🏷

Classifications

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive HP:0000007

PEPCK-C deficiency is inherited in an autosomal recessive manner; affected individuals carry biallelic pathogenic PCK1 variants.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:37924129 SUPPORT Human clinical

"PEPCK-C deficiency is a rare childhood-onset autosomal recessive metabolic disease caused by PCK1 genetic defects."

States the autosomal recessive mode of inheritance directly.

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Mechanistic Hypotheses

1

Environment rather than genotype determines PEPCK-C deficiency severity

pepckc_genotype_phenotype_environment EMERGING

Evidence balance 1 support

The clinical spectrum of PEPCK-C deficiency ranges from asymptomatic to fatal, and systematic review found no clear genotype-phenotype correlation. The leading interpretation is that environmental (catabolic) exposure, rather than the specific PCK1 genotype, is the main determinant of phenotype.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1."

States the environment-over-genotype interpretation directly.

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Discussions and Knowledge Gaps

1

Does the neonatal-lethal whole-body Pck1 knockout mouse model the viable, episodic, catabolism-triggered human disease, or only its most severe extreme?

HUMAN MODEL MISMATCH OPEN pepckc_mouse_lethality_vs_human_viability

Attached to

pathophysiology#Failure of Hepatic Gluconeogenesis

Whole-body PEPCK-C knockout mice die shortly after birth from profound hypoglycemia, whereas most humans with biallelic PCK1 variants survive and may be asymptomatic between catabolic stressors. The mouse establishes that hepatic gluconeogenesis and hypoglycemia are the critical pathomechanism, but its lethality does not reproduce the human disease's variable, often mild, stress-dependent course, so the translational validity of the model for the human phenotypic spectrum is the open question.

Proposed experiments

Hypomorphic or liver-conditional Pck1 mouse recapitulating partial deficiency

pepckc_hypomorphic_mouse

Generate mice with partial (hypomorphic) or liver-conditional PEPCK-C loss to model the residual activity seen in human missense genotypes, and test whether fasting and intercurrent catabolic challenge reproduce the episodic human phenotype.

Decision criterion

A viable model that decompensates only on catabolic challenge would support using the mouse for the human disease; persistent lethality or absence of a stress-dependent phenotype would bound its translational use.

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Pathophysiology

11

PCK1 Cytosolic PEPCK Deficiency

Biallelic loss-of-function PCK1 variants deplete cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) activity. The enzyme catalyzes the GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, the first committed and rate-limiting cytosolic step of gluconeogenesis. Expression of a mutant allele in COS-1 cells produced an enzyme incapable of normal function, confirming the variants as loss-of-function.

hepatocyte CL:0000182

PCK1 hgnc:8724

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

phosphoenolpyruvate carboxykinase (GTP) activity GO:0004613 ↓ DECREASED

cytosol GO:0005829

Downstream

Failure of Hepatic Gluconeogenesis Loss of the oxaloacetate-to-phosphoenolpyruvate step directly interrupts flux through gluconeogenesis.

Impaired Cataplerosis of Oxaloacetate Because PEPCK-C is the route by which oxaloacetate exits the tricarboxylic acid cycle for glucose synthesis, its loss blocks this cataplerotic drain.

Show evidence (1 reference)

PMID:28216384 SUPPORT In vitro / ex vivo

"The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme."

Functional expression establishes that the PCK1 variant abolishes enzyme function, supporting the DECREASED modifier on PEPCK activity.

Failure of Hepatic Gluconeogenesis

With PEPCK-C absent, the hepatocyte cannot convert lactate, glycerol, and gluconeogenic amino acids into glucose. Glycogenolysis is preserved, so glucose homeostasis is maintained in the fed and early-fasted state; the defect becomes clinically apparent only once glycogen is exhausted and the liver must rely on de novo glucose production.

hepatocyte CL:0000182

gluconeogenesis GO:0006094 ↓ DECREASED glucose homeostasis GO:0042593 ⚠ ABNORMAL

Animal models

Pck1 del/del mouse (whole-body PEPCK-C knockout) Mouse recapitulates Hepatic PEPCK-C loss produces the hypoglycemia of gluconeogenic failure, and liver-specific reexpression rescues it.

Downstream

Fasting Hypoglycemia Once glycogen is depleted, the blocked gluconeogenic pathway cannot sustain blood glucose during fasting.

Lactate Accumulation

Impaired Fasting Ketogenesis

Hepatocellular Metabolic Stress

Chronic Energy Deficit

Show evidence (1 reference)

PMID:27785616 SUPPORT Model organism

"This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice."

Liver-specific reexpression rescuing hypoglycemia identifies hepatic gluconeogenesis as the critical function lost.

Fasting Hypoglycemia

Hypoglycemia develops when gluconeogenic demand exceeds glycogenolytic supply, typically overnight or during intercurrent illness. Episodes most often present in the morning and are precipitated by catabolic stress; neonatal onset also occurs.

glucose homeostasis GO:0042593 ⚠ ABNORMAL

Downstream

Recurrent hypoglycemia

Neonatal hypoglycemia

Neuroglycopenic Brain Injury Severe or prolonged hypoglycemia deprives the brain of its principal fuel.

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"The hypoglycemic episodes manifested predominantly in the morning."

Describes the fasting (overnight) timing of the hypoglycemic episodes.

Neuroglycopenic Brain Injury

Insufficient cerebral glucose, compounded by inadequate ketone body production, produces acute neuronal energy failure. In severe cases this manifests as hypoglycemic seizures, acute encephalopathy, cerebral edema, neuroregression, and death.

Downstream

Hypoglycemic seizures

Acute encephalopathy

Cerebral edema

Global developmental delay

Show evidence (1 reference)

PMID:33445193 SUPPORT Human clinical

"After a complicated course with difficult to treat symptomatic seizures, the child died on the 5th day of admission due to progressive cerebral edema."

Documents fatal hypoglycemia-driven cerebral edema and seizures, the severe end of the neuroglycopenic injury.

Impaired Cataplerosis of Oxaloacetate

PEPCK-C is the principal cataplerotic exit removing oxaloacetate from the tricarboxylic acid cycle. When the enzyme is absent, carbon cannot leave the cycle for gluconeogenesis and tricarboxylic acid cycle intermediates back up.

oxaloacetate metabolic process GO:0006107 ⚠ ABNORMAL tricarboxylic acid cycle GO:0006099 ⚠ ABNORMAL

Downstream

TCA Cycle Intermediate Accumulation

Show evidence (1 reference)

PMID:28216384 SUPPORT Human clinical

"Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis."

