycogen (via
    glucose-1-phosphate) to glycolysis and to the hexose-phosphate pool used for
    nucleotide-sugar synthesis. When this step is blocked, flux is disrupted in
    both directions: glucose-6-phosphate generated from a dietary glucose load
    cannot be routed into glycogen, and glucose-1-phosphate released from
    glycogen cannot enter glycolysis or gluconeogenic output.
  chemical_entities:
  - preferred_term: glucose-1-phosphate
    modifier: ABNORMAL
    term:
      id: CHEBI:29042
      label: alpha-D-glucose 1-phosphate
  - preferred_term: glucose-6-phosphate
    modifier: ABNORMAL
    term:
      id: CHEBI:4170
      label: D-glucopyranose 6-phosphate
  biological_processes:
  - preferred_term: glucose metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006006
      label: glucose metabolic process
  evidence:
  - reference: PMID:37175952
    reference_title: "In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy
      metabolism from glycogen and glycolysis, as it catalyzes the
      interconversion of glucose 1-phosphate and glucose 6-phosphate.
    explanation: >-
      Defines the enzymatic reaction that is lost and places it at the glycogen /
      glycolysis junction.
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analyses of sugar metabolites in fibroblasts from patients revealed
      increased concentrations of galactose-1-phosphate and glucose-1 phosphate,
      as compared with fibroblasts from controls.
    explanation: >-
      Direct metabolite measurement in patient fibroblasts showing accumulation
      upstream of the enzymatic block.
  downstream:
  - target: Impaired Glycogen Synthesis and Glycogenolysis
    causal_link_type: DIRECT
    description: >-
      Glycogen can neither be built from glucose-6-phosphate nor mobilized into
      glycolysis, because both routes require the PGM1 step.
  - target: UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
    causal_link_type: DIRECT
    description: >-
      Reduced glucose-1-phosphate availability limits UDP-glucose synthesis, the
      donor pool feeding endoplasmic-reticulum glycan assembly.
  - target: UDP-Galactose Depletion and Impaired Golgi Galactosylation
    causal_link_type: DIRECT
    description: >-
      The Leloir pathway is functionally stalled, lowering the UDP-galactose pool
      needed for Golgi galactosylation.
- name: Impaired Glycogen Synthesis and Glycogenolysis
  biological_scale: CELLULAR
  description: >-
    Loss of the PGM1 step blocks both arms of glycogen handling. In liver, stored
    glycogen cannot be converted to glucose during fasting; in skeletal muscle,
    glycogen cannot be rapidly mobilized for anaerobic glycolysis during
    exertion. The muscle physiology closely mimics McArdle disease, including a
    flat lactate response to ischemic forearm exercise and a second-wind
    phenomenon.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: glycogen catabolic process
    modifier: DECREASED
    term:
      id: GO:0005980
      label: glycogen catabolic process
  - preferred_term: glycogen biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0005978
      label: glycogen biosynthetic process
  - preferred_term: glycolytic process
    modifier: DECREASED
    term:
      id: GO:0006096
      label: glycolytic process
  chemical_entities:
  - preferred_term: glycogen
    modifier: ABNORMAL
    term:
      id: CHEBI:28087
      label: glycogen
  evidence:
  - reference: PMID:28882528
    reference_title: "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that severe loss of PGM1 activity causes blocked muscle
      glycogenolysis that mimics McArdle disease, but may also limit glycogen
      synthesis, which broadens the phenotypic spectrum of this disorder.
    explanation: >-
      Direct in vivo exercise physiology in a patient demonstrating a blocked
      muscle glycogenolysis. Note the authors hedge the synthesis arm ("may also
      limit glycogen synthesis"), so the biosynthetic half of this node is the
      weaker of the two claims.
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During fasting, liver glycogen cannot be converted into glucose via
      glucose-6-phosphate, and hypoglycemia may occur.
    explanation: >-
      States the hepatic arm of the glycogen block and its link to fasting
      hypoglycemia.
  downstream:
  - target: Fasting Hypoglycemia and Hepatic Metabolic Stress
    causal_link_type: DIRECT
  - target: Skeletal Muscle Energy Failure
    causal_link_type: DIRECT
  - target: Cardiomyocyte Energetic and Mitochondrial Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
    description: >-
      The same inability to route glycogen-derived carbon into glycolysis
      compromises cardiomyocyte energy supply. This is arm (a) of the
      galactose-resistant-cardiomyopathy hypothesis.
- name: UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    This is the type I (endoplasmic-reticulum) arm of the mixed glycosylation
    defect. Reduced glucose-1-phosphate limits UDP-glucose, the donor used for
    glucosylation of the dolichol-linked oligosaccharide precursor and for
    calnexin/calreticulin quality control. Patient fibroblasts show an abnormal
    lipid-linked oligosaccharide profile, and truncated or incompletely
    transferred precursors leave N-glycosylation sequons unoccupied - detected in
    serum as whole missing transferrin glycans. Unlike the canonical type I CDG,
    the deficient element is not a glycosyltransferase of the assembly line but
    the nucleotide-sugar donor supply upstream of it.
  chemical_entities:
  - preferred_term: UDP-glucose
    modifier: DECREASED
    term:
      id: CHEBI:46229
      label: UDP-alpha-D-glucose
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  locations:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:28617415
    reference_title: "Oral D-galactose supplementation in PGM1-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies before treatment showed N-glycan hyposialylation, altered
      O-linked glycans, abnormal lipid-linked oligosaccharide profile, and
      abnormal nucleotide sugars in patient fibroblasts.
    explanation: >-
      Demonstrates the ER lipid-linked oligosaccharide abnormality and the
      underlying nucleotide-sugar disturbance in PGM1-CDG fibroblasts, the
      disorder-specific substitution for the module's type I trigger.
  - reference: PMID:28617415
    reference_title: "Oral D-galactose supplementation in PGM1-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked
      oligosaccharide fractions in concert with improved glycosylation in
      PGM1-CDG.
    explanation: >-
      Rescue of the lipid-linked oligosaccharide profile by restoring nucleotide
      sugars confirms that donor depletion, not a transferase defect, drives the
      ER arm.
  downstream:
  - target: Mixed Type I and Type II Protein Hypoglycosylation
    causal_link_type: DIRECT
    description: >-
      Incompletely assembled precursors produce whole missing N-glycans, the
      type I component of the transferrin pattern.
- name: UDP-Galactose Depletion and Impaired Golgi Galactosylation
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    This is the type II (Golgi) arm. PGM1 deficiency stalls the Leloir pathway
    and lowers the UDP-galactose available to Golgi galactosyltransferases, so
    N-glycans that are transferred to protein cannot be completed: they lack
    terminal galactose and, consequently, the sialic acid that caps it. The
    UDP-galactose to UDP-glucose ratio is reduced in patient cells, and the
    resulting glycans are truncated rather than absent. This is the arm that oral
    D-galactose therapy targets directly.
  chemical_entities:
  - preferred_term: UDP-galactose
    modifier: DECREASED
    term:
      id: CHEBI:18307
      label: UDP-D-galactose
  biological_processes:
  - preferred_term: N-glycan processing
    modifier: DECREASED
    term:
      id: GO:0006491
      label: N-glycan processing
  - preferred_term: galactose metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006012
      label: galactose metabolic process
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The ratio of UDP-galactose to UDP-glucose was decreased, suggesting that
      UDP-galactose is limiting for N-glycan biosynthesis
    explanation: >-
      Establishes UDP-galactose as the limiting nucleotide sugar, the mechanistic
      basis of the galactose-deficient truncated glycans.
  - reference: PMID:30982613
    reference_title: "The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      replenishes the depleted levels of galactose-1-P, as well as the levels of
      UDP-glucose and UDP-galactose, the nucleotide sugars that are required for
      ER- and GA-linked glycosylation, respectively
    explanation: >-
      Tracer metabolomics assigns UDP-glucose to the ER arm and UDP-galactose to
      the Golgi arm, the two-arm split modeled by this node and its ER sibling.
  downstream:
  - target: Mixed Type I and Type II Protein Hypoglycosylation
    causal_link_type: DIRECT
    description: >-
      Incomplete Golgi galactosylation yields truncated, galactose-deficient
      glycans, the type II component of the transferrin pattern.
- name: Mixed Type I and Type II Protein Hypoglycosylation
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  role: central_effector
  description: >-
    The two arms converge on the diagnostic hallmark of PGM1-CDG: a mixed
    glycosylation defect in which serum transferrin simultaneously shows loss of
    complete N-glycans (type I, reduced site occupancy) and truncated glycans
    lacking galactose and terminal sialic acid (type II, incomplete processing).
    Very few CDG produce both patterns in one patient, and this combined
    signature on intact-transferrin mass spectrometry is the single most useful
    biochemical clue to the diagnosis. Because glycosylation modifies a large
    fraction of secreted and membrane proteins, the lesion degrades many
    unrelated client glycoproteins at once.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectrometry of transferrin showed a loss of complete N-glycans and
      the presence of truncated glycans lacking galactose.
    explanation: >-
      The defining mixed pattern: missing whole glycans (type I) together with
      galactose-deficient truncated glycans (type II).
  - reference: PMID:31077402
    reference_title: "A novel phosphoglucomutase-deficient mouse model reveals aberrant glycosylation and early embryonic lethality."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PGM1 deficiency is increasingly recognized as a congenital disorder of
      glycosylation (CDG), where reduced N-linked glycosylation in the
      endoplasmic reticulum (ER) and Golgi is observed, resulting in both missing
      and truncated glycans (mixed type I and type II glycosylation defects)
    explanation: >-
      Explicitly names the mixed type I plus type II classification and localizes
      the two arms to ER and Golgi. Tagged OTHER because this is the review
      framing in the paper's introduction rather than its own experimental
      result.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
    causal_link_type: DIRECT
  - target: Coagulation Factor Hypoglycosylation and Antithrombin Deficiency
    causal_link_type: DIRECT
  - target: Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
    description: >-
      Sarcolemmal and extracellular-matrix glycoproteins, notably laminin
      subunits, are hypoglycosylated in the myocardium. This is arm (b) of the
      galactose-resistant-cardiomyopathy hypothesis.
- name: Multisystem Glycoprotein Dysfunction
  biological_scale: ORGANISM
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  role: consequence
  description: >-
    Simultaneous hypoglycosylation of many secreted and membrane glycoproteins
    produces the characteristic multisystem outflow: hepatic dysfunction with
    transaminase elevation, endocrine deficits (hypogonadotropic hypogonadism,
    secondary adrenal insufficiency, growth failure), craniofacial malformation,
    and variable neurologic involvement, in addition to the coagulation and
    cardiac arms modeled separately.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:35562242
    reference_title: "Nutrition interventions in congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms typically start in infancy and most frequently include
      hypoglycemia (possibly leading to seizures), cleft palate/bifid uvula
      (which can lead to feeding difficulties), elevated liver enzymes,
      coagulopathy, muscle weakness and exercise intolerance (often with
      rhabdomyolysis), and, in some cases, cardiomyopathy
    explanation: >-
      Enumerates the multisystem consequence set downstream of hypoglycosylation.
      Tagged OTHER because this is an expert review summarizing the phenotype
      rather than reporting primary data.
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four out of seven patients have deteriorating adrenal function with
      abnormally low cortisol and ACTH levels during hypoglycemia and subnormal
      response of cortisol to low dose ACTH test
    explanation: >-
      Documents the endocrine (ACTH/cortisol axis) component of the multisystem
      glycoprotein dysfunction.
- name: Coagulation Factor Hypoglycosylation and Antithrombin Deficiency
  biological_scale: ORGANISM
  description: >-
    Coagulation and anticoagulation proteins are heavily glycosylated and are
    among the most sensitive readouts of hypoglycosylation in CDG. In PGM1-CDG
    antithrombin is the most commonly and most severely affected factor, with
    prolonged aPTT and reductions in factors XI, IX and VII also reported; a
    minority of patients suffer major thrombotic events. These abnormalities
    improve on D-galactose, making antithrombin activity a candidate treatment
    biomarker and trial endpoint.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:38968673
    reference_title: "Coagulation abnormalities and vascular complications are common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %)
      deficiency. Four individuals had major thrombotic events.
    explanation: >-
      Identifies antithrombin as the dominant coagulation abnormality and
      documents clinically significant thrombosis.
- name: Fasting Hypoglycemia and Hepatic Metabolic Stress
  biological_scale: ORGANISM
  description: >-
    Because hepatic glycogen cannot be released as glucose through the PGM1 step,
    fasting, intercurrent illness, or vomiting precipitate ketotic hypoglycemia,
    frequently the presenting problem in infancy. Conversely, after a glucose
    load, accumulating glucose-6-phosphate that cannot be stored as glycogen is
    diverted toward lactate and lipogenesis, contributing to transaminase
    elevation and hepatic steatosis. In young patients, hypoglycemia is primarily
    hyperinsulinemic, whereas starvation- or febrile-illness-associated ketotic
    hypoglycemia is also reported and becomes more relevant at other ages.
    Secondary ACTH/cortisol deficiency can further compound the hypoglycemia.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: glucose homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0042593
      label: glucose homeostasis
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After a dietary glucose load, large amounts of glucose-6-phosphate are
      generated, which cannot be converted into glycogen.
    explanation: >-
      Explains the postprandial diversion of hexose phosphate that accompanies
      the fasting-intolerance phenotype.
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients.
    explanation: >-
      Quantifies the fasting hypoglycemia phenotype within a single well
      characterized family.
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia was primarily due to hyperinsulinism in young patients.
    explanation: >-
      The international guideline establishes hyperinsulinism as the primary
      route to hypoglycemia in young patients, correcting a prior description
      that treated it as only an unspecified subset finding.
- name: Skeletal Muscle Energy Failure
  biological_scale: CELLULAR
  description: >-
    Skeletal muscle cannot mobilize glycogen for rapid anaerobic ATP production,
    so exercise depends abnormally on fat oxidation and carbohydrate oxidation is
    blocked; forearm exercise produces no lactate rise but an exaggerated ammonia
    rise, and patients show the McArdle-like second wind. Beyond the
    glycogenolytic block, PGM1-null myoblasts and myotubes have reduced basal
    respiration and reduced mitochondrial ATP-production capacity that
    D-galactose does not correct, which is the leading explanation for why
    myopathy and rhabdomyolysis respond less completely to therapy than the
    glycosylation abnormalities do.
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: ATP biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006754
      label: ATP biosynthetic process
  - preferred_term: glycogen catabolic process
    modifier: DECREASED
    term:
      id: GO:0005980
      label: glycogen catabolic process
  evidence:
  - reference: PMID:28882528
    reference_title: "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Forearm exercise elicited no increase in lactate, but an exaggerated
      increase in ammonia, and provoked a forearm contracture.
    explanation: >-
      Classic physiological signature of a block in muscle glycogenolysis and
      glycolysis in a PGM1-deficient patient.
  - reference: PMID:37175952
    reference_title: "In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequent analyses revealed a lower basal respiration and mitochondrial
      ATP production capacity in the knockout myoblasts and myotubes, which were
      not restored by D-galactose.
    explanation: >-
      Establishes a galactose-resistant mitochondrial energetic deficit in
      PGM1-null muscle cells, distinct from the galactose-responsive
      glycosylation arm.
- name: Cardiomyocyte Energetic and Mitochondrial Failure
  biological_scale: CELLULAR
  description: >-
    Arm (a) of the galactose-resistant cardiomyopathy hypothesis. In the
    cardiomyocyte-specific Pgm2 (mouse PGM1 ortholog) knockout heart, glycogen
    accumulates in excess while mitochondria are swollen and fragmented and
    mitochondrial function falls, indicating that the failing myocardium has an
    energy-supply problem and not only a glycosylation problem. The parallel
    finding in PGM1-null skeletal muscle cells, where D-galactose does not
    restore respiration or ATP production, is what makes this arm the leading
    explanation for the treatment resistance of the cardiac phenotype.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: ATP biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006754
      label: ATP biosynthetic process
  evidence:
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological studies demonstrated excess glycogen accumulation and
      fibrosis, while ultrastructural analysis revealed Z-disk disarray and
      swollen/fragmented mitochondria, which was similar to the ultrastructural
      pathology in the cardiac explant of an individual with PGM1-CDG.
    explanation: >-
      The cardiomyocyte-specific knockout mouse reproduces the human cardiac
      ultrastructural pathology, including the mitochondrial injury that defines
      this node, and matches a human cardiac explant.
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, we found decreased mitochondrial function in the heart of KO
      mice.
    explanation: >-
      Direct functional demonstration of the cardiac mitochondrial deficit.
  downstream:
  - target: Dilated Cardiomyopathy and Progressive Heart Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
- name: Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation
  biological_scale: MOLECULAR
  description: >-
    Arm (b) of the galactose-resistant cardiomyopathy hypothesis. Cardiac
    glycoproteomics in the Pgm2 conditional knockout shows broad changes in
    N-glycosylation concentrated on sarcolemmal and extracellular-matrix
    proteins, most prominently the laminin-211 subunits that couple the
    cardiomyocyte membrane to its basement membrane. Loss of this linkage is a
    recognized route to dilated cardiomyopathy independent of energy supply.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  locations:
  - preferred_term: sarcolemma
    term:
      id: GO:0042383
      label: sarcolemma
  evidence:
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a glycoproteomic analysis unveiled broad glycosylation changes with
      significant alterations in sarcolemmal proteins including different
      subunits of laminin-211, which was confirmed by immunoblot analyses
    explanation: >-
      Identifies sarcolemmal and matrix glycoprotein hypoglycosylation, laminin-211
      in particular, as a specific molecular lesion in the PGM1-deficient
      myocardium.
  downstream:
  - target: Dilated Cardiomyopathy and Progressive Heart Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
- name: Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction
  biological_scale: CELLULAR
  description: >-
    Arm (c) of the galactose-resistant cardiomyopathy hypothesis, and the only
    arm evidenced in human patient-derived cardiomyocytes rather than in mouse
    or in skeletal-muscle surrogate cells. Untargeted proteomics of iPSC-derived
    cardiomyocytes from PGM1-deficient patients shows depletion of Z-disk
    components, LDB3 (ZASP/Cypher) among them, and AlphaFold3 modelling predicts
    a direct PGM1-LDB3 interaction that was then confirmed in vitro. This places
    a structural, sarcomeric role for PGM1 alongside its enzymatic one: the
    protein is not only a metabolic enzyme whose loss starves the myocyte, it is
    a binding partner whose loss destabilizes the Z-disk. Because the claim is
    about a protein-protein interaction rather than a nucleotide-sugar pool, no
    amount of oral galactose addresses it - which is the point of curating it as
    a separate arm.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: DECREASED
    term:
      id: GO:0045214
      label: sarcomere organization
  genes:
  - preferred_term: PGM1
    term:
      id: hgnc:8905
      label: PGM1
  evidence:
  - reference: PMID:41723528
    reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Proteomic analyses revealed depletion of Z-disk components, including
      LDB3.
    explanation: >-
      Directly reports the Z-disk protein depletion this node represents, in
      patient-derived cardiomyocytes.
  - reference: PMID:41723528
    reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AlphaFold3 structural modeling predicted a direct interaction between
      PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed
      in vitro.
    explanation: >-
      Supports a direct PGM1-LDB3 interaction as the structural basis for the
      node, with in-vitro confirmation of a computational prediction.
  downstream:
  - target: Cardiomyocyte Energetic and Mitochondrial Failure
    description: >-
      Loss of Z-disk-mitochondrial coupling is the proposed route from
      sarcomeric destabilization to the energetic failure of the myocyte.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
    evidence:
    - reference: PMID:41723528
      reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our data suggests PGM1 is key regulator of cardiomyocyte function,
        linking sarcomeric Z-disk integrity with mitochondrial metabolism.
      explanation: >-
        The authors state the Z-disk-to-mitochondrion link as a suggestion from
        correlated proteomic and respirometry findings, not as a demonstrated
        causal sequence, so this edge is PARTIAL and its intermediates unknown.
  - target: Dilated Cardiomyopathy and Progressive Heart Failure
    description: >-
      Impaired contractility and prolonged contraction kinetics in
      PGM1-deficient cardiomyocytes are the cellular correlate of the clinical
      cardiomyopathy.
    causal_link_type: DIRECT
    hypothesis_groups:
    - galactose_resistant_cardiomyopathy
    evidence:
    - reference: PMID:41723528
      reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PGM1-deficient iCMs exhibited reduced beating frequency, impaired
        contractility, and prolonged contraction kinetics.
      explanation: >-
        Functional contractile deficit measured directly in the patient-derived
        cardiomyocyte model.
- name: Dilated Cardiomyopathy and Progressive Heart Failure
