Cytosolic Phosphoenolpyruvate Carboxykinase (PEPCK-C) Deficiency (PCK1)

Scope and verification. I fetched and read two papers in full (Burg 2024, PMID 40092582; Vasiļevska 2026, PMID 41608521). The other claims rest on search-result summaries or on the reference list of Burg 2024. Items marked [unverified] come from my background knowledge, or from sources I did not open, and need checking before they go into the KB. Every PMID was read from a fetched source, and none was typed from memory. Only abstract-level quotes were available, so snippets need re-verification with just fetch-reference.

1. Disease information

• Overview. The paper's abstract calls it "a rare autosomal recessive gluconeogenesis disorder caused by variants in the PCK1 gene" (Vasiļevska 2026, PMID 41608521). Typical findings are fasting hypoglycemia, lactic acidosis, and urinary excretion of TCA-cycle intermediates, particularly fumarate. Presentation ranges from the neonatal period, through the first acute illness of infancy, to stress later in life. (PhenoDis summary, PMC11910243)
• Identifiers.
• OMIM 261680 is confirmed by search results.
• MONDO:0009866 comes from the task template. I did not verify it against MONDO.
• Orphanet numbers conflict between sources: PhenoDis lists 79316, ClinVar lists 2880, and PhenoDis also gives 2880 for the broader PEPCK deficiency category. Check Orphanet directly. If it is cited as ORPHA:, fetch the record with just fetch-reference.
• Gene: PCK1 at 20q13.31, HGNC symbol PCK1. In KB form the CURIE would be hgnc:<n>, which I did not look up. (MedGen)
• Synonyms. PEPCK-C deficiency, PEPCK1 deficiency, cytosolic PEPCK deficiency, PCKDC. Also called phosphoenolpyruvate carboxykinase 1 deficiency (soluble).
• Data source. The data are disease-level aggregated case reports, not EHR-derived.

2. Etiology

• Cause. Biallelic loss-of-function variants in PCK1 cause the disease. There is no known environmental cause.
• Genetic risk factors. None beyond biallelic PCK1 variants. Modifier genes have not been identified. Siblings with identical genotypes differ in severity (Vasiļevska 2026).
• Environmental triggers of decompensation. These are triggers, not causes:
• prolonged fasting;
• febrile or infectious illness with reduced intake, including gastroenteritis;
• exercise or other periods of increased energy need.
• Sources: PMID 41608521; AJCR case (amjcaserep.com/abstract/full/idArt/943118), where all four hypoglycemic decompensations were infection-triggered.
• Protective factors and gene–environment interaction. No data. The one gene-environment link is that a catabolic or fasting state exposes the gluconeogenic block. Carbohydrate supplementation mitigates it.

3. Phenotypes

Frequencies are not quantified in the literature I read. The systematic review cited by Vasiļevska counted 32 individuals. It reports a mean age at first manifestation of 2.6 years (range 0.5–13), with neonatal hypoglycemia being typical.

• Variability. The OJRD summary says some patients have hypoglycemia with normal development, while others develop liver failure, hyperammonemia and encephalopathy. Phenotypes differ even between relatives, and the authors suggest this may mean the disease is underdiagnosed.
• Quality of life. No data.

4. Genetic and molecular information

• Gene and inheritance. PCK1 encodes cytosolic PEPCK (EC 4.1.1.32). Inheritance is autosomal recessive, and the parents in Burg 2024 were heterozygous carriers.
• Variant spectrum. Burg 2024 states that fewer than 30 patients and six mutations had been reported, all missense or splice, before the first homozygous frameshift.

• Functional consequence. Loss of function. In Burg 2024's words, "PEPCK-1 loss of function impedes cytosolic gluconeogenesis".
• Not found. I found no allele-frequency data (gnomAD), no epigenetic findings, no chromosomal abnormalities, and no ClinGen gene-disease validity record. Run just check-gene-validity and check CGGV: records before asserting a tier.
• Variant origin. Germline.

5. Environmental information

Triggers are fasting, intercurrent infection, and exertion (see section 2). There are no toxins, lifestyle causes, or infectious agents. No infectious_agent or exposure-term binding is warranted. Any environmental entry would be limited to fasting or infection as a trigger, and it should be tied to a decompensation node.