Accumulation and urinary spill of tricarboxylic acid cycle intermediates is the direct biochemical signature of failed cataplerosis.

TCA Cycle Intermediate Accumulation

Tricarboxylic acid cycle intermediates accumulate behind the cataplerotic block and spill into urine (notably fumarate and alpha-ketoglutarate). The accompanying nitrogen load is buffered as glutamine, producing hyperglutaminemia, which has been proposed as a newborn-screening marker.

tricarboxylic acid cycle GO:0006099 ⚠ ABNORMAL

Downstream

Elevated urine fumaric acid

Hyperglutaminemia

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum."

Confirms elevated urinary tricarboxylic acid cycle metabolites as the characteristic pattern.

Lactate Accumulation

Lactate, a gluconeogenic substrate, accumulates when it can no longer be consumed by gluconeogenesis, driving hyperlactataemia and lactic acidosis during crises.

lactate metabolic process GO:0006089 ⚠ ABNORMAL

Downstream

Lactic acidosis

Lacticaciduria

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum"

Documents elevated serum lactate as part of the characteristic pattern.

Impaired Fasting Ketogenesis

Ketone body production during hypoglycemia is inadequate, so the brain and peripheral tissues lack the ketone fuel that normally spares glucose in the fasted state. Deficient ketogenesis was identified as a laboratory finding in the Finnish cohort.

ketone body biosynthetic process GO:0046951 ↓ DECREASED

Downstream

Hypoketotic hypoglycemia

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia."

States inadequate ketone body production during hypoglycemia, the basis of this node.

Hepatocellular Metabolic Stress

The hepatocyte, the principal site of the enzyme defect, shows metabolic injury: transient aminotransferase elevation (transaminitis), hepatic steatosis, and, in severe cases, hepatic failure.

hepatocyte CL:0000182

Downstream

Elevated alanine aminotransferase

Elevated aspartate aminotransferase

Hepatic steatosis

Hepatic failure

Hyperammonemia

Show evidence (1 reference)

PMID:32908218 SUPPORT Human clinical

"Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn error of metabolism, which can present with hypoglycemia, lactic acidosis, and liver failure."

Names liver failure as part of the clinical spectrum, the severe end of hepatocellular involvement.

Chronic Energy Deficit

Reduced fasting tolerance can produce chronic subclinical energy shortfall and growth failure even without documented hypoglycemia, driven by inadequate caloric intake relative to metabolic need; it responds to nutritional intervention.

Downstream

Failure to thrive

Show evidence (1 reference)

PMID:32908218 SUPPORT Human clinical

"Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention."

Documents growth failure from inadequate intake and its reversal with nutrition, the basis of this node.

Renal Proximal Tubular Dysfunction

PEPCK-C is also highly expressed in the renal proximal tubule, a major site of gluconeogenesis and ammoniagenesis. Prominent renal manifestations, including proximal tubulopathy with bicarbonate wasting and acute renal failure, have been reported as part of the expanding phenotype.

kidney proximal convoluted tubule epithelial cell CL:1000838

Downstream

Proximal tubulopathy

Show evidence (1 reference)

PMID:41549939 SUPPORT Human clinical

"Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both."

Directly documents proximal tubulopathy and renal failure in the cohort.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

18

Digestive 2

Hepatic steatosis OCCASIONAL HP:0001397

Show evidence (2 references)

PMID:40092582 SUPPORT Human clinical

"Liver US showed enlarged liver with increased parenchymal echogenicity due to fatty infiltration."

PCK1-confirmed patient with ultrasound-documented hepatic fatty infiltration, a disease-specific source for hepatic steatosis.

ORPHA:2880 SUPPORT Other

"HP:0001397 | Hepatic steatosis | Occasional (29-5%)"

Orphanet's clinical annotation lists hepatic steatosis as an occasional feature. This is the combined Orphanet PEPCK concept (ORPHA:2880, cytosolic and mitochondrial); evidence source is OTHER because Orphanet is an aggregating resource.

Hepatic failure OCCASIONAL HP:0001399

Show evidence (3 references)

PMID:40092582 SUPPORT Human clinical

"an acute liver failure with extreme hyper-ferritinemia of >40,000 ng/ml, high levels of ammonia and coagulopathy"

PCK1-confirmed neonate with acute liver failure and coagulopathy, a disease-specific primary report of severe hepatic involvement.

PMID:41608521 SUPPORT Human clinical

"The acute liver failure was reversible following continuous glucose infusion."

PCK1-confirmed patient whose acute liver failure reversed with continuous glucose, establishing the reversibility of the hepatic failure.

PMID:37924129 SUPPORT BACKGROUND Human clinical

"Previous studies showed a broad clinical spectrum ranging from asymptomatic to recurrent hypoglycemia with/without lactic acidosis, encephalopathy, seizures, and liver failure."

Situates liver failure at the severe end of the clinical spectrum; the quote is the paper's background framing of prior reports.

Genitourinary 3

Lacticaciduria HP:0003648

Show evidence (1 reference)

PMID:33445193 SUPPORT Human clinical

"The metabolic screening showed elevated urinary lactate and Krebs cycle intermediates in line with a primary or secondary energy deficit."

Documents elevated urinary lactate on metabolic screening.

Elevated urine fumaric acid Elevated urine fumaric acid level HP:0034648

Show evidence (1 reference)

PMID:41549939 SUPPORT Human clinical

"Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5."

Fumarate was the emphasized tricarboxylic acid cycle metabolite in the urine organic acid profile.

Proximal tubulopathy HP:0000114

Show evidence (1 reference)

PMID:41549939 SUPPORT Human clinical

"Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both."

Directly reports proximal tubulopathy with bicarbonate wasting.

Metabolism 10

Recurrent hypoglycemia VERY_FREQUENT HP:0001988

Show evidence (2 references)

PMID:37924129 SUPPORT Human clinical

"All patients presented with unexplained hypoglycemia as a common feature."

Hypoglycemia was the common presenting feature across all patients in the cohort.

PMID:35868242 SUPPORT Human clinical

"Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia."

Identifies hypoglycemia as the recognizable core manifestation of the disorder.

Neonatal hypoglycemia OCCASIONAL HP:0001998

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"Five patients presented with neonatal hypoglycemia."

Five of twenty-four patients had neonatal-onset hypoglycemia, supporting the OCCASIONAL band.