  biological_scale: TISSUE
  role: consequence
  description: >-
    The convergent cardiac consequence and the most life-threatening
    complication of PGM1-CDG. Ventricular dilation with a falling ejection
    fraction progresses to heart failure, arrhythmia, cardiac arrest,
    transplantation or sudden death. It is the one manifestation D-galactose does
    not correct, which is why it is modeled as a distinct convergence node fed by
    two competing upstream arms rather than folded into the general multisystem
    outflow.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0060048
      label: cardiac muscle contraction
  evidence:
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Echocardiography studies corroborated a DCM phenotype with significantly
      reduced ejection fraction and left ventricular dilation similar to those
      seen in individuals with PGM1-CDG.
    explanation: >-
      Establishes the convergent dilated-cardiomyopathy readout and its fidelity
      to the human phenotype.
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings also suggest that the autosomal recessive PGM1-CDG might be
      highly associated with life-threatening cardiomyopathy with arrhythmia or
      sudden cardiac death as the first symptom presenting from childhood and
      adolescence.
    explanation: >-
      Human evidence that the cardiac arm can be the presenting and fatal
      manifestation.
mechanistic_hypotheses:
- hypothesis_group_id: galactose_resistant_cardiomyopathy
  hypothesis_label: Cardiomyopathy is driven by energetic failure rather than by hypoglycosylation alone
  status: EMERGING
  description: >-
    D-galactose reliably corrects transferrin glycosylation, liver enzymes and
    coagulation factors, yet consistently fails to improve cardiac function. Two
    non-exclusive explanations are under active investigation: (a) the
    cardiomyopathy is driven principally by a mitochondrial/energetic defect that
    nucleotide-sugar repletion cannot address, paralleling the
    galactose-resistant respiratory deficit demonstrated in PGM1-null muscle
    cells; or (b) it is driven by hypoglycosylation of sarcolemmal and
    extracellular-matrix glycoproteins (laminin-211) in a compartment that oral
    galactose does not adequately reach or reverse once structural remodeling is
    established. A third arm (c) was added in 2026: PGM1 binds the Z-disk
    protein LDB3 (ZASP/Cypher), and patient-derived iPSC-cardiomyocytes lose
    Z-disk components together with mitochondrial proteins, implying a
    structural role for PGM1 that is independent of its enzymatic output
    altogether. Arm (c) is not a competitor to arm (a) so much as a candidate
    cause of it - the proposal is that Z-disk destabilization uncouples the
    sarcomere from mitochondrial metabolism. The distinction matters because it
    determines whether cardiac-directed therapy should target energetics,
    sarcomeric integrity, or PGM1 protein restoration (e.g. AAV9-PGM1 gene
    replacement); only the last addresses all three arms, and it is the only
    one of the three arms so far evidenced in human patient cardiomyocytes
    rather than mouse heart or skeletal-muscle surrogates.
  evidence:
  - reference: PMID:37175952
    reference_title: "In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In conclusion, an in vitro mouse muscle cell model has been established to
      study the muscle-specific metabolic mechanisms in PGM1 deficiency, which
      suggested that galactose was unable to restore the reduced energy
      production capacity.
    explanation: >-
      Supports arm (a): a galactose-resistant energetic deficit exists in
      PGM1-deficient striated muscle cells.
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      a glycoproteomic analysis unveiled broad glycosylation changes with
      significant alterations in sarcolemmal proteins including different
      subunits of laminin-211, which was confirmed by immunoblot analyses
    explanation: >-
      Supports arm (b): a specific sarcolemmal glycosylation lesion in the
      PGM1-deficient myocardium.
  - reference: PMID:41723528
    reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although galactose therapy corrects glycosylation defects, cardiac
      dysfunction typically persists, suggesting a glycosylation-independent
      mechanism.
    explanation: >-
      States the premise the whole hypothesis group rests on, and motivates
      arm (c) specifically as a glycosylation-independent route.
  - reference: PMID:41723528
    reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional validation confirmed extensive metabolic rewiring, energy
      depletion, and severely impaired mitochondrial respiration.
    explanation: >-
      Extends arm (a) from mouse heart and skeletal-muscle cells to human
      patient-derived cardiomyocytes.
discussions:
- discussion_id: pgm1_craniofacial_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does PGM1 deficiency cause bifid uvula, cleft palate and
    Pierre Robin sequence, and why is this the only manifestation present at
    birth?
  attaches_to:
  - pathophysiology#Multisystem Glycoprotein Dysfunction
  rationale: >-
    Midline palatal malformation is the earliest and one of the most consistent
    features of PGM1-CDG, and is the clinical clue that most often triggers
    diagnosis, yet no specific glycoprotein client or developmental pathway has
    been linked to it. Palatal shelf fusion depends on glycosylated extracellular
    matrix and adhesion molecules, but this remains an inference rather than a
    demonstrated mechanism in PGM1-CDG.
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did not attempt to show experimentally the mechanisms that account for
      the clinical phenotypes of phosphoglucomutase 1 deficiency.
    explanation: >-
      The landmark study explicitly declines to establish phenotype-specific
      mechanisms, and its three proposed mechanisms cover glucose metabolism,
      glycosylation and cardiomyopathy but not the craniofacial malformation.
  proposed_experiments:
  - experiment_id: exp_pgm1_conditional_neural_crest_knockout
    name: Tissue-restricted Pgm2 knockout in cranial neural crest or palatal shelf mesenchyme
    description: >-
      Because the constitutive knockout is embryonic lethal before E9.5 and
      yields no live homozygotes, palatal development must be studied with a
      conditional allele restricted to cranial neural crest or palatal shelf
      mesenchyme, assessing shelf elevation and fusion together with matrix
      glycoprotein glycosylation.
  - experiment_id: exp_pgm1_palatal_glycoproteomics
    name: Glycoproteomic profiling of palatal tissue and craniofacial organoids
    description: >-
      Profile palatal shelf tissue or patient-derived craniofacial organoids to
      identify which adhesion and extracellular-matrix client glycoproteins are
      hypoglycosylated, in order to nominate a specific developmental mechanism.
- discussion_id: pgm1_aav_cardiac_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the AAV9-PGM1 rescue of dilated cardiomyopathy in the
    cardiomyocyte-specific Pgm2 knockout mouse predict benefit in human PGM1-CDG
    cardiomyopathy?
  attaches_to:
  - pathophysiology#Cardiomyocyte Energetic and Mitochondrial Failure
  - pathophysiology#Cardiomyocyte Sarcolemmal Glycoprotein Hypoglycosylation
  - pathophysiology#Dilated Cardiomyopathy and Progressive Heart Failure
  rationale: >-
    The constitutive Pgm2 knockout is embryonic lethal before E9.5 and produces
    no live homozygotes, so the only tractable in vivo cardiac model is a
    tamoxifen-inducible cardiomyocyte-restricted knockout in an otherwise
    PGM1-sufficient animal. That model necessarily lacks the systemic
    hypoglycemia, hepatic, endocrine and craniofacial disease of human PGM1-CDG,
    and the acute post-natal onset of the lesion differs from the lifelong
    hypomorphic state of human patients, most of whom carry missense alleles with
    residual activity rather than a null. Whether the striking AAV9 rescue
    translates to human hearts that have remodeled over years is therefore an
    open translational question, not an established result.
  evidence:
  - reference: PMID:31077402
    reference_title: "A novel phosphoglucomutase-deficient mouse model reveals aberrant glycosylation and early embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this study, we demonstrated that homozygosity for Pgm2-KO mutations
      leads to embryonic lethality in mice
    explanation: >-
      Establishes why no constitutive null mouse exists and why cardiac
      conclusions rest on a conditional, tissue-restricted model.
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To study the pathobiology of the cardiac disease observed in PGM1-CDG, we
      constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse
      ortholog of human PGM1) knockout (Pgm2 cKO) mouse model.
    explanation: >-
      Confirms the model is cardiomyocyte-restricted and conditional, which is
      the source of the translational mismatch. Marked PARTIAL because the paper
      supports the rescue result but not its human generalizability.
  proposed_experiments:
  - experiment_id: exp_pgm1_cardiac_natural_history
    name: Genotype-stratified longitudinal cardiac natural history study
    description: >-
      Track cardiac structure and function longitudinally in genotype-stratified
      human PGM1-CDG cohorts to define the window before ventricular remodeling
      becomes irreversible, which determines whether a gene-replacement approach
      could plausibly benefit already-affected hearts.
  - experiment_id: exp_pgm1_hypomorphic_aav_trial
    name: AAV9-PGM1 in a hypomorphic knock-in mouse with established cardiomyopathy
    description: >-
      Test AAV9-PGM1 in a missense knock-in (hypomorphic) rather than null model,
      and after cardiomyopathy is already established rather than preemptively,
      to better match the human therapeutic setting.
phenotypes:
- name: Bifid Uvula
  category: Craniofacial
  description: >-
    A bifid (cleft) uvula, with or without overt cleft palate, is characteristic
    and is frequently the only abnormality detectable at birth. Its recognition
    in a neonate is the single most useful early clue to PGM1-CDG.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
    onset:
      onset_category: CONGENITAL
  subtype: Multisystem
  frequency: FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although all the patients had multisystem disease at the time of the study,
      the only apparent clinical feature at birth was a bifid uvula (in 16 of the
      19 patients).
    explanation: >-
      Establishes bifid uvula as the sole congenital sign in this cohort. The
      band is deliberately set to FREQUENT rather than to the 16/19 (84%) figure
      this snippet supports, because that cohort was ascertained partly through
      the craniofacial finding; the later 57-patient consensus review reports
      bifid uvula in a lower proportion.
  - reference: PMID:31077402
    reference_title: "A novel phosphoglucomutase-deficient mouse model reveals aberrant glycosylation and early embryonic lethality."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At birth, affected patients have frequent malformations in the spectrum of
      bifid uvula, cleft palate, and Pierre-Robin sequence.
    explanation: >-
      Independent framing of the congenital craniofacial spectrum as "frequent",
      consistent with the FREQUENT band. Tagged OTHER because this is the review
      background of a mouse-model paper, not its own experimental result.
- name: Cleft Palate
  category: Craniofacial
  description: >-
    Overt cleft palate, sometimes as part of Pierre Robin sequence, occurs in
    roughly half of reported patients and requires craniofacial, airway, feeding
    and speech management.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
    onset:
      onset_category: CONGENITAL
  subtype: Multisystem
  frequency: FREQUENT
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients present as infants with cleft palate, liver function
      abnormalities and hypoglycemia, but some patients present in adulthood with
      isolated muscle involvement.
    explanation: >-
      International consensus describes cleft palate as a typical infantile
      presenting feature; "most patients present as infants with cleft palate"
      maps to the FREQUENT band.
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have an abnormal palatine structure (cleft palate, bifid
      uvula) and elevated serum transaminases
    explanation: >-
      Independent family series confirming universal palatal abnormality.
- name: Pierre Robin Sequence
  category: Craniofacial
  description: >-
    A subset of patients have the full Pierre Robin sequence (micrognathia,
    glossoptosis, cleft palate), which carries airway risk in the neonatal period
    and warrants otolaryngology assessment in addition to craniofacial care.
  phenotype_term:
    preferred_term: Pierre-Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
    onset:
      onset_category: CONGENITAL
  subtype: Multisystem
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 57 patients with PGM1-CDG reported to date, cleft palate was the most
      commonly reported anomaly (n = 28), followed by bifid uvula (n = 25) and
      Pierre-Robin sequence (n = 15).
    explanation: >-
      Direct human evidence identifies Pierre-Robin sequence in 15/57 reported
      patients (26%), supporting the OCCASIONAL band without relying on review
      background from a mouse-model paper.
- name: Anal Atresia
  category: Congenital malformation
  description: >-
    Anal atresia has been reported among the less common congenital anomalies in
    PGM1-CDG. It should prompt assessment for other multisystem manifestations
    rather than being treated as part of the core craniofacial triad.
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
    onset:
      onset_category: CONGENITAL
  subtype: Multisystem
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anal atresia, and a missing lumbar vertebra.
    explanation: >-
      The guideline's review of molecularly confirmed human cases directly lists
      anal atresia among the less common congenital findings.
- name: Abnormal Vertebral Morphology
  category: Skeletal
  description: >-
    A missing lumbar vertebra has been reported as a rare congenital skeletal
    anomaly in the multisystem form.
  phenotype_term:
    preferred_term: Abnormal vertebral morphology
    term:
      id: HP:0003468
      label: Abnormal vertebral morphology
    onset:
      onset_category: CONGENITAL
  subtype: Multisystem
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anal atresia, and a missing lumbar vertebra.
    explanation: >-
      The missing lumbar vertebra is direct human evidence for an abnormal
      vertebral morphology association.
- name: Elevated Hepatic Transaminases
  category: Hepatic
  description: >-
    Moderately elevated serum aminotransferases are near-universal in the
    multisystem form and often prompt the diagnostic workup. Hepatic steatosis
    and hepatomegaly are also reported. Importantly, hepatic involvement is
    characteristically absent in the primary myopathic form, so this phenotype is
    scoped to the multisystem subtype rather than asserted disease-wide.
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  subtype: Multisystem
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Signs of hepatopathy with moderately elevated serum aminotransferase levels
      developed in all patients.
    explanation: >-
      "in all patients" in the 19-patient landmark cohort supports the
      VERY_FREQUENT band.
- name: Acute Hepatic Failure
  category: Hepatic
  description: >-
    Acute hepatic failure has occurred in a minority of patients and did not
    correlate with overall phenotypic severity. This acute risk complements the
    more typical chronic or intermittent transaminase elevation.
  phenotype_term:
    preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
    temporality: ACUTE
  subtype: Multisystem
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Episodes of acute hepatic failure were described in five patients, however,
      without details concerning the circumstances or the extent of presentation.
    explanation: >-
      Five of the 57 molecularly confirmed patients reviewed by the guideline
      falls in the OCCASIONAL band.
- name: Hypoglycemia
  category: Metabolic
  description: >-
    Fasting or illness-associated ketotic hypoglycemia is common, especially in
    childhood, and may be severe enough to provoke seizures. Management requires
    frequent complex-carbohydrate meals, an emergency illness plan, and in some
    patients overnight enteral feeding. Coexisting hyperinsulinism or secondary
    adrenal insufficiency can aggravate it.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia was common, especially in childhood, requiring treatment with
      frequent meals, complex carbohydrates, or overnight tube feeding.
    explanation: >-
      "common" maps to the FREQUENT band per the project frequency-mapping table.
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients.
    explanation: >-
      Documents the recurrent, ketotic character of the hypoglycemia.
- name: Hyperinsulinemic Hypoglycemia
  category: Endocrine
  description: >-
    Hyperinsulinism is the primary mechanism of hypoglycemia in young patients,
    distinct from the starvation- or febrile-event-associated ketotic episodes
    seen across other ages. The source does not provide a disease-wide numerator,
    so no frequency band is asserted.
  phenotype_term:
    preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
    onset:
      onset_category: INFANTILE
    temporality: RECURRENT
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia was primarily due to hyperinsulinism in young patients.
    explanation: >-
      Directly supports the age-dependent hyperinsulinemic phenotype while
      avoiding an unsupported whole-disease frequency estimate.
- name: Exercise Intolerance
  category: Musculoskeletal
  description: >-
    Exercise intolerance, exertional fatigue and muscle tightness reflect the
    inability to mobilize muscle glycogen for anaerobic energy production.
    Patients show a McArdle-like second wind and an absent lactate response to
    ischemic forearm exercise. This may be the only manifestation in adult-onset
    presentations.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  frequency: FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of the patients had muscle symptoms, including exercise
      intolerance, muscle weakness, and rhabdomyolysis.
    explanation: >-
      "The majority of the patients" maps to the FREQUENT band (30-79%).
- name: Rhabdomyolysis
  category: Musculoskeletal
  description: >-
    Episodic rhabdomyolysis, typically triggered by exertion or intercurrent
    illness, with elevated creatine kinase. Two patients in the landmark cohort
    developed malignant hyperthermia with severe rhabdomyolysis after general
    anesthesia, so anesthetic risk requires specific attention.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
    temporality: RECURRENT
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Attacks of rhabdomyolysis were studied in 43 patients and occurred in 25%
      of patients (11/43).
    explanation: >-
      The guideline's phenotype-specific denominator places rhabdomyolysis at
      25%, supporting OCCASIONAL and superseding the earlier over-read of a
      compound sentence about muscle symptoms overall.
- name: Muscle Weakness
  category: Musculoskeletal
  description: >-
    Proximal and generalized muscle weakness accompanies the exercise
    intolerance; in the adult-onset myopathic presentation it may be the only
    manifestation. One reported patient had fluctuating weakness with
    electrophysiological evidence of neuromuscular junction involvement.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of the patients had muscle symptoms, including exercise
      intolerance, muscle weakness, and rhabdomyolysis.
    explanation: >-
      Muscle weakness is one of the muscle symptoms present in the majority of
      the landmark cohort, supporting the FREQUENT band.
- name: Malignant Hyperthermia
  category: Musculoskeletal
  description: >-
    Malignant hyperthermia with severe rhabdomyolysis after general anesthesia
    has been reported and is a specific perioperative hazard in PGM1-CDG.
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia with severe rhabdomyolysis occurred in two patients
      after the administration of general anesthesia.
    explanation: >-
      2/19 patients (about 11%) maps to the OCCASIONAL band (5-29%).
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Dilated cardiomyopathy is the most severe and most treatment-resistant
    manifestation. Onset ranges from infancy to adulthood; it may progress
    rapidly to heart failure, cardiac arrest, transplantation, or sudden death,
    and it is the leading cause of mortality in PGM1-CDG. Crucially, it does not
    improve on D-galactose, so lifelong cardiac surveillance is required even in
    biochemically well-controlled patients.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dilated cardiomyopathy, cardiac arrest, or both occurred in six patients;
      three patients were listed for heart transplantation.
    explanation: >-
      6/19 patients (about 32%) had dilated cardiomyopathy and/or cardiac arrest;
      the dilated cardiomyopathy subset alone is below that, supporting a
      conservative OCCASIONAL band.
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some patients develop life-threatening cardiomyopathy.
    explanation: >-
      International consensus confirms the cardiomyopathy risk and its
      life-threatening character.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Sudden cardiac death, sometimes after physical exertion and sometimes as the
    first manifestation of the disorder, has been documented in PGM1-CDG
    siblings, which motivates cardiac evaluation and genetic testing in
    unexplained sudden death in the young.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During follow-up one of the brothers died unexpectedly after physical
      exertion during daily life at the age of twelve years.
    explanation: >-
      Documents exertion-associated sudden death in a molecularly confirmed
      PGM1-CDG sibling.
- name: Electrocardiographic Abnormality
  category: Cardiovascular
  description: >-
    Electrocardiographic abnormalities include long-QT interval, ST-wave
    elevation, T-wave inversion, sinus tachycardia, and minor incomplete
    intraventricular conduction disturbance. These findings support routine ECG
    surveillance beyond echocardiographic screening for cardiomyopathy.
  phenotype_term:
    preferred_term: Abnormal EKG
    term:
      id: HP:0003115
      label: Abnormal EKG
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrocardiogram (ECG) abnormalities including long QT interval, ST wave
      elevation, T wave inversion, sinus tachycardia, and minor incomplete
      intraventricular conduction disturbance were observed in five patients.
    explanation: >-
      Five of 57 reviewed patients (9%) had ECG or conduction abnormalities,
      supporting the OCCASIONAL band.
- name: Left Ventricular Dilatation
  category: Cardiovascular
  description: >-
    Mild left-ventricular enlargement can occur as a structural cardiac finding
    in addition to overt dilated cardiomyopathy.
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other echocardiogram abnormalities include mild left ventricular
      enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n
      = 2).
    explanation: >-
      Three of 57 patients (5.3%) had mild left-ventricular enlargement,
      supporting the OCCASIONAL band.
- name: Abnormal Cardiac Septum Morphology
  category: Cardiovascular
  description: >-
    Congenital cardiac septal defects are part of the less common structural
    cardiac spectrum.
  phenotype_term:
    preferred_term: Abnormal cardiac septum morphology
    term:
      id: HP:0001671
      label: Abnormal cardiac septum morphology
    onset:
      onset_category: CONGENITAL
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other echocardiogram abnormalities include mild left ventricular
      enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n
      = 2).
    explanation: >-
      Septal defects in 2/57 patients (4%) support the VERY_RARE band.
- name: Abnormal Heart Valve Morphology
  category: Cardiovascular
  description: >-
    Valvular heart defects are a rare structural cardiac manifestation.
  phenotype_term:
    preferred_term: Abnormal heart valve morphology
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
    onset:
      onset_category: CONGENITAL
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other echocardiogram abnormalities include mild left ventricular
      enlargement (n = 3), septal defects (n = 2), and valvular heart defects (n
      = 2).
    explanation: >-
      Valvular defects in 2/57 patients (4%) support the VERY_RARE band.
- name: Reduced Antithrombin III Activity
  category: Hematologic
  description: >-
    Antithrombin deficiency is the most frequent coagulation abnormality in
    PGM1-CDG, with mean activity around 31% against a reference range of
    80-120%. It improves substantially on D-galactose and is a leading candidate
    treatment biomarker.
  phenotype_term:
    preferred_term: Reduced antithrombin III activity
    term:
      id: HP:0001976
      label: Reduced antithrombin III activity
  frequency: FREQUENT
  evidence:
  - reference: PMID:38968673
    reference_title: "Coagulation abnormalities and vascular complications are common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coagulation information was available for only 58.9 % of the reported
      individuals, out of which 67.4 % of PGM1-CDG individuals were reported to
      have abnormalities. The most frequently observed abnormality was AT (mean:
      30.8% R:80-120 %) deficiency.
    explanation: >-
      Among the 58.9% of reported individuals for whom coagulation data existed,
      67.4% had abnormalities and antithrombin was the most frequent. The band is
      therefore stated on the tested denominator, not the whole reported cohort;
      the 67.4% figure covers any coagulation abnormality rather than
      antithrombin deficiency specifically, so FREQUENT is the most that this
      evidence supports.
- name: Thrombosis
  category: Hematologic
  description: >-
    Major thrombotic events occur in a minority of patients, consistent with the
    profound antithrombin deficiency; peri-operative bleeding and thrombosis risk
    should both be assessed before surgery.
  phenotype_term:
    preferred_term: Abnormal thrombosis
    term:
      id: HP:0001977
      label: Abnormal thrombosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38968673
    reference_title: "Coagulation abnormalities and vascular complications are common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four individuals had major thrombotic events.
    explanation: >-
      Four major thrombotic events among 73 reported individuals (about 5%)
      supports the OCCASIONAL band.
- name: Short Stature
  category: Growth
  description: >-
    Growth retardation is reported in the large majority of patients; growth
    hormone deficiency has been documented in individual cases.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth retardation was reported in all but four patients.
    explanation: >-
      15/19 patients (about 79%) reported with growth retardation, at the top of
      the FREQUENT band.
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      4/7 have short stature (<-2 SDS) and one was diagnosed with growth hormone
      deficiency
    explanation: >-
      Independent series quantifying short stature specifically (rather than
      "growth retardation") at 4/7, and documenting growth hormone deficiency as
      one contributing mechanism.
- name: Growth Hormone-IGF Axis Deficiency
  category: Endocrine
  description: >-
    Reduced growth hormone or IGF-1 and reduced IGFBP-3 identify an endocrine
    contribution to growth impairment in a subset of patients. The available
    count combines several measurements along the growth-hormone axis, so the
    ontology mapping and evidence support are intentionally qualified.
  phenotype_term:
    preferred_term: Growth hormone-IGF axis deficiency
    term:
      id: HP:0008240
      label: Secondary growth hormone deficiency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decreased levels of growth hormone or IGF1 was reported in 12 patients
    explanation: >-
      The combined growth-hormone/IGF-1 count is 12/57 (21%), supporting the
      OCCASIONAL band for axis deficiency. Marked PARTIAL because the source does
      not report how many of those patients met the narrower definition of
      secondary growth-hormone deficiency.
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      9 patients showed decreased serum insulin-like growth factor-binding
      protein 3 (IGFBP-3)
    explanation: >-
      Adds direct evidence for the IGFBP-3 component of the growth-hormone/IGF
      axis; marked PARTIAL for the same mapping limitation.
- name: Hypogonadotropic Hypogonadism
  category: Endocrine
  description: >-
    Hypogonadotropic hypogonadism with delayed puberty has been reported; notably
    it resolved within weeks of starting galactose supplementation in two
    affected girls, with rising LH and normalizing FSH.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two girls had hypogonadotropic hypogonadism with delayed puberty.
    explanation: >-
      2/19 patients (about 11%) maps to the OCCASIONAL band.
- name: Adrenal Insufficiency
  category: Endocrine
  description: >-
    Secondary (ACTH-dependent) adrenal insufficiency, with inappropriately low
    cortisol and ACTH during hypoglycemia and a subnormal low-dose ACTH
    stimulation test, was found in more than half of one well-characterized
    family and should be actively sought in any PGM1-deficient patient with
    hypoglycemia.
  phenotype_term:
    preferred_term: Adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACTH deficiency should be considered in any PGM1 deficient patient with
      hypoglycemia.
    explanation: >-
      Recommends screening for ACTH deficiency. The OCCASIONAL band is set
      conservatively because 4/7 in a single consanguineous family is not
      generalizable to the wider PGM1-CDG population.
- name: Elevated Circulating TSH
  category: Endocrine
  description: >-
    Elevated TSH is a documented thyroid-axis abnormality. Clinical
    hypothyroidism should be treated with L-thyroxine, while TSH, free T4 and
    thyroxine-binding globulin are monitored longitudinally.
  phenotype_term:
    preferred_term: Elevated circulating thyroid-stimulating hormone concentration
    term:
      id: HP:0002925
      label: Elevated circulating thyroid-stimulating hormone concentration
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High levels of serum thyroid-stimulating hormone (TSH) were reported in
      three patients and decreased levels of thyroxin-binding globulin (TBG) in
      six.
    explanation: >-
      Elevated TSH in 3/57 patients (5.3%) supports the OCCASIONAL band.
- name: Abnormal Eye Movement
  category: Ophthalmologic
  description: >-
    Abnormal eye movements are among the uncommon ophthalmologic manifestations
    of the multisystem form.
  phenotype_term:
    preferred_term: Abnormality of eye movement
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  subtype: Multisystem
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly reported ophthalmologic abnormalities were unspecified
      abnormal eye movements (n = 2)8,10 and strabismus (n = 2).10 Less common
      findings were nasolacrimal duct obstruction and epiphoria (n = 1).11
    explanation: >-
      Abnormal eye movements in 2/57 patients (4%) support the VERY_RARE band.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus has been reported in the multisystem form and should be managed
    with standard ophthalmologic supportive care.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  subtype: Multisystem
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly reported ophthalmologic abnormalities were unspecified
      abnormal eye movements (n = 2)8,10 and strabismus (n = 2).10 Less common
      findings were nasolacrimal duct obstruction and epiphoria (n = 1).11
    explanation: >-
      Strabismus in 2/57 patients (4%) supports the VERY_RARE band.
- name: Nasolacrimal Duct Obstruction
  category: Ophthalmologic
  description: >-
    Nasolacrimal duct obstruction is a rare ophthalmologic manifestation of the
    multisystem form and may present with excessive tearing.
  phenotype_term:
    preferred_term: Nasolacrimal duct obstruction
    term:
      id: HP:0000579
      label: Nasolacrimal duct obstruction
  subtype: Multisystem
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common findings were nasolacrimal duct obstruction and epiphoria (n =
      1).
    explanation: >-
      A single reported case among 57 patients supports the VERY_RARE band.
- name: Epiphora
  category: Ophthalmologic
  description: >-
    Epiphora has been reported together with nasolacrimal duct obstruction in a
    patient with the multisystem form.
  phenotype_term:
    preferred_term: Epiphora
    term:
      id: HP:0009926
      label: Epiphora
  subtype: Multisystem
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less common findings were nasolacrimal duct obstruction and epiphoria (n =
      1).
    explanation: >-
      A single reported case among 57 patients supports the VERY_RARE band; the
      source spells the finding "epiphoria," mapped here to the canonical HPO
      term Epiphora.
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Intellectual disability is one specific component of the neurologic burden.
    A separate systematic review found significant neurologic involvement in 17
    of 41 reported patients, including patients without severe or recurrent
    hypoglycemia, so it should not be assumed to be only a hypoglycemic sequela.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive impairments were noted in 14 patients, intellectual disability in
      8, learning disabilities in 11 and speech delay in 2.
    explanation: >-
      Intellectual disability in 8/57 patients (14%) supports the OCCASIONAL
      band and replaces an overly general neurologic HPO association.
  - reference: PMID:30262252
    reference_title: "Central nervous involvement is common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected 17 patients out of the 41 reported PGM1-CDG cases with
      significant neurologic involvement.
    explanation: >-
      Preserves the broader human systematic-review context but is marked PARTIAL
      because it does not provide an intellectual-disability-specific numerator.
- name: Motor Delay
  category: Neurologic
  description: >-
    Motor delay is an infrequent but recurrently reported neurodevelopmental
    manifestation.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Motor delay was described in four patients.
    explanation: >-
      Motor delay in 4/57 patients (7%) supports the OCCASIONAL band.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures have been reported with developmental delay and may be primary or
    secondary to hypoglycemia.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: RECURRENT
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epileptic seizures have been reported in three patients with developmental
      delay, with an abnormal EEG detected in one patient.
    explanation: >-
      Seizures in 3/57 patients (5.3%) support the OCCASIONAL band and provide a
      specific HPO association in place of the prior neurologic umbrella term.
- name: Failure to Thrive
  category: Growth
  description: >-
    Failure to thrive, often compounded by feeding difficulty from cleft palate
    and by recurrent hypoglycemia, is among the most common presenting features.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:38968673
    reference_title: "Coagulation abnormalities and vascular complications are common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common clinical presentations include muscle involvement, failure
      to thrive, cleft palate, and cardiac involvement.
    explanation: >-
      Lists failure to thrive among the most common presenting features across
      73 reported individuals.
histopathology:
- name: Hepatic Steatosis, Cholestasis, or Slight Fibrosis
  description: >-
    Liver biopsies in the multisystem form have shown steatosis, cholestasis,
    and/or slight fibrosis. These findings are supportive but nonspecific and a
    biopsy is not required to establish PGM1-CDG.
  diagnostic: false
  context: Liver biopsy; five reported patients
  subtype: Multisystem
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver biopsy, performed in five patients, showed steatosis, cholestasis
      and/or slight fibrosis.
    explanation: >-
      Directly documents the spectrum of human liver-biopsy findings in five
      patients.
- name: PAS-Positive Hepatic Glycogen Accumulation
  description: >-
    Increased periodic acid-Schiff staining identified hepatic glycogen
    accumulation in a subset of the biopsied patients.
  frequency: FREQUENT
  diagnostic: false
  context: Liver biopsy; frequency is 2/5 among biopsied patients
  subtype: Multisystem
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glycogen accumulation, defined by increased PAS-positive staining, was
      observed in two out of five liver biopsies.
    explanation: >-
      Two of five biopsies (40%) were PAS-positive, supporting FREQUENT within
      the explicitly scoped biopsy denominator rather than disease-wide.
- name: Myopathic Changes or Fat/Glycogen Accumulation
  description: >-
    Most reported skeletal-muscle biopsies were abnormal, with increased internal
    nuclei, variation in fiber size, and/or accumulation of fat or glycogen.
    These findings are nonspecific and muscle biopsy is reserved for research
    rather than routine diagnosis.
  frequency: VERY_FREQUENT
  diagnostic: false
  context: Skeletal muscle biopsy; frequency is 10/12 among biopsied patients
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy was performed in 12 patients; 10 biopsies were abnormal,
      showing myopathic changes (increase of internal nuclei or fiber size
      variation) and/or accumulation of fat or glycogen.
    explanation: >-
      Abnormal findings in 10/12 biopsies (83%) support VERY_FREQUENT within the
      biopsied cohort.
- name: Intramuscular Fat Accumulation
  description: >-
    Fat accumulation was present in a majority of the abnormal skeletal-muscle
    biopsies.
  frequency: FREQUENT
  diagnostic: false
  context: Skeletal muscle biopsy; frequency is 6/10 among abnormal biopsies
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The fat accumulation, indicative for glycogen storage disease, was reported
      in 6 of these 10 patients.
    explanation: >-
      Fat accumulation in 6/10 abnormal biopsies (60%) supports FREQUENT within
      that scoped denominator.
biochemical:
- name: Mixed type I and type II serum transferrin isoform pattern
  presence: ABNORMAL
  context: >-
    The diagnostic biochemical signature. Intact-transferrin mass spectrometry
    (MALDI-TOF, ESI-MS/QTOF or LC-MS) shows both loss of complete N-glycans (the
    type I component) and truncated glycans lacking galactose and terminal sialic
    acid (the type II component). Transferrin isoelectric focusing, HPLC or
    capillary electrophoresis can screen for carbohydrate-deficient transferrin
    but resolve the mixed structural signature less well. Transferrin
    glycosylation normalizes substantially on D-galactose and is used as a
    treatment-response readout.
  biomarker_term:
    preferred_term: carbohydrate-deficient transferrin measurement
    term:
      id: NCIT:C101016
      label: Carbohydrate-Deficient Transferrin Measurement
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectrometry revealed the presence of a variety of transferrin
      glycoforms, including forms lacking one or both glycans as well as forms
      with truncated glycans
    explanation: >-
      Describes the coexistence of missing and truncated glycoforms that defines
      the mixed pattern.
- name: Creatine kinase
  presence: INCREASED
  context: >-
    Creatine kinase is elevated during and between rhabdomyolysis episodes and is
    part of the recommended monitoring panel; it improved on D-galactose in a
    subset of treated patients.
  biomarker_term:
    preferred_term: creatine kinase measurement
    term:
      id: NCIT:C64489
      label: Creatine Kinase Measurement
  evidence:
  - reference: PMID:37181075
    reference_title: "Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there was a significant improvement or normalization in transferrin
      glycosylation, liver transaminases and coagulation factors in three
      patients, creatine kinase (CK) levels in two
    explanation: >-
      Confirms CK as an abnormal, treatment-responsive analyte in PGM1-CDG.
- name: PGM1 enzyme activity in fibroblasts or leukocytes
  presence: DECREASED
  context: >-
    Direct enzymatic assay in cultured fibroblasts or leukocytes shows severely
    reduced activity (the 2021 consensus guideline, PMID:32681750, reports a
    range from undetectable to 20% of controls; red blood cells cannot be used
    because PGM1 is absent there). It is supportive but not independently
    definitive, and residual activity does not correlate reliably with clinical
    severity, so the final diagnosis rests on molecular testing.
  evidence:
  - reference: PMID:27206562
    reference_title: "Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regression analysis showed that there is no significant correlation between
      genotype, enzyme activity, and TPCRS score.
    explanation: >-
      Establishes the important caveat that residual enzyme activity does not
      predict disease severity.
genetic:
- name: PGM1
  notes: >-
    PGM1 (1p31.3) encodes cytosolic phosphoglucomutase-1. Disease results from
    biallelic loss-of-function alleles, predominantly missense; the consensus
    synthesis catalogued 41 variants, of which c.112A>T recurred in nine patients
    and c.988G>C in five. Missense alleles impair catalysis and can destabilize
    local enzyme structure. Genotype does not reliably predict phenotype.
  gene_term:
    preferred_term: PGM1
    term:
      id: hgnc:8905
      label: PGM1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 21 different mutations in PGM1 in 19 patients.
    explanation: >-
      Establishes PGM1 as the causal gene and documents substantial allelic
      heterogeneity.
  - reference: PMID:27206562
    reference_title: "Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regression analysis showed that there is no significant correlation between
      genotype, enzyme activity, and TPCRS score.
    explanation: >-
      Supports the absence of a usable genotype-phenotype correlation in
      PGM1-CDG.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    More than 60 patients reported in the literature as of 2023; population
    prevalence and incidence remain unknown. PGM1-CDG is nonetheless described as
    the third most common N-linked CDG.
  evidence:
  - reference: PMID:37181075
    reference_title: "Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, more than 60 patients have been reported.
    explanation: >-
      Provides the cumulative reported-case count; no population-based prevalence
      estimate exists.
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most
      common N-linked congenital disorders of glycosylation (CDG) in humans.
    explanation: >-
      Places PGM1-CDG in relative rank among the N-linked CDG despite the absence
      of an absolute prevalence figure.
diagnosis:
- name: Intact Transferrin Mass Spectrometry
  description: >-
    First-line biochemical screen and the test that best resolves the
    characteristic mixed type I / type II signature. Transferrin isoelectric
    focusing, HPLC or capillary electrophoresis may be used as an initial
    carbohydrate-deficient-transferrin screen but resolve the structural pattern
    less well.
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of serum transferrin by means of isoelectric focusing was
      performed to screen for congenital disorders of glycosylation.
    explanation: >-
      Documents transferrin analysis as the screening entry point that first
      identified the disorder.
- name: PGM1 Molecular Genetic Testing
  description: >-
    Confirmatory testing identifies two pathogenic or likely pathogenic PGM1
    variants, with phase established where possible. Targeted PGM1 sequencing
    plus deletion/duplication analysis, CDG or metabolic-myopathy gene panels
    including PGM1, or exome/genome sequencing are all appropriate routes
    depending on the presentation.
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping followed by whole-exome sequencing was used to
      identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two
      siblings.
    explanation: >-
      Illustrates the genomic route to molecular confirmation.
- name: Tulane PGM1-CDG Rating Scale
  description: >-
    A clinical severity scoring system (TPCRS) that stratifies patients into
    phenotypic groups from clinical history and examination. Five variables
    predict severity: congenital malformation, cardiac involvement, endocrine
    deficiency, myopathy, and growth; two of these can be assessed on physical
    examination alone, allowing rapid triage.
  evidence:
  - reference: PMID:27206562
    reference_title: "Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Principal component analysis identified 5 variables that contributed to 54%
      variance in the cohort and are predictive of disease severity: congenital
      malformation, cardiac involvement, endocrine deficiency, myopathy, and
      growth.
    explanation: >-
      Defines the severity predictors underlying the TPCRS scoring instrument.
treatments:
- name: Oral D-Galactose Supplementation
  description: >-
    The disease-directed therapy and the feature that makes PGM1-CDG unusual
    among the CDG. Oral D-galactose enters the Leloir pathway downstream of the
    PGM1 block and directly replenishes UDP-galactose and UDP-glucose, restoring
    the nucleotide-sugar donors required for both ER and Golgi glycosylation.
    Recommended dosing is approximately 1.0 to 1.5 g/kg/day (younger patients may
    require up to 3.0 g/kg/day), maximum 50 g/day, given in divided doses with
    gradual titration to avoid gastrointestinal effects. Transferrin
    glycosylation, transaminases, antithrombin III and hypoglycemia improve;
    exercise intolerance and rhabdomyolysis improve in some. Cardiomyopathy does
    NOT improve, so galactose therapy must not create false reassurance about
    cardiac risk and lifelong cardiac surveillance remains mandatory. Monitoring
    should include ALT/AST, CK, coagulation factors including antithrombin III,
    intact transferrin or N-glycan analysis, serum galactose-1-phosphate and
    urine galactitol.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: oral monosaccharide (D-galactose) supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: D-galactose
      term:
        id: CHEBI:12936
        label: D-galactose
  target_mechanisms:
  - target: UDP-Galactose Depletion and Impaired Golgi Galactosylation
    treatment_effect: INHIBITS
    description: >-
      D-galactose bypasses the PGM1 block via the Leloir pathway and replenishes
      the depleted UDP-galactose pool, reversing the Golgi galactosylation defect
      that produces the truncated type II glycans.
  - target: UDP-Glucose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
    treatment_effect: INHIBITS
    description: >-
      Galactose loading also raises UDP-glucose and improves the lipid-linked
      oligosaccharide profile, partially correcting the ER (type I) arm.
  evidence:
  - reference: PMID:28617415
    reference_title: "Oral D-galactose supplementation in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal baseline results (alanine transaminase, aspartate transaminase,
      activated partial thromboplastin time) improved or normalized already using
      1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation
      showed significant improvement, and increase in galactosylation and whole
      glycan content.
    explanation: >-
      Prospective nine-patient pilot trial establishing efficacy on liver,
      coagulation and glycosylation endpoints.
  - reference: PMID:28617415
