GYG1-Related Disorder of Glycogen Metabolism (Glycogen Storage Disease XV, glycogenin-1 deficiency): research report

Method and limits. I ran three web searches only, so this is not an exhaustive review. Items marked [verified] were seen in those results. Items marked [unverified] come from my background knowledge. Check those, especially PMIDs, MONDO and HPO IDs, and all numeric frequencies, with just fetch-reference and just validate-terms before using them in the KB. Per the repo rules, none of the CURIEs below were looked up in a cache, so treat them as leads and not as bindings.

Searches that returned too little or nothing. Prevalence and incidence, newborn screening, treatment trials and NCT numbers, and OMIA/VBO veterinary data were not searched. Population-specific data, such as the Sardinian cluster, rest on one search snippet.

1. Disease information

• Overview [verified]. Glycogenin-1 deficiency is a rare glycogen storage disorder. Biallelic (homozygous or compound heterozygous) deleterious variants in GYG1 cause either a slowly progressive adult-onset myopathy with polyglucosan storage in muscle fibres, or a cardiomyopathy with little or no skeletal muscle weakness. (Hedberg-Oldfors review/cohort, PMC7046021; PubMed 31628455)
• Identifiers.
• Gene OMIM 603942 (GYG1) [verified]. The OMIM disease entry is "Glycogen storage disease XV" (GSD15); I recall 613507 for the disease entry [unverified].
• MONDO:0100314 is as given in the template and was not checked. KEGG Medicus H01955 appeared in results [verified].
• Orphanet, ICD-10 (E74.0x) and MeSH IDs were not retrieved.
• Synonyms.
• Glycogenin-1 deficiency.
• GSD XV / GSD15.
• Polyglucosan body myopathy type 2 (PGBM2) [unverified].
• Muscle glycogen storage disease associated with glycogenin-1 deficiency.
• Data provenance. The literature is case reports and small cohorts of individual patients. Disease-level resources such as OMIM and Orphanet aggregate these reports. No EHR-derived source was found.

2. Etiology

• Cause. Biallelic loss-of-function or hypomorphic GYG1 variants. Variants that are compatible with expressed protein can nonetheless be harmful, as the p.Asp102His cardiac cases show (see section 4).
• Genetic risk factors. Biallelic GYG1 variants are the only established cause. No modifier genes were identified in the sources I saw.
• Environmental and protective factors, gene-environment interactions. None known.

3. Phenotypes

• Frequency and severity. Frequencies per phenotype were not retrieved. Do not assign percentages without a source.
• Quality of life. No data found.

4. Genetic and molecular information

• Gene. GYG1 (glycogenin-1; HGNC ID not looked up, so verify against cache/hgnc before using the lowercase hgnc: form).
• Index case. Moslemi et al. described a 27-year-old man with muscle weakness and cardiac arrhythmia who was compound heterozygous for a nonsense variant and the missense variant p.Thr83Met. The missense variant abolished glycogenin-1 autoglucosylation, which primes glycogen synthesis (N Engl J Med 2010, PMID:20357282) [verified].
• Cohort. Malfatti and colleagues (Ann Neurol 2014, PMID not confirmed) described 7 unrelated adults with homozygous or compound heterozygous deleterious variants [verified]. Most had no detectable glycogenin-1 in muscle. One had a protein lacking the C-terminus, which normally binds glycogen synthase. The authors concluded that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies the disease.
• Cardiac variant. Three unrelated men with cardiomyopathy were homozygous for p.Asp102His. The mutant protein expressed in heart had lost autoglucosylation (Hedberg-Oldfors et al., PMC4724519 is a likely source; confirm) [verified for the finding; unverified for the citation].
• Variant class. Nonsense, missense, splice and null alleles. Functional consequence is loss of function, or loss of autoglucosylation or glycogen synthase binding.
• Epigenetic and chromosomal data. None.

5. Environmental information

No environmental, lifestyle or infectious factors are known.

6. Mechanism and pathophysiology

Causal chain

1. Biallelic GYG1 variants lead to absent, truncated or catalytically inactive glycogenin-1.
2. Without functional glycogenin-1, the autoglucosylation (self-priming) step of glycogen synthesis is lost. This is demonstrated for p.Thr83Met and p.Asp102His in vitro.
3. Branch point A, skeletal muscle with glycogenin-1 absent: muscle can still make glycogen, because glycogenin-2 or other priming routes compensate. This is inferred from the finding that glycogen synthesis proceeds without glycogenin (PubMed 31628455, "dispensable for glycogen synthesis in human muscle"). The result is focal accumulation of glycogen and polyglucosan, vacuolar myopathy and progressive weakness.
4. Branch point B, heart with a mutant protein that is expressed but inactive: abnormal glycogen is stored, which leads to cardiomyopathy. The proposed explanation is that the expressed mutant protein is deleterious in cardiac tissue, whereas complete absence is better tolerated [verified in the search summary; mechanism is the authors' interpretation].
5. Polyglucosan storage disrupts myofibre architecture and cardiac contractility, leading to the clinical phenotype. This step is inferred.