Hypoketotic hypoglycemia HP:0001985

Show evidence (2 references)

PMID:34622459 SUPPORT Human clinical

"identifying deficient ketogenesis as a novel laboratory finding"

Deficient ketogenesis during hypoglycemia defines the hypoketotic character of the episodes.

PMID:37924129 REFUTE DIRECT Human clinical

"Patient 2.1 had ketonuria, although not a common finding in our cohort and previous reports"

Qualifies the universality of the hypoketotic pattern: ketonuria was observed in one patient, showing the finding is not absolute even though it remains uncommon.

Lactic acidosis FREQUENT HP:0003128

Show evidence (1 reference)

PMID:33445193 SUPPORT Human clinical

"Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM 261680, EC 4.1.1.32, encoded by PCK1) is a rare disorder of gluconeogenesis presenting with recurrent hypoglycemia, hepatic dysfunction, and lactic acidosis."

Names lactic acidosis as a defining feature of the disorder.

Hyperglutaminemia HP:0003217

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening."

Directly reports elevated plasma glutamine.

Hyperammonemia OCCASIONAL HP:0001987

Show evidence (1 reference)

PMID:40092582 SUPPORT Human clinical

"an acute liver failure with extreme hyper-ferritinemia of >40,000 ng/ml, high levels of ammonia and coagulopathy"

PCK1-confirmed neonate with high ammonia levels during acute liver failure, a disease-specific primary report of hyperammonemia.

Elevated alanine aminotransferase FREQUENT Elevated circulating alanine aminotransferase concentration HP:0031964

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum"

Reports mild alanine aminotransferase elevation as part of the typical pattern.

Elevated aspartate aminotransferase FREQUENT Elevated circulating aspartate aminotransferase concentration HP:0031956

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum"

Reports mild aspartate aminotransferase elevation as part of the typical pattern.

Hypoglycemic seizures FREQUENT HP:0002173

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"Hypoglycemic seizures occurred in half of the patients (12 out of 24)."

Twelve of twenty-four patients had hypoglycemic seizures, supporting the FREQUENT band.

Cerebral edema HP:0002181

Show evidence (1 reference)

PMID:33445193 SUPPORT Human clinical

"the child died on the 5th day of admission due to progressive cerebral edema"

Fatal progressive cerebral edema in a child with molecularly confirmed disease.

Nervous System 2

Acute encephalopathy OCCASIONAL HP:0006846

Show evidence (1 reference)

PMID:37924129 SUPPORT Human clinical

"Two out of the seven patients presented with episodes of encephalopathy that resulted in seizures and neuroregression leading to global developmental delay"

Documents encephalopathy episodes and their neurodevelopmental consequences.

Global developmental delay OCCASIONAL HP:0001263

Show evidence (1 reference)

PMID:37924129 SUPPORT Human clinical

"episodes of encephalopathy that resulted in seizures and neuroregression leading to global developmental delay"

Documents global developmental delay as the lasting neurodevelopmental outcome of encephalopathic crises.

Growth 1

Failure to thrive OCCASIONAL HP:0001508

Show evidence (1 reference)

PMID:41549939 SUPPORT Human clinical

"A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants."

Documents failure to thrive in a severely affected individual.

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Genetic Associations

1

PCK1 (Causal biallelic variant)

Gene: PCK1 hgnc:8724 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:32908218 SUPPORT Human clinical

"It is caused by biallelic pathogenic variants in the PCK1 gene."

Directly states biallelic PCK1 variants as the cause.

PMID:28216384 SUPPORT Human clinical

"A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals."

Original molecular identification of the recurrent homozygous PCK1 variant.

Variants (2)

c.925G>A (p.Gly309Arg)

Recurrent missense founder variant, endemic in the Finnish population and the predominant reported genotype; also seen in the compound-heterozygous state.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population"

Identifies the recurrent Finnish founder variant as the predominant allele.

c.978delC

Novel homozygous single-base (C) frameshift deletion, the first frameshift variant reported in PCK1; presented as neonatal transient hypoglycemia and acute liver failure.

Show evidence (1 reference)

PMID:40092582 SUPPORT Human clinical

"The deletion of C at position 978 (chr20:56139240, hg19) results in frameshift of the open reading frame culminating in termination 15 amino-acids downstream."

Describes the homozygous c.978 single-base deletion and its frameshift consequence.

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Medical Actions

3

Acute intravenous glucose

Action: Supportive Care NCIT:C15747

Agent: glucose CHEBI:17234

Platform: Small molecule

Acute hypoglycemic crises are treated with intravenous glucose, supplying the glucose that the blocked gluconeogenic pathway cannot produce.

Mechanism Target:

BYPASSES Fasting Hypoglycemia — Exogenous glucose substitutes for the absent endogenous glucose production.

Show evidence (2 references)

PMID:37924129 SUPPORT Human clinical

"hypoglycemia, ketonuria, and mild lactic acidosis that were corrected by intravenous (IV) dextrose treatment"

Documents acute intravenous dextrose correcting the hypoglycemia of a metabolic crisis, directly supporting this treatment.

PMID:35868242 SUPPORT Human clinical

"It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity."

Supports treatability and the importance of preventing metabolic decompensation.

Avoidance of fasting

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

Platform: Behavioral / lifestyle

Preventive management centers on avoiding fasting and catabolic triggers, with a sick-day regimen and prompt carbohydrate during illness, exercise, and other fasting stress.

Mechanism Target:

INHIBITS Fasting Hypoglycemia — Preventing the catabolic state removes the trigger that converts the compensated gluconeogenic block into symptomatic hypoglycemia.

Show evidence (2 references)

PMID:37924129 SUPPORT Human clinical

"prompt reversal of the catabolic state is mandatory to avoid metabolic insult to the brain, which is achievable through gluconeogenesis prevention by the avoidance of fasting and the administration of glucose polymer emergency regimen to patients under metabolic attack"

States that avoidance of fasting (with an emergency glucose regimen) is the management strategy, directly supporting this preventive treatment.

PMID:34622459 SUPPORT Human clinical

"Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors."

Identifying the triggers defines the avoidance targets of preventive management.

Nutritional support for growth failure

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Platform: Behavioral / lifestyle

Growth failure driven by inadequate caloric intake responds to nutritional intervention.

Mechanism Target:

BYPASSES Chronic Energy Deficit — Adequate caloric intake offsets the reduced fasting tolerance that drives the chronic energy shortfall.

Show evidence (1 reference)

PMID:32908218 SUPPORT Human clinical

"Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention."