    reference_title: "Oral D-galactose supplementation in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral D-gal supplementation is a safe and effective treatment for PGM1-CDG
      in this pilot study.
    explanation: >-
      Safety and efficacy conclusion of the prospective pilot study.
  - reference: PMID:35562242
    reference_title: "Nutrition interventions in congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The maximum safe dose that has been well tolerated without adverse effects
      is 50 g/day
    explanation: >-
      Source for the maximum tolerated daily dose in the dosing recommendation.
      Tagged OTHER because this is an expert review synthesizing dosing practice.
  - reference: PMID:37181075
    reference_title: "Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      D-gal also failed to improve the cardiac function, which was initially
      abnormal in three patients, and remains the biggest challenge in treating
      PGM1-CDG.
    explanation: >-
      Documents the key limitation: the cardiac phenotype is not corrected.
      Marked PARTIAL because it refutes efficacy for the cardiac arm while the
      same series supports efficacy elsewhere.
  - reference: PMID:30982613
    reference_title: "The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their
      sugar metabolism
    explanation: >-
      Tracer-metabolomic mechanism of action underpinning the treatment.
- name: Fasting Avoidance and Complex Carbohydrate Feeding
  description: >-
    Prevention of hypoglycemia by frequent complex-carbohydrate meals and snacks,
    overnight enteral feeding where needed, and a written emergency plan for
    intercurrent illness. Uncooked cornstarch before bedtime can be introduced
    after six months of age, and modified cornstarch (Glycosade) can be used after
    three years. Stabilizing glucose homeostasis by dietary means remains
    standard care alongside D-galactose.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Fasting Hypoglycemia and Hepatic Metabolic Stress
    treatment_effect: INHIBITS
    description: >-
      Continuous exogenous carbohydrate supply substitutes for the unavailable
      hepatic glycogen output.
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      supplementation with complex carbohydrates stabilizes blood glucose
    explanation: >-
      The landmark study's own conclusion supporting complex-carbohydrate
      management of the hypoglycemia.
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The oral administration of uncooked corn starch before bedtime can be
      initiated over the age of 6 months. Modified cornstarch (Glycosade) can be
      used in children over 3 years.
    explanation: >-
      Provides guideline-backed age thresholds for uncooked and modified
      cornstarch rather than leaving complex-carbohydrate feeding as prose only.
- name: Diazoxide for Hyperinsulinemic Hypoglycemia
  description: >-
    Oral diazoxide should be considered when hypoglycemia is hyperinsulinemic,
    particularly in young patients, alongside frequent feeding, complex
    carbohydrates and D-galactose.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazoxide
      term:
        id: CHEBI:4495
        label: diazoxide
  target_phenotypes:
  - preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral diazoxide therapy should be considered for hyperinsulinemic
      hypoglycemia.
    explanation: >-
      The international guideline directly recommends diazoxide for the
      hyperinsulinemic hypoglycemia phenotype.
- name: Avoidance of Hepatotoxic Medications
  description: >-
    Avoid hepatotoxic medications where alternatives exist because the
    multisystem form has chronic hepatopathy and a documented risk of acute
    hepatic failure.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: medication avoidance and supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Acute hepatic failure
    term:
      id: HP:0006554
      label: Acute hepatic failure
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatotoxic medication should be avoided.
    explanation: >-
      Captures the guideline's explicit medication-avoidance recommendation as a
      structured preventive action.
- name: Cardiac Surveillance
  description: >-
    Because D-galactose does not correct the cardiomyopathy, cardiac
    surveillance must continue lifelong in every patient regardless of
    biochemical response. Baseline assessment at diagnosis and periodic
    echocardiography and ECG (with Holter monitoring, cardiac MRI or exercise
    testing where indicated) are the practical implementation, and screening of
    at-risk first-degree relatives is warranted once a proband is identified.
  action_category: MONITORING
  treatment_term:
    preferred_term: cardiac surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35562242
    reference_title: "Nutrition interventions in congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, it does not treat the cardiomyopathy observed in some patients
    explanation: >-
      Establishes the rationale for cardiac management independent of
      D-galactose. Tagged OTHER because this is an expert review.
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All first-degree relatives underwent clinical examination including cardiac
      ultrasound, Holter-ECG, exercise stress test and biochemistry panel.
    explanation: >-
      Documents the concrete cardiac screening protocol applied to a PGM1-CDG
      family, which detected affected siblings.
- name: Heart Transplantation
  description: >-
    Refractory dilated cardiomyopathy may require heart transplantation, which
    has been performed successfully as early as 12 months of age in PGM1-CDG.
    Transplantation addresses only the cardiac arm; D-galactose is continued for
    the systemic disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Dilated Cardiomyopathy and Progressive Heart Failure
    treatment_effect: INHIBITS
    description: >-
      Transplantation replaces the failing PGM1-deficient myocardium; it does not
      address the systemic disorder, which still requires D-galactose.
  evidence:
  - reference: PMID:36873091
    reference_title: "Successful heart transplantation in an infant with phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac function was stable in the first 18 months of follow-up, and
      hematologic, hepatic, and endocrine laboratory findings improved during
      D-galactose therapy.
    explanation: >-
      Documents a successful infant heart transplant with concurrent D-galactose
      therapy for the systemic disease.
  - reference: PMID:36873091
    reference_title: "Successful heart transplantation in an infant with phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter therapy improves several systemic symptoms and biochemical
      abnormalities in PGM1-CDG but does not correct the heart failure related to
      cardiomyopathy.
    explanation: >-
      States the division of labour between D-galactose and transplantation.
- name: Perioperative and Anesthetic Precautions
  description: >-
    PGM1-CDG carries two distinct perioperative hazards that should be planned
    for before any surgery. Malignant hyperthermia with severe rhabdomyolysis has
    occurred after general anesthesia, and the coagulation abnormalities (notably
    antithrombin deficiency, but also reduced procoagulant factors) create both
    thrombotic and hemorrhagic risk, so a hemostasis panel should be reviewed
    preoperatively.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: perioperative supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia with severe rhabdomyolysis occurred in two patients
      after the administration of general anesthesia.
    explanation: >-
      Documents the anesthetic hazard that motivates pre-anesthetic evaluation.
  - reference: PMID:38968673
    reference_title: "Coagulation abnormalities and vascular complications are common in PGM1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recommend coagulation parameters should be routinely checked in
      individuals with PGM1-CDG or suspected of having PGM1-CDG.
    explanation: >-
      Supports routine coagulation assessment, which in the perioperative setting
      is the actionable form of that recommendation.
- name: Hydrocortisone Replacement for Secondary Adrenal Insufficiency
  description: >-
    Patients with documented ACTH/cortisol deficiency benefit from hydrocortisone
    replacement, which reduces but does not entirely eliminate hypoglycemic
    episodes. Morning cortisol and ACTH should be checked at least annually in
    patients with hypoglycemia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: CHEBI:17650
        label: cortisol
  evidence:
  - reference: PMID:26768186
    reference_title: "Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hydrocortisone replacement therapy improved, but not entirely eliminated
      hypoglycemic episodes.
    explanation: >-
      Directly reports the effect of hydrocortisone replacement on hypoglycemia
      in PGM1-deficient patients.
- name: L-Thyroxine for Clinical Hypothyroidism
  description: >-
    Treat clinical hypothyroidism with L-thyroxine. Thyroid-axis surveillance is
    warranted because elevated TSH and reduced thyroxine-binding globulin are
    reported in PGM1-CDG.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-thyroxine
      term:
        id: CHEBI:18332
        label: L-thyroxine
  target_phenotypes:
  - preferred_term: Elevated circulating thyroid-stimulating hormone concentration
    term:
      id: HP:0002925
      label: Elevated circulating thyroid-stimulating hormone concentration
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therapy with L-thyroxine is indicated for clinical hypothyroidism
      treatment.
    explanation: >-
      Direct guideline recommendation for thyroid-hormone replacement.
- name: Growth Hormone Therapy
  description: >-
    Growth hormone can be used for documented growth impairment associated with
    growth-hormone-axis deficiency, although response is variable and not all
    patients improve.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: CHEBI:749556
        label: somatropin
  target_phenotypes:
  - preferred_term: Growth hormone-IGF axis deficiency
    term:
      id: HP:0008240
      label: Secondary growth hormone deficiency
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32681750
    reference_title: "International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth impairment can be managed with growth hormone therapy, although not
      all patients respond to this treatment.
    explanation: >-
      Captures both the guideline recommendation and the explicitly stated
      response limitation.
- name: Cleft Palate Repair and Craniofacial Care
  description: >-
    Surgical repair of cleft palate with multidisciplinary craniofacial, airway,
    feeding, dental and speech support. Bifid uvula alone generally requires no
    surgical intervention but is the diagnostic clue that should prompt
    biochemical testing.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cleft palate repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:31077402
    reference_title: "A novel phosphoglucomutase-deficient mouse model reveals aberrant glycosylation and early embryonic lethality."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At birth, affected patients have frequent malformations in the spectrum of
      bifid uvula, cleft palate, and Pierre-Robin sequence.
    explanation: >-
      Establishes the craniofacial malformations that require repair and
      multidisciplinary care. Marked PARTIAL because it documents the indication
      rather than the intervention; there is no PGM1-specific craniofacial
      surgical protocol, and management follows standard cleft/Pierre Robin care.
- name: AAV9-PGM1 Gene Replacement Therapy
  description: >-
    Experimental, preclinical only. AAV9-delivered PGM1 gene replacement both
    prevented and halted progression of dilated cardiomyopathy in the
    cardiomyocyte-specific Pgm2 knockout mouse. This is the most promising
    candidate for the galactose-resistant cardiac phenotype, but no human safety
    or efficacy data exist.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic PGM1 Loss of Function
    treatment_effect: INHIBITS
    description: >-
      Gene replacement restores PGM1 protein and enzymatic activity at the level
      of the primary lesion rather than downstream of it.
  evidence:
  - reference: PMID:36709920
    reference_title: "AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (PGM1-CDG)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement
      therapy prevented and halted the progression of the DCM phenotype.
    explanation: >-
      Preclinical proof of concept in the cardiac conditional knockout mouse.
      This is model-organism evidence only; no human data exist.
- name: Genetic Counseling and Family Testing
  description: >-
    Autosomal recessive counseling with a 25% recurrence risk per pregnancy for
    carrier couples, and cascade testing of siblings, who may have mild or
    late-onset disease and in reported families have been identified only after
    an index event. Prenatal and preimplantation genetic testing are available
    once the familial variants are known.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that there is a need of multidisciplinary discussion
      and genetic testing after unexpected cardiac death in the young.
    explanation: >-
      Supports family-level genetic testing, which in this kindred identified two
      additional affected siblings after the index sudden death.
  - reference: PMID:31563034
    reference_title: "The congenital disorder of glycosylation in PGM1 (PGM1-CDG) can cause severe cardiomyopathy and unexpected sudden cardiac death in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both parents and three other siblings were found to be heterozygous gene
      carriers without risk for the disease.
    explanation: >-
      Demonstrates the carrier-testing outcome that recessive counseling
      delivers: unaffected heterozygous relatives can be reassured while affected
      homozygotes are identified.
differential_diagnoses:
- name: McArdle disease
  description: >-
    Myophosphorylase (PYGM) deficiency produces an almost identical muscle
    physiology, including a flat lactate response to ischemic forearm exercise
    and the second-wind phenomenon, which was long considered pathognomonic for
    McArdle disease. PGM1-CDG is distinguished by the multisystem features
    (palatal malformation, hepatopathy, coagulopathy, cardiomyopathy) and the
    abnormal transferrin glycosylation.
  evidence:
  - reference: PMID:28882528
    reference_title: "Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second wind phenomenon has been considered to be pathognomonic for
      McArdle disease, but we demonstrate that it can also be present in PGM1
      deficiency.
    explanation: >-
      Explicitly establishes the diagnostic overlap that makes McArdle disease a
      key differential.
- name: Glycogen storage disease type I
  description: >-
    Glucose-6-phosphatase deficiency shares fasting hypoglycemia, lactic
    acidosis, hepatomegaly and exercise intolerance with PGM1-CDG because both
    disorders obstruct hepatic glucose output at adjacent steps, but GSD I lacks
    the glycosylation abnormality and the craniofacial and cardiac features.
  evidence:
  - reference: PMID:24499211
    reference_title: "Multiple phenotypes in phosphoglucomutase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These characteristics are also seen with glycogen storage disease Ia, in
      which there is a defect in hepatic glucose-6-phosphatase.
    explanation: >-
      The landmark paper itself draws the comparison with GSD Ia for the
      hypoglycemia and exercise-intolerance phenotype.
- name: MPI-congenital disorder of glycosylation
  description: >-
    MPI-CDG is the other classically treatable CDG (with oral D-mannose) and
    likewise presents with hypoglycemia, hyperinsulinism and hepatopathy, but it
    causes protein-losing enteropathy and hepatic fibrosis rather than
    craniofacial malformation, myopathy or cardiomyopathy, and it produces a pure
    type I transferrin pattern.
  evidence:
  - reference: PMID:35562242
    reference_title: "Nutrition interventions in congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is especially true for MPI-CDG; which almost always presents with
      hypoglycemia and hyperinsulinism
    explanation: >-
      Documents the shared hypoglycemia/hyperinsulinism presentation that makes
      MPI-CDG a differential. Marked PARTIAL because it supports the shared
      feature rather than the full discriminating comparison.
experimental_models:
- name: PGM1-deficient patient-derived iPSC-cardiomyocytes
  description: >-
    Induced pluripotent stem cell-derived cardiomyocytes reprogrammed from
    PGM1-deficient patient fibroblasts, characterized by multielectrode-array
    recording, untargeted (glyco)proteomics, tracer metabolomics, and
    mitochondrial respiration assays. This is the first human cardiomyocyte
    model of PGM1-CDG; the cardiac arm of the disease had previously been
    studied in cardiomyocyte-specific Pgm2 knockout mice and in PGM1-null
    skeletal-muscle cells, neither of which is a human cardiomyocyte.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Fibroblasts from PGM1-deficient patients, reprogrammed to iPSC
  culture_system: iPSC-derived cardiomyocyte monolayer on multielectrode arrays
  publication: PMID:41723528
  modeled_mechanisms:
  - target: Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model is where the Z-disk lesion was discovered, so it recapitulates
      it by construction.
    limitations: >-
      iPSC-derived cardiomyocytes are immature relative to adult myocardium,
      with fetal-like sarcomere organization and a glycolytic rather than
      oxidative metabolic profile - both of which are the very properties this
      model is used to measure. The PGM1-LDB3 interaction rests on an
      AlphaFold3 prediction confirmed in vitro, not on structural data from
      cardiac tissue.
    readouts:
    - name: Z-disk component abundance, LDB3 included
      target: Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction
      direction: DECREASED
      interpretation: >-
        Proteomic depletion of Z-disk proteins is the primary measurement
        behind this node.
      evidence:
      - reference: PMID:41723528
        reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Proteomic analyses revealed depletion of Z-disk components, including
          LDB3.
        explanation: Reports the measurement and its direction.
    - name: Contractile function by multielectrode array
      target: Z-Disk Destabilization via Loss of PGM1-LDB3 Interaction
      direction: DECREASED
      interpretation: >-
        Reduced beating frequency and impaired contractility are the functional
        consequence of the sarcomeric lesion in this model.
      evidence:
      - reference: PMID:41723528
        reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          PGM1-deficient iCMs exhibited reduced beating frequency, impaired
          contractility, and prolonged contraction kinetics.
        explanation: Reports the contractile measurements directly.
    evidence:
    - reference: PMID:41723528
      reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were
        generated from PGM1-deficient patient fibroblasts.
      explanation: >-
        Establishes that the model is patient-derived and therefore informative
        for the human cardiac node.
  - target: Cardiomyocyte Energetic and Mitochondrial Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Extends the mitochondrial arm from mouse heart and PGM1-null skeletal
      muscle cells into human cardiomyocytes.
    limitations: >-
      iPSC-cardiomyocyte metabolism is fetal-like and predominantly glycolytic,
      so a measured respiration deficit may understate or overstate what an
      adult myocardium would show. No galactose-rescue arm was reported in this
      model, so it does not itself test the treatment-resistance claim.
    readouts:
    - name: Mitochondrial respiration
      target: Cardiomyocyte Energetic and Mitochondrial Failure
      direction: DECREASED
      interpretation: >-
        Respirometry is the direct functional measurement of the energetic
        failure node.
      evidence:
      - reference: PMID:41723528
        reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Functional validation confirmed extensive metabolic rewiring, energy
          depletion, and severely impaired mitochondrial respiration.
        explanation: Reports the respiration and energy measurements.
    evidence:
    - reference: PMID:41723528
      reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Recent evidence of mitochondrial abnormalities in PGM1-deficient human
        and murine heart
      explanation: >-
        Places the model's mitochondrial finding in the context of prior human
        and mouse cardiac evidence.
  evidence:
  - reference: PMID:41723528
    reference_title: "PGM1 deficiency is linked to sarcomeric and mitochondrial dysfunction in patient-derived iPSC-cardiomyocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and
      pathway analysis were performed to assess functional and molecular
      changes.
    explanation: Describes the model's readout platform.
clinical_trials:
- name: NCT05402332
  phase: PHASE_II
  status: NOT_RECRUITING
  description: >-
    A Phase 2b multicenter, randomized, double-blind, placebo-controlled
    crossover trial of AVTX-801 (D-galactose) in adults with PGM1-CDG already
    taking D-galactose, evaluating efficacy, safety and tolerability. The
    registry lists a future estimated start date, so the trial had not begun
    enrolling at the time of curation.
  target_phenotypes:
  - preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  - preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: clinicaltrials:NCT05402332
    reference_title: "A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-Controlled, Crossover, Trial Assessing the Efficacy, Safety, and Tolerability of AVTX-801 in Subjects With Phosphoglucomutase 1 Deficiency Related Congenital Disorders of Glycosylation (PGM1-CDG)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a clinical trial to evaluate the efficacy of AVTX-801 (D-galactose)
      on the clinical manifestations of PGM1-CDG in participants currently taking
      D-galactose.
    explanation: >-
      Registered randomized crossover trial formally testing the D-galactose
      treatment arm curated in this entry.
- name: NCT03404856
  status: UNKNOWN
  description: >-
    A single-group Phase 1/2 pediatric study of ORL-1G (D-galactose), registered
    under the disorder's former name glycogen storage disease type 14, with
    liver-enzyme reduction as the primary endpoint and transferrin-glycosylation
    improvement as a secondary endpoint. Registry information is stale, so the
    current status should not be inferred from the record. The phase slot is left
    unset because the registry records a combined Phase 1/2 design that the
    dismech phase enum cannot express.
  target_phenotypes:
  - preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: clinicaltrials:NCT03404856
    reference_title: "Study of ORL-1G (D-galactose) in Patients With Glycogen Storage Disease Type 14"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study of ORL-1G in Patients With Glycogen Storage Disease Type 14
    explanation: >-
      Registry record for the pediatric D-galactose study; the GSD type 14 title
      reflects the disorder's former name.
references:
- reference: PMID:20301507
  title: "Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
notes: >-
  GeneReviews baseline: no dedicated PGM1-CDG GeneReviews chapter exists. The
  only GeneReviews record retrievable for this disorder is the multi-gene
  overview "Congenital Disorders of N-Linked Glycosylation and Multiple Pathway
  Overview" (PMID:20301507), which is a RETIRED chapter kept for historical
  reference and whose PubMed abstract contains no PGM1-specific clinical
  characteristics. The phenotype baseline for this entry was therefore taken from
  the 2021 international consensus guidelines (PMID:32681750) and the landmark
  19-patient NEJM cohort (PMID:24499211), which together play the equivalent
  role.

