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.

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

1. Upstream genetic lesion: biallelic PGM1 loss-of-function variants.
2. Primary biochemical defect: reduced conversion between glucose-1-phosphate and glucose-6-phosphate.
3. Metabolic consequences: impaired glycogen synthesis and glycogenolysis, reduced access of glycogen-derived carbon to glycolysis, and impaired energetic flexibility during fasting or exercise.
4. 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.
5. 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.
6. 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:

1. targeted PGM1 sequencing plus deletion/duplication analysis when suspicion is high;
2. CDG, hypoglycemia, glycogen-storage, metabolic-myopathy, or cardiomyopathy panels including PGM1;
3. 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

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2. (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.

3. (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.

4. (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.

5. (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.

6. (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.

7. (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.

8. (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.

9. (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.

10. (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.

11. (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.

12. (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.

13. (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.

14. (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.

15. (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.

16. (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.

17. (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.

18. (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.

19. (NCT03404856 chunk 1): Study of ORL-1G (D-galactose) in Patients With Glycogen Storage Disease Type 14. Orpha Labs. 2017. ClinicalTrials.gov Identifier: NCT03404856

20. (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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