Documents nutritional intervention reversing the growth failure.

🌍

Environmental Factors

1

Fasting and catabolic stress

Catabolic states precipitate the metabolic crises of PEPCK-C deficiency by raising demand for endogenous glucose output. Identified triggers include infections, fasting or poor intake, heavy exercise, alcohol, and breastfeeding.

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors."

Establishes that catabolic/fasting exposures are the documented triggers of metabolic crises in cytosolic PEPCK deficiency.

Mechanism Target:

TRIGGERS Fasting Hypoglycemia — Increased gluconeogenic demand during catabolic stress converts the compensated state into symptomatic hypoglycemia.

Show evidence (1 reference)

PMID:34622459 SUPPORT Human clinical

"Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors."

Lists the catabolic exposures that trigger hypoglycemic episodes.

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Biochemical Markers

3

Glucose (DECREASED)

Context: Low blood glucose during fasting or catabolic stress is the cardinal biochemical abnormality.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"The typical biochemical pattern was hypoglycemia triggered by catabolic situations"

Catabolism-triggered hypoglycemia is the core biochemical finding.

Lactate (INCREASED)

Context: Elevated blood lactate accompanies crises and reflects accumulation of a gluconeogenic substrate behind the block.

Pathograph Readouts

Readout of Lactate Accumulation Positive Diagnostic

Rising lactate reports accumulation of gluconeogenic carbon proximal to the PEPCK-C step.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum"

Reports elevated serum lactate as part of the typical pattern.

Plasma glutamine (INCREASED)

Context: Elevated plasma glutamine has been proposed as a newborn-screening marker and reflects nitrogen handling around the metabolic block.

Pathograph Readouts

Readout of TCA Cycle Intermediate Accumulation Positive Diagnostic

Hyperglutaminemia reports the nitrogen load buffered around the cataplerotic block.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood."

Supports elevated glutamine as a measurable marker usable in newborn screening.

🔬

Diagnosis

2

Molecular genetic testing of PCK1

Identification of biallelic pathogenic PCK1 variants establishes the diagnosis; given nonspecific clinical manifestations, sequencing is the practical diagnostic route.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:28216384 SUPPORT Human clinical

"A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals."

Molecular identification of biallelic PCK1 variants is the diagnostic confirmation.

Urine organic acid analysis

A recognizable urine organic acid pattern — elevated tricarboxylic acid cycle intermediates (especially fumarate) and lactate, with inadequate ketones during hypoglycemia — is the practical trigger for targeted PCK1 testing.

urine organic acid analysis NCIT:C18020

Show evidence (1 reference)

PMID:28216384 SUPPORT Human clinical

"Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis."

Identifies the urine organic acid pattern that should prompt testing.

📊

Prevalence

2

Worldwide

Point prevalence <1 in 1,000,000

Orphanet records a worldwide point prevalence of <1/1,000,000 for phosphoenolpyruvate carboxykinase deficiency. This figure is for the broader Orphanet concept (ORPHA:2880), which combines the cytosolic (PCK1) and mitochondrial (PCK2) forms; most molecularly confirmed cytosolic cases are Finnish carriers of the c.925G>A founder allele.

Show evidence (1 reference)

ORPHA:2880 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"

Orphanet epidemiology table for the combined PEPCK deficiency concept. Evidence source is OTHER because Orphanet is an aggregating clinical resource rather than a primary cohort study.

Published literature (2022 systematic review)

Cases/families reported in the literature Ultra-rare

The 2022 systematic analysis of cytosolic PEPCK (PCK1) deficiency found 32 individuals from 25 families reported to date, including one previously unpublished patient, indicating an ultra-rare disorder.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"Thirty-two individuals from 25 families were found, including one previously unreported patient."

Reports the total number of molecularly confirmed cytosolic PEPCK deficiency cases in the literature at the time of the systematic review.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Phosphoenolpyruvate Carboxykinase Deficiency, Cytosolic:

Mitochondrial PEPCK (PCK2) deficiency

Overlapping Features PCK2 encodes the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M), a separate entity from the cytosolic (PCK1) form curated here; the two share the Orphanet umbrella concept (ORPHA:2880) but are genetically and biochemically distinct.

Show evidence (1 reference)

PMID:35868242 SUPPORT Human clinical

"Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency"

Establishes that the cytosolic form is specifically a PCK1 disorder, distinguishing it from the mitochondrial PCK2 form.

Other gluconeogenesis and fasting disorders

Overlapping Features Because hypoglycemia with lactic acidosis and hepatopathy is shared with other gluconeogenesis defects (fructose-1,6-bisphosphatase deficiency), glycogen storage diseases, and mitochondrial disorders, these are routinely considered first.

Show evidence (1 reference)

PMID:28216384 SUPPORT Human clinical

"Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis."

Situates the disorder within the differential diagnosis of childhood hypoglycemia with hepatic dysfunction.

🐁

Animal Models

1

Pck1 del/del mouse (whole-body PEPCK-C knockout)

Whole-body cytosolic PEPCK knockout mice die early after birth with profound hypoglycemia. Early postnatal hepatic reexpression partially rescues hypoglycemia and allows survival, identifying the liver as the critical organ and hypoglycemia as the critical pathomechanism.

Species

Mouse

Genotype

Pck1 del/del (whole-body cytosolic PEPCK knockout)

Publication

PMID:27785616

Pathograph links

Failure of Hepatic Gluconeogenesis recapitulates fidelity: moderate observes: organism Hepatic PEPCK-C loss produces the hypoglycemia of gluconeogenic failure, and liver-specific reexpression rescues it.

Limitations: The whole-body knockout is neonatally lethal with profound hypoglycemia, unlike the viable, episodic, catabolism-triggered human disease, so the model reproduces the severe hepatic-gluconeogenesis phenotype but not the human clinical spectrum.

Show evidence (1 reference)

PMID:27785616 SUPPORT Model organism

"This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice."

Liver reexpression rescuing hypoglycemia supports the model as informative for hepatic gluconeogenic failure.

Show evidence (1 reference)

PMID:27785616 SUPPORT Model organism

"Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed."

Establishes the whole-body knockout phenotype of neonatal lethal hypoglycemia.