  Deliberately out of scope for this first pass. (a) Orphanet-sourced prevalence
  evidence, because the pinned Orphadata snapshot in data/orphadata/MANIFEST.yaml
  no longer matches the upstream file checksum and refreshing it would churn all
  8,823 ORPHA cache files; the reported-case count from PMID:37181075 is used
  instead. (b) Membership of the Congenital_Disorders_of_Glycosylation grouping,
  which is maintained separately (several existing CDG entries, for example
  ALG1-CDG, are also not yet listed there). (c) Creatine supplementation
  (PMID:40242152) and the hexose-phosphate LC-MS pathophysiology work
  (PMID:41018607), which are recent single reports not yet reflected in consensus
  guidance.
  Dataset coverage (searched 2026-08-20): no relevant public dataset was found,
  and none was added. `just discover-datasets` returned only GENE_ONLY matches
  driven by the gene symbol - yeast and Candida deletion-mutant expression
  compendia in which PGM1 is a deleted yeast gene. Direct GEO DataSets searches
  for "PGM1-CDG" and "PGM1 deficiency" both return zero series. Adding any of
  the gene-name hits would be Named Entity Confusion reached through dataset
  search, which is exactly the failure mode the dataset-curation SOP warns
  about, so the datasets block is deliberately left empty rather than filled.
  The 2026 patient iPSC-cardiomyocyte study (PMID:41723528) reports proteomics
  and metabolomics but its cached text carries no repository accession.
datasets: []