6. Mechanism and pathophysiology

Causal chain

1. Biallelic PCK1 loss-of-function variants reduce cytosolic PEPCK (PEPCK-C) activity. This is demonstrated for p.Gly309Arg in cells (Vieira 2017). For other alleles it is inferred.
2. PEPCK-C normally converts oxaloacetate to phosphoenolpyruvate, a rate-limiting gluconeogenic step in liver and kidney. Its loss "impedes cytosolic gluconeogenesis" (Burg 2024).
3. During fasting or illness, glycogen runs out and gluconeogenesis cannot compensate. The result is fasting or illness-triggered hypoglycemia.
4. A proximal gluconeogenic block would be expected to cause lactate accumulation (lactate and alanine feed gluconeogenesis) and to lead to ketosis through lipolysis. Ketotic and lactic acidosis were observed (Burg 2024). The causal link to the block is inferred.
5. TCA intermediates such as fumarate, along with glutaric and α-hydroxyglutaric acids, accumulate and are excreted in urine (observed; the mechanism is not demonstrated).
6. Hepatic injury and steatosis follow. The proposed drivers are energy failure and altered substrate flux during decompensation. This is inferred.
7. Extreme hyperferritinemia was seen in the neonate. The authors only hypothesize iron–glucose cross-talk.
8. Neuroglycopenia can cause seizures, cerebral edema and death (Becker 2021).

Branch or modifier. Mitochondrial PEPCK2 is "thought to be partially replaced by the mitochondrial isoenzyme" (Burg 2024). This is a hypothesis. It could explain why many patients are mild or asymptomatic between insults. I did not find evidence on what determines severity.

Other categories. I found no data on immune involvement, tissue-specific transcriptomics, proteomics, single-cell work, or CRISPR screens.

Suggested ontology terms (to be looked up, not copied). - GO: - gluconeogenesis (GO:0006094); - phosphoenolpyruvate carboxykinase (GTP) activity (GO:0004613); - cytosol (GO:0005829). - CL: hepatocyte (CL:0000182), renal proximal tubule epithelial cell.

7. Anatomical structures

• Primary tissues. Liver and kidney, the gluconeogenic organs. The affected organs are inferred from enzyme biology. Direct tissue enzyme assays were not in my sources.
• Secondary involvement. Brain (hypoglycemic seizures and edema), and kidney (transient injury in the Vasiļevska proband).
• Subcellular. Cytosol.
• UBERON. liver (UBERON:0002107), kidney (UBERON:0002113).
• Lateralization. Not applicable.

8. Temporal development

• Onset. Neonatal to childhood. The mean age at first manifestation is 2.6 years, range 0.5–13 (Vasiļevska 2026, citing the systematic review). Neonatal hypoglycemia is typical.
• Course. Episodic, with decompensations at times of fasting or infection and well-being in between. Burg 2024's patient had a neonatal ALF episode, a decompensation at 7 months, and was stable at 15 months apart from one hypoglycemic episode.
• Remission. Episodes resolve with glucose. Neonatal liver failure and ferritin resolved in Burg 2024. The ALF was reversible with continuous glucose in Vasiļevska 2026.
• Critical periods. Intercurrent illness is the window of vulnerability.
• Stages. None defined.

9. Inheritance and population

• Prevalence. Not established. "Fewer than 30" patients were reported before 2024. A review of 32 individuals is cited in Vasiļevska 2026. This is a case count, so use CASES_IN_LITERATURE and do not give a rate.
• Inheritance. Autosomal recessive (HP:0000007). The Burg 2024 parents were heterozygous carriers.
• Penetrance and expressivity. Expressivity is highly variable. Two sisters in Vasiļevska 2026 share the same compound heterozygous genotype, but one had acute liver failure and the other was asymptomatic.
• Founder effects and geography. The p.Gly309Arg allele is reported in 84% of patients. Whether this is a founder effect is not stated in what I read. I did not find sex ratio, carrier frequency, or consanguinity data.

10. Diagnostics

• Laboratory.
• Critical-sample glucose, lactate, ketones, ammonia, transaminases and coagulation tests.
• Urine organic acids: fumarate and other TCA intermediates, dicarboxylic acids.
• Amino acids: glutamine, glutamate, aspartate.
• Ferritin, which was extreme in the neonate.
• LOINC codes should be seeded with just loinc-seed-cache, never typed.
• Imaging. Liver ultrasound can show fatty infiltration or increased echogenicity.
• Genetic testing. Exome sequencing made the diagnosis in Burg 2024, which calls the diagnosis "nearly impossible to diagnose at the pre-exome sequencing era." A gene panel or single-gene PCK1 sequencing is reasonable. The Vasiļevska siblings also had segregation analysis.
• Enzyme assay and biopsy. I found no information in my sources. The 2026 proband was not biopsied.
• Differential diagnosis. Other causes of ketotic or lactic hypoglycemia:
• glycogen storage disease type I;
• fructose-1,6-bisphosphatase deficiency;
• pyruvate carboxylase deficiency;
• fatty acid oxidation disorders;
• hyperinsulinism.
• Causes of neonatal liver failure with hyperferritinemia (neonatal hemochromatosis was initially suspected in Burg 2024). [unverified] as a distinguishing list, because it is from my background knowledge.
• Screening. No newborn screening program is described in the sources. The Burg 2024 family was offered prenatal diagnosis or PGT but did not pursue them, and a later daughter tested negative.