{ }

Source YAML

click to show

name: Phosphoenolpyruvate Carboxykinase Deficiency, Cytosolic
creation_date: "2026-10-16T00:00:00Z"
category: Metabolic Disorder
synonyms:
- PCKDC
- PEPCK-C deficiency
- cytosolic PEPCK deficiency
- PEPCK 1 deficiency
- phosphoenolpyruvate carboxykinase-1 (PCK1) deficiency
- PEP carboxykinase deficiency
description: >-
  Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is a rare
  autosomal recessive inborn error of gluconeogenesis caused by biallelic
  pathogenic variants in PCK1. PEPCK-C is the rate-limiting cytosolic enzyme that
  converts oxaloacetate to phosphoenolpyruvate, the step that commits
  tricarboxylic-acid-cycle carbon to glucose synthesis, so its loss impairs
  hepatic (and renal) gluconeogenesis. Affected individuals are typically well
  between episodes but decompensate during catabolic stress, presenting with
  hypoglycemia, hyperlactataemia, and hepatopathy, together with a recognizable
  urine organic acid pattern of elevated tricarboxylic acid cycle intermediates
  (especially fumarate) and, during hypoglycemia, inadequate ketone production.
  The clinical spectrum is broad, ranging from asymptomatic individuals to
  recurrent hypoglycemic seizures, encephalopathy, liver failure, and death.
  Molecular confirmation of isolated cytosolic PEPCK deficiency is recent; a
  Finnish founder allele (c.925G>A, p.Gly309Arg) accounts for most reported
  cases, and the disorder is treatable by avoidance of fasting and prompt
  glucose during illness.
parents:
- hereditary disease
- metabolic disorder
- Inborn Error of Carbohydrate Metabolism
disease_term:
  preferred_term: phosphoenolpyruvate carboxykinase deficiency, cytosolic
  term:
    id: MONDO:0009866
    label: phosphoenolpyruvate carboxykinase deficiency, cytosolic
classifications:
  icimd_category:
  - classification_value: gluconeogenesis
    notes: >-
      PCK1 catalyzes the first committed cytosolic step of gluconeogenesis, so
      PEPCK-C deficiency is classified in the ICIMD disorders-of-gluconeogenesis
      group alongside FBP1, PC, and G6PC deficiencies.
references:
- reference: PMID:35868242
  title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
- reference: PMID:34622459
  title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet records a worldwide point prevalence of <1/1,000,000 for
    phosphoenolpyruvate carboxykinase deficiency. This figure is for the broader
    Orphanet concept (ORPHA:2880), which combines the cytosolic (PCK1) and
    mitochondrial (PCK2) forms; most molecularly confirmed cytosolic cases are
    Finnish carriers of the c.925G>A founder allele.
  evidence:
  - reference: ORPHA:2880
    reference_title: Phosphoenolpyruvate carboxykinase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: >-
      Orphanet epidemiology table for the combined PEPCK deficiency concept.
      Evidence source is OTHER because Orphanet is an aggregating clinical
      resource rather than a primary cohort study.
- population: Published literature (2022 systematic review)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The 2022 systematic analysis of cytosolic PEPCK (PCK1) deficiency found 32
    individuals from 25 families reported to date, including one previously
    unpublished patient, indicating an ultra-rare disorder.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty-two individuals from 25 families were found, including one previously
      unreported patient.
    explanation: >-
      Reports the total number of molecularly confirmed cytosolic PEPCK deficiency
      cases in the literature at the time of the systematic review.
pathophysiology:
- name: PCK1 Cytosolic PEPCK Deficiency
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Biallelic loss-of-function PCK1 variants deplete cytosolic phosphoenolpyruvate
    carboxykinase (PEPCK-C) activity. The enzyme catalyzes the GTP-dependent
    decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate,
    the first committed and rate-limiting cytosolic step of gluconeogenesis.
    Expression of a mutant allele in COS-1 cells produced an enzyme incapable of
    normal function, confirming the variants as loss-of-function.
  genes:
  - preferred_term: PCK1
    term:
      id: hgnc:8724
      label: PCK1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: phosphoenolpyruvate carboxykinase (GTP) activity
    term:
      id: GO:0004613
      label: phosphoenolpyruvate carboxykinase (GTP) activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: cytosol
    term:
      id: GO:0005829
      label: cytosol
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The COS-1 transfected cells showed the mutant gene to be incapable of
      producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase
      (PEPCK) enzyme.
    explanation: >-
      Functional expression establishes that the PCK1 variant abolishes enzyme
      function, supporting the DECREASED modifier on PEPCK activity.
  downstream:
  - target: Failure of Hepatic Gluconeogenesis
    causal_link_type: DIRECT
    description: >-
      Loss of the oxaloacetate-to-phosphoenolpyruvate step directly interrupts
      flux through gluconeogenesis.
    evidence:
    - reference: PMID:35868242
      reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting
        with hypoglycemia, lactic acidosis, and hepatopathy
      explanation: >-
        Identifies the disorder as a defect of gluconeogenesis caused by the
        enzyme deficiency.
  - target: Impaired Cataplerosis of Oxaloacetate
    causal_link_type: DIRECT
    description: >-
      Because PEPCK-C is the route by which oxaloacetate exits the
      tricarboxylic acid cycle for glucose synthesis, its loss blocks this
      cataplerotic drain.
- name: Failure of Hepatic Gluconeogenesis
  conforms_to: "hepatic_gluconeogenesis_failure#Failure of Hepatic De Novo Glucose Production"
  biological_scale: CELLULAR
  description: >-
    With PEPCK-C absent, the hepatocyte cannot convert lactate, glycerol, and
    gluconeogenic amino acids into glucose. Glycogenolysis is preserved, so
    glucose homeostasis is maintained in the fed and early-fasted state; the
    defect becomes clinically apparent only once glycogen is exhausted and the
    liver must rely on de novo glucose production.
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:27785616
    reference_title: >-
      PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1
      (del/del) mice, unmasking role in non-gluconeogenic tissues.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This maneuver was sufficient to partially rescue hypoglycemia and allow the
      pups to survive and identifies the liver as a critical organ, and
      hypoglycemia as the critical pathomechanism, leading to early postnatal
      death in the whole-body PEPCK-C knockout mice.
    explanation: >-
      Liver-specific reexpression rescuing hypoglycemia identifies hepatic
      gluconeogenesis as the critical function lost.
  downstream:
  - target: Fasting Hypoglycemia
    causal_link_type: DIRECT
    description: >-
      Once glycogen is depleted, the blocked gluconeogenic pathway cannot sustain
      blood glucose during fasting.
    evidence:
    - reference: PMID:35868242
      reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The typical biochemical pattern was hypoglycemia triggered by catabolic
        situations
      explanation: >-
        Hypoglycemia precipitated by catabolic (fasting) states is the direct