📚

References & Deep Research

References

1

PMID:20301507

Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview - RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

PGM1-Congenital Disorder of Glycosylation: Disease-Characteristics Report

Edison Scientific Literature 26 citations 2026-08-01T17:17:03.063741

PGM1-Congenital Disorder of Glycosylation: Disease-Characteristics Report

Executive summary

PGM1-congenital disorder of glycosylation (PGM1-CDG) is an ultra-rare, autosomal-recessive, treatable disorder of both carbohydrate metabolism and protein glycosylation. Biallelic pathogenic variants in PGM1 reduce phosphoglucomutase-1 activity, disrupting interconversion of glucose-1-phosphate and glucose-6-phosphate. This impairs glycogen synthesis/mobilization, glycolytic energy supply, UDP-glucose/UDP-galactose production, and N-linked glycosylation. The result is a mixed biochemical CDG-I/CDG-II pattern and a variable phenotype ranging from adult-onset exercise intolerance to congenital craniofacial anomalies, hypoglycemia, hepatopathy, coagulopathy, rhabdomyolysis, endocrine disease, and potentially fatal dilated cardiomyopathy. International experts emphasize early recognition because oral D-galactose improves glycosylation, liver abnormalities, coagulation, hypoglycemia, and some muscle outcomes, although cardiac disease is often treatment-resistant. (altassan2021internationalconsensusguidelines pages 10-12, radenkovic2023novelinsightsinto pages 2-3, altassan2021internationalconsensusguidelines pages 1-3)

The following table summarizes the strongest quantitative evidence.

Domain	Strongest quantitative finding	Evidence type	Source / date / DOI or NCT
Human cohort phenotypes	Among 57 molecularly confirmed patients, cleft palate occurred in 28, bifid uvula in 25, and Pierre-Robin sequence in 15; cardiac involvement affected 24 patients, including dilated cardiomyopathy in 12; hypoglycemia was reported in 38 patients; cardiac complications caused death in 6 patients (altassan2021internationalconsensusguidelines pages 3-4, altassan2021internationalconsensusguidelines pages 4-6, altassan2021internationalconsensusguidelines pages 6-7)	Human clinical cohort / consensus synthesis	Altassan et al., J Inherit Metab Dis, Sep 2021, doi:10.1002/jimd.12286
2023 five-patient D-galactose outcomes	In 5 treated patients, notable clinical improvement occurred in 4; transferrin glycosylation, liver transaminases, and coagulation factors improved/normalized in 3; CK improved in 2; hypoglycemia resolved in 2; 1 discontinued for urinary frequency/lack of benefit; cardiac function did not improve in 3 with baseline abnormalities (radenkovic2023novelinsightsinto pages 1-2, radenkovic2023novelinsightsinto pages 5-6)	Human case series	Radenkovic et al., Ther Adv Rare Dis, Jan 2023, doi:10.1177/26330040221150269
Standard D-galactose management	Recommended dose range 500-2500 mg/kg/day (about 1 g/kg/day typical), divided up to 6 doses, maximum 50 g/day; monitoring every 6 months includes ALT/AST, ATIII, CK, CDT/N-glycans, Gal-1-P, and urine galactitol (boyer2022nutritioninterventionsin pages 30-30, altassan2021internationalconsensusguidelines pages 13-15)	Human management guideline / review	Boyer et al., Trends Mol Med, Jun 2022, doi:10.1016/j.molmed.2022.04.003; Altassan et al., Sep 2021, doi:10.1002/jimd.12286
Skeletal muscle mechanism (C2C12)	CRISPR Pgm1-knockout myoblasts/myotubes showed significantly reduced basal respiration, ATP production, and spare respiratory capacity; ^13C6-galactose tracing showed a block in galactose use for energy production, and D-galactose did not rescue the energetic deficit (conte2023invitroskeletal pages 15-16, conte2023invitroskeletal pages 1-2)	In vitro cellular model	Conte et al., Int J Mol Sci, May 2023, doi:10.3390/ijms24098247
Constitutive mouse model	Homozygous constitutive knockout produced 0 homozygous live births among 78 pups, indicating embryonic lethality before E9.5; heterozygotes had abnormal serum glycosylation similar to human PGM1-CDG (balakrishnan2019anovelphosphoglucomutase‐deficient pages 1-3)	Animal model	Balakrishnan et al., J Inherit Metab Dis, Jun 2019, doi:10.1002/jimd.12110
Cardiac mouse multi-omics	In Pgm2cKO hearts, mitochondrial complex III activity was reduced by 25%; proteomics quantified 4,396 proteins; glycoproteomics identified 1,640 N-glycopeptides and 147 N-glycan compositions; 213 glycopeptides from 71 proteins changed significantly, with 74/213 from laminin subunits and 71/74 downregulated (balakrishnan2023aavbasedgenetherapy pages 13-15, balakrishnan2023aavbasedgenetherapy pages 10-12, balakrishnan2023aavbasedgenetherapy pages 1-3)	Animal multi-omics	Balakrishnan et al., Transl Res, Jul 2023, doi:10.1016/j.trsl.2023.01.004
Cardiac gene therapy rescue	AAV9-PGM1 gene replacement prevented and halted progression of dilated cardiomyopathy in the cardiomyocyte-specific knockout mouse model; in the index human comparator case, LVEF fell from 54% at 6 months to 10% by 12 months before transplant (balakrishnan2023aavbasedgenetherapy pages 15-16, balakrishnan2023aavbasedgenetherapy pages 3-4)	Animal therapeutic study with human comparator case	Balakrishnan et al., Transl Res, Jul 2023, doi:10.1016/j.trsl.2023.01.004
Clinical trial: ORL-1G	Phase 1/2, single-group pediatric trial; estimated enrollment 5; primary completion Oct 31, 2019; primary outcome was decrease in plasma liver enzymes at 3 months; secondary outcome was transferrin glycosylation improvement by day 30 (NCT03404856 chunk 1)	Interventional trial registry	NCT03404856, Orpha Labs, study start Oct 31, 2017
Clinical trial: AVTX-801	Phase 2b randomized double-blind placebo-controlled crossover trial; planned enrollment 8 adults; AVTX-801 1.5 g/kg/day (max 50 g/day); estimated start Oct 1, 2026; primary endpoint is proportion with PGM1-CDG-related events during treatment periods (NCT05402332 chunk 1)	Interventional trial registry	NCT05402332, Icahn School of Medicine at Mount Sinai, status verified Mar 2026

Table: This table compiles the most decision-relevant quantitative findings for PGM1-CDG across clinical cohorts, treatment outcomes, mechanistic models, and registered trials. It is useful as a compact evidence map for disease characterization and management planning.

1. Disease information

Definition and classification

PGM1-CDG is a Mendelian inborn error of metabolism caused by phosphoglucomutase-1 deficiency. It was historically called glycogen-storage disease type XIV, GSD XIV, or CDG type It, but is now classified as PGM1-CDG because abnormal protein glycosylation is integral to the disorder. Two broad presentations are recognized: a congenital/multisystem phenotype and a predominantly myopathic phenotype that may not become evident until adolescence or adulthood. (altassan2021internationalconsensusguidelines pages 3-4, altassan2021internationalconsensusguidelines pages 1-3)

Key identifiers and names

OMIM phenotype: 614921.
Causal gene: PGM1, chromosome 1p31.3; 11 exons.
Synonyms: PGM1 deficiency; phosphoglucomutase-1 deficiency; glycogen-storage disease XIV/GSD14; CDG-It; phosphoglucomutase-1 congenital disorder of glycosylation.
MONDO: A MONDO identifier was not established in the retrieved primary sources and should be verified directly against the current MONDO release before database ingestion.
Orphanet, MeSH, ICD-10/ICD-11: Dedicated identifiers were not verified in the retrieved evidence. Clinically, it may be coded under broader congenital glycosylation or glycogen-metabolism categories, but such coding should not be treated as disease-specific without terminology-server confirmation.

The evidence summarized here is aggregated disease-level evidence from published cohorts, international consensus review, case series, models, and trial registries—not individual EHR extraction. The 2023 report contributes individual-level data from five patients enrolled through a natural-history framework. (radenkovic2023novelinsightsinto pages 1-2, radenkovic2023novelinsightsinto pages 5-6)

2. Etiology, risks, protective factors, and gene–environment interaction

Primary cause

The necessary cause is biallelic germline pathogenic or likely pathogenic variation in PGM1, producing autosomal-recessive enzyme deficiency. PGM1 contributes about 90% of phosphoglucomutase activity in most cell types and is broadly expressed, except in erythrocytes. Residual activity in affected fibroblasts or leukocytes is generally undetectable to 20% of control, but residual activity has not shown a reliable severity correlation. (altassan2021internationalconsensusguidelines pages 10-12, altassan2021internationalconsensusguidelines pages 3-4)

Forty-one variants were reported in the consensus synthesis; c.112A>T occurred in nine patients and c.988G>C in five. Most reported alleles were missense, although other loss-of-function classes are possible. Variant-level ACMG status and gnomAD frequency must be checked individually in current ClinVar/gnomAD records; the available literature does not support assigning one classification or frequency to all alleles. (altassan2021internationalconsensusguidelines pages 10-12)

Risk and protective factors

Genetic risk: two disease-causing PGM1 alleles; parental consanguinity increases the probability of homozygosity but is not required.
Family history: affected siblings and carrier parents are expected under autosomal-recessive inheritance.
Environmental susceptibility: fasting, illness, vomiting, and strenuous exercise plausibly expose limited glucose mobilization and energy reserve, precipitating hypoglycemia or rhabdomyolysis. These are clinical triggers, not primary causes.
Protective/mitigating factors: regular complex-carbohydrate intake, avoidance of prolonged fasting and excessive alcohol, individualized exercise precautions, and D-galactose therapy reduce metabolic stress or downstream biochemical abnormalities. (boyer2022nutritioninterventionsin pages 30-30, altassan2021internationalconsensusguidelines pages 1-3)
No validated protective PGM1 allele, modifier gene, toxin, infectious cause, smoking association, or formal gene–environment interaction model has been established.

3. Phenotypes

Core phenotype spectrum

The strongest broad dataset comprised 57 molecularly confirmed patients. Congenital craniofacial findings included cleft palate in 28/57, bifid uvula in 25/57, and Pierre Robin sequence in 15/57; combined dysmorphic features were reported in approximately 85%. Endocrine involvement was reported in 39 patients, including hypoglycemia in 38. Cardiac involvement occurred in 24, including dilated cardiomyopathy in 12, heart failure in nine, and cardiac arrest in eight. Six reported patients died from cardiac complications. (altassan2021internationalconsensusguidelines pages 3-4, altassan2021internationalconsensusguidelines pages 4-6, altassan2021internationalconsensusguidelines pages 6-7)

Suggested phenotype annotations include:

Craniofacial: cleft palate, bifid uvula, Pierre Robin sequence, micrognathia. Suggested HPO concepts: Cleft palate, Bifid uvula, Pierre Robin sequence, Micrognathia.
Metabolic/endocrine: fasting or illness-associated hypoglycemia, hyperinsulinism in some patients, short stature/growth-hormone–IGF1 abnormalities, occasional hypothyroidism, hypogonadotropic hypogonadism, or adrenal dysfunction. Suggested HPO: Hypoglycemia, Hyperinsulinemic hypoglycemia, Short stature, Growth hormone deficiency, Hypothyroidism, Hypogonadotropic hypogonadism.
Hepatic: chronically or episodically elevated aminotransferases, steatosis, hepatomegaly, cholestasis, and fibrosis. Suggested HPO: Elevated hepatic transaminases, Hepatic steatosis, Hepatomegaly, Cholestasis, Hepatic fibrosis.
Muscle: exercise intolerance, fatigue, weakness, elevated creatine kinase, myopathy, and recurrent exercise- or illness-associated rhabdomyolysis. Suggested HPO: Exercise intolerance, Muscle weakness, Elevated serum creatine kinase, Rhabdomyolysis, Myopathy.
Cardiac: dilated cardiomyopathy, reduced ejection fraction, conduction/ECG abnormalities, ventricular dilation, heart failure, cardiac arrest, and occasional septal or valvular defects. Suggested HPO: Dilated cardiomyopathy, Reduced left ventricular ejection fraction, Cardiac conduction abnormality, Congestive heart failure, Ventricular septal defect, Mitral regurgitation.
Hemostatic/vascular: reduced coagulation or anticoagulation proteins, prolonged coagulation measurements, bleeding or thrombotic concern. Suggested HPO: Abnormality of coagulation, Prolonged prothrombin time, Reduced antithrombin III activity.
Neurologic/developmental: cognitive impairment, intellectual or learning disability, speech/motor delay, balance problems, abnormal movements, and uncommon seizures. Suggested HPO: Global developmental delay, Intellectual disability, Learning disability, Motor delay, Seizure, Abnormality of coordination.
Gastrointestinal/nutritional: feeding difficulty, vomiting, dysphagia, gastroesophageal reflux, constipation, and failure to thrive. Suggested HPO: Feeding difficulties, Recurrent vomiting, Dysphagia, Gastroesophageal reflux, Constipation, Failure to thrive.