Suggested terms (to verify) - GO: glycogen biosynthetic process (GO:0005978), glycogenin glucosyltransferase activity (GO:0008466), glycogen metabolic process (GO:0005977). - CL: skeletal muscle fibre (CL:0008002), cardiac muscle cell (CL:0000746). - UBERON: skeletal muscle tissue, heart. - Subcellular: sarcoplasm, subsarcolemmal and intermyofibrillar regions. - Molecular profiling, advanced technologies and immune involvement: nothing found.

7. Anatomical structures affected

• Primary: skeletal muscle, mainly proximal and limb-girdle, and heart.
• Tissue: muscle fibres with vacuoles containing polyglucosan.
• Laterality: presumably bilateral and symmetric. This was not documented in the sources I saw.

8. Temporal development

• Onset: mostly adult onset (5th–6th decade in the Sardinian patients), but cardiac presentations occurred in the 3rd to 6th decade (ages 34–52 in the p.Asp102His men) [verified].
• Progression: slowly progressive myopathy. Cardiac course is variable and can reach severe heart failure [verified].

9. Inheritance and population

• Inheritance: autosomal recessive.
• Founder effects: a cluster of five Sardinian patients was reported [verified; variant not retrieved]. The p.Asp102His recurrence in unrelated men suggests a recurrent or founder allele [inferred].
• Prevalence, incidence, carrier frequency, sex ratio: not found.

10. Diagnostics

• Muscle biopsy: vacuoles with PAS-positive, partly diastase-resistant polyglucosan. Immunohistochemistry or Western blot shows absent or reduced glycogenin-1 in most patients [verified].
• Genetic testing: GYG1 sequencing, or a neuromuscular or cardiomyopathy gene panel or exome.
• Other tests: CK, EMG, cardiac MRI, echocardiography and ECG are reasonable. I did not retrieve specific findings.
• Differential diagnosis: other polyglucosan storage diseases (GBE1-related disease, Pompe disease and other glycogenoses).
• Screening: none established.

11. Outcome and prognosis

Not retrieved. Prognosis is driven by cardiac involvement, which can cause severe cardiac failure [verified]. No survival data found.

12. Treatment

No disease-specific therapy found. Management is supportive: cardiac surveillance and standard heart-failure or arrhythmia care, and physical therapy. No clinical trials were identified, and I did not search ClinicalTrials.gov. Suggested NCIT terms (verify): Supportive Care (NCIT:C15747), Physical Therapy (NCIT:C15302), Pharmacotherapy (NCIT:C15986).

13. Prevention

Genetic counselling for autosomal recessive risk (NCIT:C15240). Cascade testing of relatives and cardiac surveillance of carriers of cardiomyopathy-associated genotypes are reasonable but unsourced here.

14. Other species and natural disease

Not searched. OMIA and VBO have not been checked.

15. Model organisms

• Mouse: a constitutive Gyg knockout (gene-trap) mouse has been reported [verified in search summary; the primary citation was not seen]. About 90% of embryos were lost, but survivors still synthesised glycogen and accumulated high levels of it, especially in skeletal and cardiac muscle. This parallels the human finding that glycogen synthesis continues without glycogenin-1.
• Limits: the high lethality and the glycogen accumulation phenotype are not clearly the same as the adult human myopathy. Other models were not searched.
• Evidence-source tagging: the mouse work should be tagged MODEL_ORGANISM, and the human biopsy and genetic data HUMAN_CLINICAL.

Priority follow-ups before curation

1. Fetch and quote the primary papers: PMID:20357282 (Moslemi 2010), the Malfatti 2014 Ann Neurol paper (find its PMID), PMID:31628455, PMC4724519 and PMC7046021.
2. Check for a GeneReviews chapter with just check-genereviews, and check ClinGen validity with just list-gene-validity.
3. Search for Orphanet prevalence and the HPO annotations for GSD XV.
4. Verify every HPO, GO and CL CURIE above, and replace the phenotype row where I did not give a confident term.

Sources: - PubMed 31628455 - PMC7046021 - PMC4724519 - OMIM *603942 mirror - Institut de Myologie - Reactome R-HSA-3814838 - Malfatti cohort and mouse model (UB repository)

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0003546 (1 mention) - the report calls it "Exercise intolerance / myalgia"; HP calls it Exercise intolerance
• GO:0005978 (1 mention) - the report calls it "GO: glycogen biosynthetic process"; GO calls it glycogen biosynthetic process
• CL:0008002 (1 mention) - the report calls it "CL: skeletal muscle fibre"; CL calls it skeletal muscle fiber

Every term resolved, and every label the report gave matched.