        clinical consequence of the gluconeogenic block.
  - target: Lactate Accumulation
    causal_link_type: DIRECT
  - target: Impaired Fasting Ketogenesis
    causal_link_type: DIRECT
  - target: Hepatocellular Metabolic Stress
    causal_link_type: DIRECT
  - target: Chronic Energy Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced endogenous glucose output lowers fasting tolerance, so adequate growth depends on frequent exogenous caloric intake.
- name: Fasting Hypoglycemia
  conforms_to: "hepatic_gluconeogenesis_failure#Fasting Hypoglycemia"
  biological_scale: ORGANISM
  description: >-
    Hypoglycemia develops when gluconeogenic demand exceeds glycogenolytic
    supply, typically overnight or during intercurrent illness. Episodes most
    often present in the morning and are precipitated by catabolic stress;
    neonatal onset also occurs.
  biological_processes:
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hypoglycemic episodes manifested predominantly in the morning.
    explanation: >-
      Describes the fasting (overnight) timing of the hypoglycemic episodes.
  downstream:
  - target: Recurrent hypoglycemia
    causal_link_type: DIRECT
  - target: Neonatal hypoglycemia
    causal_link_type: DIRECT
  - target: Neuroglycopenic Brain Injury
    causal_link_type: DIRECT
    description: >-
      Severe or prolonged hypoglycemia deprives the brain of its principal fuel.
- name: Neuroglycopenic Brain Injury
  conforms_to: "hepatic_gluconeogenesis_failure#Neuroglycopenic Dysfunction"
  biological_scale: TISSUE
  description: >-
    Insufficient cerebral glucose, compounded by inadequate ketone body
    production, produces acute neuronal energy failure. In severe cases this
    manifests as hypoglycemic seizures, acute encephalopathy, cerebral edema,
    neuroregression, and death.
  evidence:
  - reference: PMID:33445193
    reference_title: "Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After a complicated course with difficult to treat symptomatic seizures,
      the child died on the 5th day of admission due to progressive cerebral
      edema.
    explanation: >-
      Documents fatal hypoglycemia-driven cerebral edema and seizures, the severe
      end of the neuroglycopenic injury.
  downstream:
  - target: Hypoglycemic seizures
    causal_link_type: DIRECT
  - target: Acute encephalopathy
    causal_link_type: DIRECT
  - target: Cerebral edema
    causal_link_type: DIRECT
  - target: Global developmental delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Repeated encephalopathic crises cause neuroregression, leaving lasting global developmental delay.
- name: Impaired Cataplerosis of Oxaloacetate
  biological_scale: MOLECULAR
  description: >-
    PEPCK-C is the principal cataplerotic exit removing oxaloacetate from the
    tricarboxylic acid cycle. When the enzyme is absent, carbon cannot leave the
    cycle for gluconeogenesis and tricarboxylic acid cycle intermediates back up.
  biological_processes:
  - preferred_term: oxaloacetate metabolic process
    term:
      id: GO:0006107
      label: oxaloacetate metabolic process
    modifier: ABNORMAL
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transient elevation of alanine transaminase, lactate and tricarboxylic acid
      cycle intermediates, especially fumarate, were noticed in urine organic acid
      analysis.
    explanation: >-
      Accumulation and urinary spill of tricarboxylic acid cycle intermediates is
      the direct biochemical signature of failed cataplerosis.
  downstream:
  - target: TCA Cycle Intermediate Accumulation
    causal_link_type: DIRECT
- name: TCA Cycle Intermediate Accumulation
  biological_scale: CELLULAR
  description: >-
    Tricarboxylic acid cycle intermediates accumulate behind the cataplerotic
    block and spill into urine (notably fumarate and alpha-ketoglutarate). The
    accompanying nitrogen load is buffered as glutamine, producing
    hyperglutaminemia, which has been proposed as a newborn-screening marker.
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typical biochemical pattern was hypoglycemia triggered by catabolic
      situations, elevated urinary concentrations of tricarboxylic acid cycle
      metabolites, mildly elevated alanine and aspartate aminotransferase and
      elevated lactate concentrations in serum.
    explanation: >-
      Confirms elevated urinary tricarboxylic acid cycle metabolites as the
      characteristic pattern.
  downstream:
  - target: Elevated urine fumaric acid
    causal_link_type: DIRECT
  - target: Hyperglutaminemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Nitrogen that cannot be disposed of through gluconeogenic amino acid utilization is buffered as glutamine.
    evidence:
    - reference: PMID:35868242
      reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Plasma glutamine concentrations were elevated in some patients and may be
        a suitable marker for newborn screening.
      explanation: >-
        Reports hyperglutaminemia as a consequence of the metabolic block,
        supporting the edge.
- name: Lactate Accumulation
  conforms_to: "hepatic_gluconeogenesis_failure#Lactate Overproduction"
  biological_scale: CELLULAR
  description: >-
    Lactate, a gluconeogenic substrate, accumulates when it can no longer be
    consumed by gluconeogenesis, driving hyperlactataemia and lactic acidosis
    during crises.
  biological_processes:
  - preferred_term: lactate metabolic process
    term:
      id: GO:0006089
      label: lactate metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mildly elevated alanine and aspartate aminotransferase and elevated lactate
      concentrations in serum
    explanation: >-
      Documents elevated serum lactate as part of the characteristic pattern.
  downstream:
  - target: Lactic acidosis
    causal_link_type: DIRECT
  - target: Lacticaciduria
    causal_link_type: DIRECT
- name: Impaired Fasting Ketogenesis
  biological_scale: CELLULAR
  description: >-
    Ketone body production during hypoglycemia is inadequate, so the brain and
    peripheral tissues lack the ketone fuel that normally spares glucose in the
    fasted state. Deficient ketogenesis was identified as a laboratory finding in
    the Finnish cohort.
  biological_processes:
  - preferred_term: ketone body biosynthetic process
    term:
      id: GO:0046951
      label: ketone body biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory results showed abnormal urine organic acid profile with
      increased tricarboxylic acid cycle intermediates and inadequate ketone body
      production during hypoglycemia.
    explanation: >-
      States inadequate ketone body production during hypoglycemia, the basis of
      this node.
  downstream:
  - target: Hypoketotic hypoglycemia
    causal_link_type: DIRECT
- name: Hepatocellular Metabolic Stress
  biological_scale: CELLULAR
  description: >-
    The hepatocyte, the principal site of the enzyme defect, shows metabolic
    injury: transient aminotransferase elevation (transaminitis), hepatic
    steatosis, and, in severe cases, hepatic failure.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:32908218
    reference_title: Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn
      error of metabolism, which can present with hypoglycemia, lactic acidosis,
      and liver failure.
    explanation: >-