The five-patient 2023 series illustrates variability but should not be generalized as population prevalence: onset was congenital in all five; liver abnormalities and muscle involvement occurred in 5/5, hypoglycemia in 4/5, growth delay in 4/5, developmental delay in 4/5, craniofacial anomalies in 5/5, and heterogeneous cardiovascular findings in 5/5. (radenkovic2023novelinsightsinto pages 5-6)

Severity, progression, and quality of life

Severity ranges from mild isolated adult myopathy to fatal pediatric cardiomyopathy. Hypoglycemia, transaminase elevation, CK elevation, and rhabdomyolysis may fluctuate with fasting, illness, or exertion. Cardiomyopathy may arise in childhood or adulthood and can progress rapidly; reported onset included five cases before age five, two at 5–10 years, and six after age ten, with the oldest onset at 49 years. (altassan2021internationalconsensusguidelines pages 1-3, altassan2021internationalconsensusguidelines pages 6-7)

No disease-specific EQ-5D, SF-36, PROMIS, or validated quality-of-life dataset was identified. Nevertheless, recurrent hypoglycemia, dietary burden, exercise limitation, rhabdomyolysis, cardiac surveillance, cleft-palate care, and possible transplantation are expected to affect education, employment, mobility, and family burden. This is a clinical inference rather than quantified PGM1-CDG QoL evidence.

4. Genetic and molecular information

Gene and protein

PGM1 encodes cytosolic phosphoglucomutase-1, which reversibly converts glucose-1-phosphate and glucose-6-phosphate. Suggested annotations include HGNC-approved symbol PGM1, protein phosphoglucomutase-1, and molecular-function concepts phosphoglucomutase activity and magnesium-ion binding. The exact HGNC and GO accession numbers should be validated against current ontology releases before automated loading.

The disease mechanism is predominantly loss of enzymatic function from germline biallelic variants. The evidence does not support a recurrent somatic mechanism, dominant-negative inheritance, repeat expansion, mitochondrial-DNA cause, or characteristic chromosomal rearrangement. Large deletions could theoretically cause loss of function but are not established as a common mechanism in the retrieved cohort.

Variants and modifiers

Reported variants are predominantly missense. A severe cardiac example was homozygous c.1544G>A (p.Arg515Gln); the child’s ejection fraction fell from 54% at six months to 10% at 12 months before cardiac transplantation. (balakrishnan2023aavbasedgenetherapy pages 3-4)

No replicated modifier gene or disease-specific epigenetic signature has been established. Transcriptomic and proteomic changes observed in cardiac models are downstream consequences or candidate mechanisms, not proven inherited modifiers. Epigenetic testing is therefore not part of routine diagnosis.

5. Environmental, lifestyle, and infectious information

PGM1-CDG is not caused by toxins, radiation, pollution, occupational exposure, smoking, alcohol, or infection. Environmental and behavioral factors matter chiefly as metabolic stressors:

fasting and poor intake can provoke hypoglycemia;
febrile illness or vomiting can precipitate catabolism;
intense exercise can precipitate myalgia, CK elevation, or rhabdomyolysis;
alcohol can worsen hepatic/metabolic risk and is discouraged;
regular complex-carbohydrate intake may stabilize glucose availability. (boyer2022nutritioninterventionsin pages 30-30)

No pathogen, zoonotic transmission, or vaccine-preventable mechanism applies. Routine immunization remains appropriate as general care, subject to individual clinical status.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: biallelic PGM1 loss-of-function variants.
Primary biochemical defect: reduced conversion between glucose-1-phosphate and glucose-6-phosphate.
Metabolic consequences: impaired glycogen synthesis and glycogenolysis, reduced access of glycogen-derived carbon to glycolysis, and impaired energetic flexibility during fasting or exercise.
Glycosylation consequences: reduced UDP-glucose and UDP-galactose supply causes incompletely occupied N-glycosylation sites and truncated, galactose-deficient glycans—a mixed ER-associated type-I and Golgi-associated type-II pattern.
Tissue consequences: hepatocyte metabolic stress and abnormal secreted proteins; skeletal-muscle energetic failure and rhabdomyolysis; abnormal glycosylation plus energetic/mitochondrial dysfunction in cardiomyocytes; altered coagulation-protein abundance or processing; and developmental craniofacial defects.
Clinical manifestations: hypoglycemia, hepatopathy, coagulopathy, myopathy, exercise intolerance, and dilated cardiomyopathy. (altassan2021internationalconsensusguidelines pages 10-12, balakrishnan2023aavbasedgenetherapy pages 1-3, balakrishnan2019anovelphosphoglucomutase‐deficient pages 1-3)

Suggested GO biological-process concepts are glycogen biosynthetic process, glycogen catabolic process, glycolytic process, glucose metabolic process, UDP-glucose metabolic process, UDP-galactose metabolic process, protein N-linked glycosylation, mitochondrial ATP synthesis, muscle-cell differentiation, and cardiac-muscle contraction.

Cell and tissue mechanisms

Skeletal muscle—cellular evidence. CRISPR/Cas9 Pgm1-knockout C2C12 cells showed impaired myotube maturation, reduced basal respiration, reduced mitochondrial ATP-production capacity, and reduced spare respiratory capacity. Stable-isotope tracing demonstrated impaired use of galactose for energy production. Galactose did not rescue the energetic defect, explaining why glycosylation correction may not fully resolve myopathy. Suggested CL concepts: skeletal muscle satellite cell/myoblast and skeletal muscle fiber. (conte2023invitroskeletal pages 15-16, conte2023invitroskeletal pages 1-2)

Heart—animal multi-omics. Cardiomyocyte-specific knockout caused ventricular dilation, reduced ejection fraction, glycogen accumulation, fibrosis, Z-disk disorganization, swollen mitochondria, a 25% reduction in mitochondrial complex III activity, TCA-metabolite depletion, and lactate accumulation. Of 1,640 detected N-glycopeptides, 213 from 71 proteins changed significantly; 74 involved laminin subunits and 71/74 were reduced. These findings support combined energetic failure and defective extracellular-matrix/sarcolemmal glycosylation. Suggested CL: cardiomyocyte, cardiac fibroblast; GO cellular components: cytosol, glycogen granule, mitochondrion, sarcolemma, extracellular matrix, endoplasmic reticulum, Golgi apparatus. (balakrishnan2023aavbasedgenetherapy pages 13-15, balakrishnan2023aavbasedgenetherapy pages 10-12)

No established PGM1-CDG single-cell atlas, spatial-transcriptomic study, patient-tissue lipidomic signature, or validated disease epigenome was identified. The most mature profiling evidence is bulk cardiac transcriptomics/proteomics/glycoproteomics and tracer metabolomics in cultured cells.

7. Anatomical structures affected

Primary organs and tissues include liver, skeletal muscle, myocardium/conduction system, endocrine pancreas and counter-regulatory endocrine axes, craniofacial structures, and the hemostatic system. Secondary involvement includes gastrointestinal feeding structures, growth axis, and variably the nervous system.

Suggested anatomical mappings include:

Liver—UBERON liver; hepatocyte CL concept.
Skeletal muscle tissue—UBERON skeletal muscle organ; skeletal muscle fiber/myoblast CL concepts.
Heart and left ventricle—UBERON heart/left ventricle; cardiomyocyte and cardiac fibroblast.
Palate and uvula—UBERON palate/soft palate/uvula.
Pancreas/islet beta cell for hyperinsulinism, although hyperinsulinism is not universal.
Blood plasma/hemostatic system for transferrin and coagulation abnormalities.

No consistent lateralization is described. Cardiomyopathy and metabolic myopathy are systemic rather than unilateral.

8. Temporal development

The congenital/multisystem form often begins prenatally or in infancy with cleft palate/Pierre Robin sequence, feeding problems, hypoglycemia, or liver abnormalities. The myopathic form can be insidious and present in adolescence or adulthood with exercise intolerance or recurrent rhabdomyolysis. (altassan2021internationalconsensusguidelines pages 3-4, altassan2021internationalconsensusguidelines pages 1-3)

The course is chronic and lifelong but heterogeneous:

metabolic and hepatic abnormalities may fluctuate and improve with D-galactose;
exercise-associated muscle episodes are recurrent/episodic;
growth and developmental effects accrue during childhood;
cardiomyopathy can be absent, slowly evolving, or rapidly progressive and fatal.

Critical intervention periods are infancy after metabolic or craniofacial presentation and any time before irreversible cardiomyopathy or organ injury. No formal staging system or spontaneous-remission pattern exists.

9. Inheritance and population

Inheritance is autosomal recessive. For two carrier parents, the conventional per-pregnancy risks are 25% affected, 50% carrier, and 25% unaffected/non-carrier. Penetrance for individuals with two genuinely pathogenic alleles appears high, but expressivity is markedly variable. Anticipation is not expected. Germline mosaicism has not been established as a characteristic feature, although low residual recurrence risk can never be categorically excluded in apparently de novo situations.

More than 60 patients had been reported by 2023, while population prevalence and incidence remain unknown. There is no established sex bias, ethnic restriction, endemic region, or robust carrier frequency. No confirmed founder effect was demonstrated by the retrieved evidence. (radenkovic2023novelinsightsinto pages 1-2, altassan2021internationalconsensusguidelines pages 3-4)

10. Diagnostics

Clinical and biochemical testing

PGM1-CDG should be considered in any combination of cleft palate/bifid uvula, hypoglycemia, unexplained aminotransferase elevation, coagulopathy, exercise intolerance/rhabdomyolysis, short stature, or dilated cardiomyopathy.

The characteristic screening finding is a mixed transferrin glycosylation abnormality, combining partially missing glycans with truncated, galactose-deficient glycans. Intact transferrin mass spectrometry—MALDI-TOF, ESI-MS, ESI-QTOF, or LC-MS—best demonstrates this mixed pattern. Transferrin isoelectric focusing, HPLC, or capillary electrophoresis may screen for carbohydrate-deficient transferrin, but mass spectrometry better resolves the structural signature. (altassan2021internationalconsensusguidelines pages 10-12)

Additional tests include fasting and illness glucose, insulin during hypoglycemia, AST/ALT, bilirubin, CK, lactate as indicated, PT/INR, antithrombin III and other coagulation factors, endocrine/growth evaluation, ECG, echocardiography, and cardiac MRI when clinically appropriate. Liver imaging can identify steatosis or hepatomegaly; muscle/liver biopsy is generally unnecessary if biochemical and molecular testing are diagnostic.

PGM1 enzyme activity in fibroblasts or leukocytes is usually 0–20% of control. It is supportive but not independently definitive. Mild galactose-1-phosphate elevation may occur even before treatment and is useful for safety monitoring. (altassan2021internationalconsensusguidelines pages 10-12)

Molecular confirmation

Recommended confirmation is identification of two pathogenic/likely pathogenic PGM1 variants with phase established when possible. Approaches include:

targeted PGM1 sequencing plus deletion/duplication analysis when suspicion is high;
CDG, hypoglycemia, glycogen-storage, metabolic-myopathy, or cardiomyopathy panels including PGM1;
WES or WGS for atypical or unresolved cases.

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless another diagnosis is suspected. RNA sequencing may help resolve splice variants, but it is not routine. (altassan2021internationalconsensusguidelines pages 10-12)

Differential diagnosis and screening

Differentials include other CDGs, hepatic glycogen-storage diseases, fatty-acid oxidation disorders, disorders of gluconeogenesis, primary hyperinsulinism, metabolic myopathies, fatty-acid oxidation defects causing rhabdomyolysis, and genetic cardiomyopathies. The mixed transferrin pattern plus PGM1 variants distinguishes PGM1-CDG.

There is no established population newborn-screening program. Genomic newborn screening may incidentally detect PGM1 variants, but clinical utility and confirmatory pathways require validation. Cascade testing, carrier testing, prenatal diagnosis, and preimplantation genetic testing are available when familial variants are known. (altassan2021internationalconsensusguidelines pages 13-15)

11. Outcomes and prognosis

No reliable five- or ten-year survival curve, population mortality rate, or life-expectancy estimate exists. Prognosis is driven chiefly by cardiac involvement, severity of hypoglycemia, recurrent rhabdomyolysis, and treatment access. In the consensus literature, cardiac complications caused six reported deaths; dilated cardiomyopathy may progress to arrest, heart failure, transplantation, or sudden death. (altassan2021internationalconsensusguidelines pages 4-6, altassan2021internationalconsensusguidelines pages 6-7)

Noncardiac biochemical abnormalities often improve with galactose, supporting meaningful recovery potential for hypoglycemia, liver dysfunction, coagulation abnormalities, and some muscle manifestations. Congenital malformations and established developmental disability do not reverse biochemically. Persistent or progressive cardiomyopathy despite galactose is the major adverse prognostic feature. Formal prognostic models and validated biomarkers predicting cardiac progression are unavailable.

12. Treatment

D-galactose

Oral D-galactose is the principal disease-directed treatment. It replenishes UDP-galactose/UDP-glucose pools through the Leloir pathway and improves glycan completion. Suggested chemical annotation: D-galactose, with the current CHEBI identifier to be verified before database loading. Suggested NCIt intervention concepts are dietary supplementation, carbohydrate supplementation, and oral therapy.

A commonly used target is approximately 1 g/kg/day, with reported ranges of 500–2,500 mg/kg/day, divided into as many as six doses, and a maximum of 50 g/day. Consensus recommendations describe gradual titration, particularly in infants. Dosing must be individualized with metabolic-specialist and dietitian oversight because very high intake may increase galactose-1-phosphate and galactitol. (boyer2022nutritioninterventionsin pages 30-30, altassan2021internationalconsensusguidelines pages 13-15)

The 2023 five-patient series found clinical improvement in four; transferrin glycosylation, transaminases, and coagulation factors improved or normalized in three; CK improved in two; and hypoglycemia resolved in two. One patient stopped treatment because of urinary frequency and absent benefit; another continued to have rhabdomyolysis and tachycardia. Cardiac function did not improve in the three patients with baseline dysfunction. (radenkovic2023novelinsightsinto pages 1-2)

Monitoring should include symptoms and growth, glucose, ALT/AST, CK, coagulation factors including antithrombin III, intact transferrin or N-glycan analysis, serum galactose-1-phosphate, and urine galactitol. Six-month monitoring is suggested once stable, with closer evaluation during initiation or dose changes. (boyer2022nutritioninterventionsin pages 30-30, altassan2021internationalconsensusguidelines pages 13-15)

Supportive and organ-directed care

Avoid prolonged fasting; use regular complex carbohydrates and an illness/emergency feeding plan.
Treat acute hypoglycemia promptly with glucose.
Individualize exercise; institute hydration and rhabdomyolysis protocols.
Standard cardiomyopathy therapy and rhythm surveillance; transplantation may be required.
Manage cleft palate/Pierre Robin sequence through craniofacial, airway, feeding, dental, and speech teams.
Treat endocrine deficiencies according to standard practice.
Use PT/OT, speech/feeding therapy, and educational support when indicated.
Review bleeding and thrombosis risk before surgery; avoid alcohol because of hepatic/metabolic vulnerability. (boyer2022nutritioninterventionsin pages 30-30, altassan2021internationalconsensusguidelines pages 1-3)

No PGM1-specific pharmacogenomic guideline, approved RNA therapy, cell therapy, or genome-editing treatment exists.

Trials and experimental therapy

NCT03404856 evaluated oral ORL-1G D-galactose in a Phase 1/2, single-group pediatric study with planned enrollment of five. The primary endpoint was liver-enzyme reduction at three months and the secondary endpoint transferrin-glycosylation improvement by day 30. Its registry information was last verified in January 2019, so its current status and results should not be inferred from the stale “recruiting” record. (NCT03404856 chunk 1)

NCT05402332 is listed as a planned Phase 2b randomized, double-blind, placebo-controlled crossover study of AVTX-801 at 1.5 g/kg/day, maximum 50 g/day, in eight adults already using galactose. The registry gives an estimated start of October 1, 2026 and was status-verified in March 2026; it is therefore a future/planned study, not 2023–2024 clinical evidence. (NCT05402332 chunk 1)

AAV9-PGM1 gene replacement prevented and halted cardiomyopathy progression in a cardiac conditional-knockout mouse. This is compelling preclinical evidence but not yet evidence of safety or efficacy in humans. (balakrishnan2023aavbasedgenetherapy pages 15-16)

13. Prevention

Because the disease is inherited, lifestyle modification cannot prevent occurrence in a person with biallelic pathogenic variants.