11. Outcome and prognosis

• Survival. There are no systematic data. Outcomes range from asymptomatic to fatal.
• A hypoglycemia-induced seizure with cerebral edema and death in a 3-year-old (Becker 2021).
• Reversible ALF in Burg 2024 and Vasiļevska 2026.
• Morbidity. Growth impairment, mild motor delay and recurrent decompensations in individual cases. The 2026 authors note that no follow-up guidelines exist.
• Prognostic factors. Not established.

12. Treatment

• Core management.
• Avoid fasting.
• Provide extra carbohydrate during illness, exercise, or other increased energy demand (PMC12834696).
• Give IV dextrose or glucose at decompensation (Burg 2024). Continuous 5% glucose infusion reversed the ALF in Vasiļevska 2026.
• Night-time glucose monitoring was recommended in Burg 2024.
• The 2026 sisters are advised to limit sugar intake and avoid rapidly absorbed sugars. This runs partly against the extra-carbohydrate advice, so treat it as one group's practice.
• KB mapping.
• Dietary intervention, NCIT:C15447 (BEHAVIORAL).
• Glucose infusion: Pharmacotherapy, NCIT:C15986, with CHEBI glucose as therapeutic_agent.
• Verify all CURIEs by lookup.
• Other options.
• Liver transplant was considered, and the proband was transferred for evaluation, but she recovered without it.
• IVIg was given empirically in Burg 2024 for suspected neonatal hemochromatosis. It is not a disease-specific treatment.
• I found no gene therapy, enzyme replacement, or clinical trials (a ClinicalTrials.gov search was not run).
• Pharmacogenomics: not applicable.

13. Prevention

• Primary and secondary. Genetic counseling, cascade testing of siblings, and prenatal diagnosis or PGT (offered in Burg 2024). Carrier screening is not described.
• Tertiary. Fasting avoidance, an emergency glucose plan for illness, and monitoring.
• Immunization. Standard vaccination to reduce infectious triggers is a reasonable inference. I found no direct statement in my sources.

14. Other species and natural disease

I found no OMIA entry or veterinary reports. Searching OMIA for PCK1 is a gap.

15. Model organisms

My searches did not retrieve a source on animal models, and Burg 2024 explicitly does not mention one. The following is from my background knowledge only and is [unverified]:

• A global Pck1 knockout mouse reportedly dies in the first days of life with severe hypoglycemia, and liver-specific knockouts retain fasting glucose through other gluconeogenic tissues.
• Before using this in the KB, confirm the primary papers and the MGI record, and take PMIDs from a fetched record. Do not use this paragraph as evidence.
• Likely animal_models: fields: species Mus musculus (NCBITaxon:10090), a modeled_mechanisms link to the gluconeogenesis node, and a fidelity rating.

Curation notes

• Evidence. Candidate sources, with PMIDs from Burg 2024's reference list, which I did not independently fetch:

• I did not locate the AJCR case's PMID or year. Fetch it before citing.
• Hommes 1976 may be the first-case description. This is unconfirmed.
• Santra is dated 2016 in that reference list, not 2019.
• All snippets above come from abstracts or summaries. Rerun just count-verified-snippets before use.
• Stub and MONDO check. Confirm that MONDO:0009866 matches the entry name and disease_term before drafting.
• Gaps to fill. The mouse model, the true Orphanet ID, ClinGen validity, a full-text review of phenotype frequencies (the 32-patient systematic review, which I did not read), and HPO and LOINC lookups.

Sources

• Burg et al. 2024, Mol Genet Metab Rep, PMID 40092582
• Vasiļevska et al. 2026, JIMD Rep, PMID 41608521
• Am J Case Rep, article 943118
• Vieira 2017 (Centogene-hosted PDF)
• OJRD article s13023-023-02946-5
• PhenoDis
• MedGen

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• HP:0033360 (1 mention) - the report calls it "Hyperglutaminemia"; HP calls it Impaired ability to shift attention
• NCIT:C15447 (1 mention) - the report calls it "BEHAVIORAL"; NCIT calls it Dietary Intervention
• NCBITaxon:10090 (1 mention) - the report calls it "Likely animal_models: fields: species Mus musculus"; NCBITaxon calls it Mus musculus

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:0002910 (1 mention) - the report calls it "Elevated hepatic transaminase"; HP calls it Elevated circulating hepatic transaminase concentration, and lists "Elevated transaminases" among its other names
• HP:0003281 (1 mention) - the report calls it "Hyperferritinemia"; HP calls it Increased circulating ferritin concentration, and lists "Hyperferritinemia" among its other names
• CL:0000182 (1 mention) - the report calls it "CL: hepatocyte"; CL calls it hepatocyte