      Names liver failure as part of the clinical spectrum, the severe end of
      hepatocellular involvement.
  downstream:
  - target: Elevated alanine aminotransferase
    causal_link_type: DIRECT
  - target: Elevated aspartate aminotransferase
    causal_link_type: DIRECT
  - target: Hepatic steatosis
    causal_link_type: DIRECT
  - target: Hepatic failure
    causal_link_type: DIRECT
  - target: Hyperammonemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatocellular dysfunction during acute decompensation impairs ureagenesis and nitrogen disposal, allowing ammonia to accumulate.
- name: Chronic Energy Deficit
  biological_scale: ORGANISM
  description: >-
    Reduced fasting tolerance can produce chronic subclinical energy shortfall
    and growth failure even without documented hypoglycemia, driven by inadequate
    caloric intake relative to metabolic need; it responds to nutritional
    intervention.
  evidence:
  - reference: PMID:32908218
    reference_title: Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth restriction happened due to insufficient caloric intake, and it was
      improved with nutritional intervention.
    explanation: >-
      Documents growth failure from inadequate intake and its reversal with
      nutrition, the basis of this node.
  downstream:
  - target: Failure to thrive
    causal_link_type: DIRECT
- name: Renal Proximal Tubular Dysfunction
  biological_scale: TISSUE
  description: >-
    PEPCK-C is also highly expressed in the renal proximal tubule, a major site
    of gluconeogenesis and ammoniagenesis. Prominent renal manifestations,
    including proximal tubulopathy with bicarbonate wasting and acute renal
    failure, have been reported as part of the expanding phenotype.
  cell_types:
  - preferred_term: kidney proximal convoluted tubule epithelial cell
    term:
      id: CL:1000838
      label: kidney proximal convoluted tubule epithelial cell
  evidence:
  - reference: PMID:41549939
    reference_title: "Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prominent renal manifestations were noted in two, including proximal
      tubulopathy with bicarbonate wasting, and acute renal failure,
      respectively, with markedly elevated plasma glutamine in both.
    explanation: >-
      Directly documents proximal tubulopathy and renal failure in the cohort.
  downstream:
  - target: Proximal tubulopathy
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: pepckc_genotype_phenotype_environment
  hypothesis_label: Environment rather than genotype determines PEPCK-C deficiency severity
  status: EMERGING
  description: >-
    The clinical spectrum of PEPCK-C deficiency ranges from asymptomatic to fatal,
    and systematic review found no clear genotype-phenotype correlation. The
    leading interpretation is that environmental (catabolic) exposure, rather than
    the specific PCK1 genotype, is the main determinant of phenotype.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Environmental factors appear to be the main determinant for the phenotype in
      patients with biallelic variants in PCK1.
    explanation: >-
      States the environment-over-genotype interpretation directly.
discussions:
- discussion_id: pepckc_mouse_lethality_vs_human_viability
  prompt: >-
    Does the neonatal-lethal whole-body Pck1 knockout mouse model the viable,
    episodic, catabolism-triggered human disease, or only its most severe
    extreme?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of Hepatic Gluconeogenesis
  rationale: >-
    Whole-body PEPCK-C knockout mice die shortly after birth from profound
    hypoglycemia, whereas most humans with biallelic PCK1 variants survive and may
    be asymptomatic between catabolic stressors. The mouse establishes that
    hepatic gluconeogenesis and hypoglycemia are the critical pathomechanism, but
    its lethality does not reproduce the human disease's variable, often mild,
    stress-dependent course, so the translational validity of the model for the
    human phenotypic spectrum is the open question.
  proposed_experiments:
  - experiment_id: pepckc_hypomorphic_mouse
    experiment_design: TARGETED_PERTURBATION
    name: Hypomorphic or liver-conditional Pck1 mouse recapitulating partial deficiency
    description: >-
      Generate mice with partial (hypomorphic) or liver-conditional PEPCK-C loss
      to model the residual activity seen in human missense genotypes, and test
      whether fasting and intercurrent catabolic challenge reproduce the episodic
      human phenotype.
    decision_criterion: >-
      A viable model that decompensates only on catabolic challenge would support
      using the mouse for the human disease; persistent lethality or absence of a
      stress-dependent phenotype would bound its translational use.
phenotypes:
- name: Recurrent hypoglycemia
  description: >-
    Recurrent, catabolism-triggered hypoglycemia is the cardinal and nearly
    universal manifestation, typically the presenting problem.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent hypoglycemia
    term:
      id: HP:0001988
      label: Recurrent hypoglycemia
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with unexplained hypoglycemia as a common feature.
    explanation: >-
      Hypoglycemia was the common presenting feature across all patients in the
      cohort.
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause
      of childhood hypoglycemia.
    explanation: >-
      Identifies hypoglycemia as the recognizable core manifestation of the
      disorder.
- name: Neonatal hypoglycemia
  description: >-
    A subset of patients present with hypoglycemia in the neonatal period.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Neonatal hypoglycemia
    term:
      id: HP:0001998
      label: Neonatal hypoglycemia
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients presented with neonatal hypoglycemia.
    explanation: >-
      Five of twenty-four patients had neonatal-onset hypoglycemia, supporting the
      OCCASIONAL band.
- name: Hypoketotic hypoglycemia
  description: >-
    Hypoglycemia with inappropriately low ketone production, reflecting deficient
    fasting ketogenesis. The hypoketotic pattern is not absolute: ketonuria has
    been documented in at least one reported patient, interpreted as a hypoketotic
    response to extreme metabolic stress rather than preserved ketogenesis.
  phenotype_term:
    preferred_term: Hypoketotic hypoglycemia
    term:
      id: HP:0001985
      label: Hypoketotic hypoglycemia
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identifying deficient ketogenesis as a novel laboratory finding
    explanation: >-
      Deficient ketogenesis during hypoglycemia defines the hypoketotic character
      of the episodes.
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 2.1 had ketonuria, although not a common finding in our cohort and
      previous reports
    explanation: >-
      Qualifies the universality of the hypoketotic pattern: ketonuria was
      observed in one patient, showing the finding is not absolute even though it
      remains uncommon.
- name: Lactic acidosis
  description: >-
    High-anion-gap lactic acidosis accompanies acute crises, reflecting lactate
    accumulation behind the gluconeogenic block.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:33445193
    reference_title: "Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM 261680,