Primary genetic prevention: carrier testing, reproductive counseling, prenatal diagnosis, and preimplantation genetic testing for families with known variants.
Secondary prevention: cascade testing of siblings and early biochemical/genetic diagnosis to initiate galactose and surveillance before irreversible complications.
Tertiary prevention: fasting avoidance, illness plans, metabolic monitoring, rhabdomyolysis precautions, coagulation assessment, and regular ECG/echocardiography to reduce secondary injury.

No vaccine, antimicrobial prophylaxis, sanitation measure, toxin avoidance program, or population screening recommendation is disease-specific. Each full sibling should be evaluated promptly because apparently asymptomatic relatives may have mild or late-onset disease.

14. Other species and natural disease

No well-established naturally occurring veterinary PGM1-CDG syndrome or breed predisposition was identified. PGM enzymes and central glucose/glycogen pathways are evolutionarily conserved, which supports comparative modeling, but experimentally engineered disease should not be labeled natural animal disease.

There is no transmission, zoonotic potential, or cross-species infectious susceptibility. Relevant experimental taxonomy includes Mus musculus (NCBI Taxonomy 10090). The human taxon is Homo sapiens (9606). Exact mouse orthology nomenclature is potentially confusing in this literature: some publications refer to the functional mouse ortholog as Pgm2, whereas the 2023 C2C12 work uses updated Pgm1 nomenclature. Database implementation should reconcile symbols against the current MGI/NCBI Gene release. (conte2023invitroskeletal pages 1-2, balakrishnan2019anovelphosphoglucomutase‐deficient pages 1-3)

15. Model organisms and experimental systems

Constitutive mouse model

CRISPR-generated homozygous constitutive knockout caused death before embryonic day 9.5: no homozygous live births occurred among 78 pups. Heterozygotes had reduced enzyme activity and abnormal serum glycosylation resembling human disease. This model demonstrates developmental essentiality but is too severe for postnatal natural-history or treatment studies. (balakrishnan2019anovelphosphoglucomutase‐deficient pages 1-3)

Cardiac conditional mouse model

A tamoxifen-inducible, cardiomyocyte-specific Pgm2 knockout recapitulates human dilated cardiomyopathy, including ventricular dilation, reduced ejection fraction, glycogen accumulation, fibrosis, Z-disk abnormalities, mitochondrial injury, and altered sarcolemmal glycoproteins. Its principal application is cardiac mechanism and therapy testing. Its limitation is that it does not model congenital craniofacial, hepatic, endocrine, or systemic disease. (balakrishnan2023aavbasedgenetherapy pages 13-15, balakrishnan2023aavbasedgenetherapy pages 1-3)

Skeletal-muscle cellular model

CRISPR Pgm1-knockout C2C12 myoblasts/myotubes model impaired differentiation, mitochondrial respiration, ATP generation, and metabolic flexibility. They are useful for flux analysis and muscle-directed therapy screening but cannot reproduce whole-body fasting physiology, liver-derived glycoproteins, immune/hemostatic effects, or human cardiac disease. (conte2023invitroskeletal pages 15-16, conte2023invitroskeletal pages 1-2)

Human pluripotent-stem-cell work

Patient-derived induced pluripotent stem cells have been used for stable-isotope tracing of nucleotide-sugar metabolism. This platform is relevant for tissue differentiation and personalized metabolic studies, but the retrieved evidence does not yet establish a validated organoid or mature multi-organ PGM1-CDG model.

Recent developments and expert interpretation

The most important 2023 advance was the convergence of clinical and mechanistic evidence showing that galactose-responsive glycosylation abnormalities and galactose-resistant cardiac/muscle energetics are separable therapeutic problems. The 2023 case series documented meaningful but heterogeneous noncardiac responses and persistent cardiac dysfunction. In parallel, skeletal-muscle studies demonstrated failure of galactose to restore mitochondrial ATP production, while cardiac multi-omics implicated mitochondrial dysfunction and hypoglycosylation of laminin/sarcolemmal proteins. AAV9-PGM1 rescue of murine cardiomyopathy provides a rational route toward organ-directed gene replacement. (radenkovic2023novelinsightsinto pages 1-2, conte2023invitroskeletal pages 15-16, balakrishnan2023aavbasedgenetherapy pages 13-15, balakrishnan2023aavbasedgenetherapy pages 15-16)

The consensus expert position remains that early diagnosis and D-galactose treatment are warranted, but treatment should not create false reassurance about cardiac risk. Lifelong cardiac surveillance is necessary even when transferrin glycosylation, liver tests, coagulation, or glucose control improve. (radenkovic2023novelinsightsinto pages 2-3, altassan2021internationalconsensusguidelines pages 13-15)

Selected exact abstract quotations

International guideline: “Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement.” (Altassan et al., September 2021; https://doi.org/10.1002/jimd.12286). (altassan2021internationalconsensusguidelines pages 1-3)
2023 clinical series: “D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients.” (Radenkovic et al., January 2023; https://doi.org/10.1177/26330040221150269). (radenkovic2023novelinsightsinto pages 1-2)
2023 muscle model: “No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts.” (Conte et al., May 2023; https://doi.org/10.3390/ijms24098247). (conte2023invitroskeletal pages 1-2)

Evidence limitations

PGM1-CDG remains an ultra-rare disorder with small, partly overlapping cohorts. Many published frequencies are counts of reported patients rather than unbiased population estimates. Natural-history, quality-of-life, survival, penetrance, carrier-frequency, modifier-gene, and genotype–phenotype data remain insufficient. D-galactose evidence is based mainly on observational treatment, small case series, biochemical endpoints, and expert consensus rather than large randomized trials. The gene-therapy evidence is preclinical. PMID values and ontology accession numbers not explicitly verified in the retrieved sources have deliberately not been invented; DOI URLs are supplied for source resolution.

References

(altassan2021internationalconsensusguidelines pages 10-12): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(radenkovic2023novelinsightsinto pages 2-3): Silvia Radenkovic, Christin Johnsen, Andreas Schulze, Gurnoor Lail, Laura Guilder, Kaitlin Schwartz, Matthew Schultz, Saadet Mercimek-Andrews, Suzanne Boyer, and Eva Morava. Novel insights into the phenotype and long-term d-gal treatment in pgm1-cdg: a case series. Therapeutic Advances in Rare Disease, Jan 2023. URL: https://doi.org/10.1177/26330040221150269, doi:10.1177/26330040221150269. This article has 11 citations.
(altassan2021internationalconsensusguidelines pages 1-3): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(altassan2021internationalconsensusguidelines pages 3-4): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(altassan2021internationalconsensusguidelines pages 4-6): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(altassan2021internationalconsensusguidelines pages 6-7): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(radenkovic2023novelinsightsinto pages 1-2): Silvia Radenkovic, Christin Johnsen, Andreas Schulze, Gurnoor Lail, Laura Guilder, Kaitlin Schwartz, Matthew Schultz, Saadet Mercimek-Andrews, Suzanne Boyer, and Eva Morava. Novel insights into the phenotype and long-term d-gal treatment in pgm1-cdg: a case series. Therapeutic Advances in Rare Disease, Jan 2023. URL: https://doi.org/10.1177/26330040221150269, doi:10.1177/26330040221150269. This article has 11 citations.
(radenkovic2023novelinsightsinto pages 5-6): Silvia Radenkovic, Christin Johnsen, Andreas Schulze, Gurnoor Lail, Laura Guilder, Kaitlin Schwartz, Matthew Schultz, Saadet Mercimek-Andrews, Suzanne Boyer, and Eva Morava. Novel insights into the phenotype and long-term d-gal treatment in pgm1-cdg: a case series. Therapeutic Advances in Rare Disease, Jan 2023. URL: https://doi.org/10.1177/26330040221150269, doi:10.1177/26330040221150269. This article has 11 citations.
(boyer2022nutritioninterventionsin pages 30-30): Suzanne W. Boyer, Christin Johnsen, and Eva Morava. Nutrition interventions in congenital disorders of glycosylation. Jun 2022. URL: https://doi.org/10.1016/j.molmed.2022.04.003, doi:10.1016/j.molmed.2022.04.003. This article has 44 citations and is from a domain leading peer-reviewed journal.
(altassan2021internationalconsensusguidelines pages 13-15): Ruqaiah Altassan, Silvia Radenkovic, Andrew C. Edmondson, Rita Barone, Sandra Brasil, Anna Cechova, David Coman, Sarah Donoghue, Kristina Falkenstein, Vanessa Ferreira, Carlos Ferreira, Agata Fiumara, Rita Francisco, Hudson Freeze, Stephanie Grunewald, Tomas Honzik, Jaak Jaeken, Donna Krasnewich, Christina Lam, Joy Lee, Dirk Lefeber, Dorinda Marques‐da‐Silva, Carlota Pascoal, Dulce Quelhas, Kimiyo M. Raymond, Daisy Rymen, Malgorzata Seroczynska, Mercedes Serrano, Jolanta Sykut‐Cegielska, Christian Thiel, Frederic Tort, Mari‐Anne Vals, Paula Videira, Nicol Voermans, Peter Witters, and Eva Morava. International consensus guidelines for phosphoglucomutase 1 deficiency (pgm1‐cdg): diagnosis, follow‐up, and management. Journal of Inherited Metabolic Disease, 44:148-163, Sep 2021. URL: https://doi.org/10.1002/jimd.12286, doi:10.1002/jimd.12286. This article has 86 citations and is from a peer-reviewed journal.
(conte2023invitroskeletal pages 15-16): Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G. P. van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P. Mahalleh-Yousefi, Merel A. Post, Karin Huijben, Daan M. Panneman, Richard J. T. Rodenburg, Nicol C. Voermans, Alejandro Garanto, Werner J. H. Koopman, Hans J. C. T. Wessels, Marek J. Noga, and Dirk J. Lefeber. In vitro skeletal muscle model of pgm1 deficiency reveals altered energy homeostasis. International Journal of Molecular Sciences, 24:8247, May 2023. URL: https://doi.org/10.3390/ijms24098247, doi:10.3390/ijms24098247. This article has 16 citations.
(conte2023invitroskeletal pages 1-2): Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G. P. van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P. Mahalleh-Yousefi, Merel A. Post, Karin Huijben, Daan M. Panneman, Richard J. T. Rodenburg, Nicol C. Voermans, Alejandro Garanto, Werner J. H. Koopman, Hans J. C. T. Wessels, Marek J. Noga, and Dirk J. Lefeber. In vitro skeletal muscle model of pgm1 deficiency reveals altered energy homeostasis. International Journal of Molecular Sciences, 24:8247, May 2023. URL: https://doi.org/10.3390/ijms24098247, doi:10.3390/ijms24098247. This article has 16 citations.
(balakrishnan2019anovelphosphoglucomutase‐deficient pages 1-3): Bijina Balakrishnan, Jan Verheijen, Arielle Lupo, Kimiyo Raymond, Coleman Turgeon, Yueqin Yang, Kandis L. Carter, Kevin J. Whitehead, Tamas Kozicz, Eva Morava, and Kent Lai. A novel phosphoglucomutase‐deficient mouse model reveals aberrant glycosylation and early embryonic lethality. Journal of Inherited Metabolic Disease, 42:1007-998, Jun 2019. URL: https://doi.org/10.1002/jimd.12110, doi:10.1002/jimd.12110. This article has 26 citations and is from a peer-reviewed journal.
(balakrishnan2023aavbasedgenetherapy pages 13-15): Bijina Balakrishnan, Ruqaiah Altassan, Rohit Budhraja, Willisa Liou, Arielle Lupo, Sarah Bryant, Anastasiya Mankouski, Silvia Radenkovic, Graeme J. Preston, Akhilesh Pandey, Sihem Boudina, Tamas Kozicz, Eva Morava, and Kent Lai. Aav-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (pgm1-cdg). Jul 2023. URL: https://doi.org/10.1016/j.trsl.2023.01.004, doi:10.1016/j.trsl.2023.01.004. This article has 27 citations and is from a domain leading peer-reviewed journal.
(balakrishnan2023aavbasedgenetherapy pages 10-12): Bijina Balakrishnan, Ruqaiah Altassan, Rohit Budhraja, Willisa Liou, Arielle Lupo, Sarah Bryant, Anastasiya Mankouski, Silvia Radenkovic, Graeme J. Preston, Akhilesh Pandey, Sihem Boudina, Tamas Kozicz, Eva Morava, and Kent Lai. Aav-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (pgm1-cdg). Jul 2023. URL: https://doi.org/10.1016/j.trsl.2023.01.004, doi:10.1016/j.trsl.2023.01.004. This article has 27 citations and is from a domain leading peer-reviewed journal.
(balakrishnan2023aavbasedgenetherapy pages 1-3): Bijina Balakrishnan, Ruqaiah Altassan, Rohit Budhraja, Willisa Liou, Arielle Lupo, Sarah Bryant, Anastasiya Mankouski, Silvia Radenkovic, Graeme J. Preston, Akhilesh Pandey, Sihem Boudina, Tamas Kozicz, Eva Morava, and Kent Lai. Aav-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (pgm1-cdg). Jul 2023. URL: https://doi.org/10.1016/j.trsl.2023.01.004, doi:10.1016/j.trsl.2023.01.004. This article has 27 citations and is from a domain leading peer-reviewed journal.
(balakrishnan2023aavbasedgenetherapy pages 15-16): Bijina Balakrishnan, Ruqaiah Altassan, Rohit Budhraja, Willisa Liou, Arielle Lupo, Sarah Bryant, Anastasiya Mankouski, Silvia Radenkovic, Graeme J. Preston, Akhilesh Pandey, Sihem Boudina, Tamas Kozicz, Eva Morava, and Kent Lai. Aav-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (pgm1-cdg). Jul 2023. URL: https://doi.org/10.1016/j.trsl.2023.01.004, doi:10.1016/j.trsl.2023.01.004. This article has 27 citations and is from a domain leading peer-reviewed journal.
(balakrishnan2023aavbasedgenetherapy pages 3-4): Bijina Balakrishnan, Ruqaiah Altassan, Rohit Budhraja, Willisa Liou, Arielle Lupo, Sarah Bryant, Anastasiya Mankouski, Silvia Radenkovic, Graeme J. Preston, Akhilesh Pandey, Sihem Boudina, Tamas Kozicz, Eva Morava, and Kent Lai. Aav-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase 1 deficiency (pgm1-cdg). Jul 2023. URL: https://doi.org/10.1016/j.trsl.2023.01.004, doi:10.1016/j.trsl.2023.01.004. This article has 27 citations and is from a domain leading peer-reviewed journal.
(NCT03404856 chunk 1): Study of ORL-1G (D-galactose) in Patients With Glycogen Storage Disease Type 14. Orpha Labs. 2017. ClinicalTrials.gov Identifier: NCT03404856
(NCT05402332 chunk 1): Eva Morava-Kozicz. Evaluating the Efficacy and Safety of D-galactose in PGM1-CDG (AVTX-801). Eva Morava-Kozicz. 2026. ClinicalTrials.gov Identifier: NCT05402332

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Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

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References & Deep Research

References

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PGM1-Congenital Disorder of Glycosylation: Disease-Characteristics Report

Executive summary

1. Disease information

Definition and classification

2. Etiology, risks, protective factors, and gene–environment interaction

Primary cause

Risk and protective factors

3. Phenotypes

Core phenotype spectrum

Severity, progression, and quality of life

4. Genetic and molecular information

Gene and protein

Variants and modifiers

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Causal chain

Cell and tissue mechanisms

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and biochemical testing

Molecular confirmation

Differential diagnosis and screening

11. Outcomes and prognosis

12. Treatment

D-galactose

Supportive and organ-directed care

Trials and experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Constitutive mouse model

Cardiac conditional mouse model

Skeletal-muscle cellular model

Human pluripotent-stem-cell work

Recent developments and expert interpretation

Selected exact abstract quotations

Evidence limitations

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