      EC 4.1.1.32, encoded by PCK1) is a rare disorder of gluconeogenesis
      presenting with recurrent hypoglycemia, hepatic dysfunction, and lactic
      acidosis.
    explanation: >-
      Names lactic acidosis as a defining feature of the disorder.
- name: Lacticaciduria
  description: >-
    Elevated urinary lactate is part of the characteristic urine organic acid
    pattern during metabolic crises.
  phenotype_term:
    preferred_term: Lacticaciduria
    term:
      id: HP:0003648
      label: Lacticaciduria
  evidence:
  - reference: PMID:33445193
    reference_title: "Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metabolic screening showed elevated urinary lactate and Krebs cycle
      intermediates in line with a primary or secondary energy deficit.
    explanation: >-
      Documents elevated urinary lactate on metabolic screening.
- name: Hyperglutaminemia
  description: >-
    Elevated plasma glutamine reflects nitrogen buffering around the metabolic
    block and has been proposed as a newborn-screening marker.
  phenotype_term:
    preferred_term: Hyperglutaminemia
    term:
      id: HP:0003217
      label: Hyperglutaminemia
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma glutamine concentrations were elevated in some patients and may be a
      suitable marker for newborn screening.
    explanation: >-
      Directly reports elevated plasma glutamine.
- name: Hyperammonemia
  description: >-
    Elevated blood ammonia can accompany severe hepatic decompensation, reflecting
    impaired nitrogen disposal during acute liver dysfunction; it is not a constant
    feature and ammonia is often normal between or during milder episodes.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:40092582
    reference_title: Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an acute liver failure with extreme hyper-ferritinemia of >40,000 ng/ml,
      high levels of ammonia and coagulopathy
    explanation: >-
      PCK1-confirmed neonate with high ammonia levels during acute liver failure,
      a disease-specific primary report of hyperammonemia.
- name: Elevated urine fumaric acid
  description: >-
    Fumarate is the most consistently elevated tricarboxylic acid cycle
    intermediate in the urine organic acid pattern of PEPCK-C deficiency.
  phenotype_term:
    preferred_term: Elevated urine fumaric acid level
    term:
      id: HP:0034648
      label: Elevated urine fumaric acid level
  evidence:
  - reference: PMID:41549939
    reference_title: "Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid analysis identified elevated lactate, dicarboxylic
      aciduria, and tricarboxylic acid cycle metabolites, especially fumarate
      which was detected in 3/5.
    explanation: >-
      Fumarate was the emphasized tricarboxylic acid cycle metabolite in the urine
      organic acid profile.
- name: Elevated alanine aminotransferase
  description: >-
    Mild transient elevation of alanine aminotransferase reflects hepatocellular
    involvement.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alanine aminotransferase concentration
    term:
      id: HP:0031964
      label: Elevated circulating alanine aminotransferase concentration
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mildly elevated alanine and aspartate aminotransferase and elevated lactate
      concentrations in serum
    explanation: >-
      Reports mild alanine aminotransferase elevation as part of the typical
      pattern.
- name: Elevated aspartate aminotransferase
  description: >-
    Mild transient elevation of aspartate aminotransferase accompanies the
    transaminitis of hepatocellular stress.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating aspartate aminotransferase concentration
    term:
      id: HP:0031956
      label: Elevated circulating aspartate aminotransferase concentration
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mildly elevated alanine and aspartate aminotransferase and elevated lactate
      concentrations in serum
    explanation: >-
      Reports mild aspartate aminotransferase elevation as part of the typical
      pattern.
- name: Hepatic steatosis
  description: >-
    Hepatic steatosis (fatty infiltration of the liver) is reported in cytosolic
    PEPCK (PCK1) deficiency, demonstrated on ultrasound during a metabolic crisis,
    and is listed as an occasional feature of the broader Orphanet concept.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:40092582
    reference_title: Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver US showed enlarged liver with increased parenchymal echogenicity due
      to fatty infiltration.
    explanation: >-
      PCK1-confirmed patient with ultrasound-documented hepatic fatty
      infiltration, a disease-specific source for hepatic steatosis.
  - reference: ORPHA:2880
    reference_title: Phosphoenolpyruvate carboxykinase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001397 | Hepatic steatosis | Occasional (29-5%)"
    explanation: >-
      Orphanet's clinical annotation lists hepatic steatosis as an occasional
      feature. This is the combined Orphanet PEPCK concept (ORPHA:2880, cytosolic
      and mitochondrial); evidence source is OTHER because Orphanet is an
      aggregating resource.
- name: Hepatic failure
  description: >-
    Liver failure occurs at the severe end of the hepatic spectrum. In PCK1-confirmed
    patients it can present as acute liver failure with coagulopathy, including a
    neonatal presentation, and is typically reversible once glucose is restored.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:40092582
    reference_title: Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an acute liver failure with extreme hyper-ferritinemia of >40,000 ng/ml,
      high levels of ammonia and coagulopathy
    explanation: >-
      PCK1-confirmed neonate with acute liver failure and coagulopathy, a
      disease-specific primary report of severe hepatic involvement.
  - reference: PMID:41608521
    reference_title: "A Novel PCK1 Gene Variant Associated With Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Two Siblings With Different Clinical Presentations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The acute liver failure was reversible following continuous glucose infusion.
    explanation: >-
      PCK1-confirmed patient whose acute liver failure reversed with continuous
      glucose, establishing the reversibility of the hepatic failure.
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous studies showed a broad clinical spectrum ranging from asymptomatic
      to recurrent hypoglycemia with/without lactic acidosis, encephalopathy,
      seizures, and liver failure.
    explanation: >-
      Situates liver failure at the severe end of the clinical spectrum; the
      quote is the paper's background framing of prior reports.
- name: Hypoglycemic seizures
  description: >-
    Seizures accompany severe hypoglycemic episodes and occurred in about half of
    the Finnish cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypoglycemic seizures
    term:
      id: HP:0002173
      label: Hypoglycemic seizures
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemic seizures occurred in half of the patients (12 out of 24).
    explanation: >-
      Twelve of twenty-four patients had hypoglycemic seizures, supporting the
      FREQUENT band.
- name: Acute encephalopathy
  description: >-
    Acute encephalopathy can follow severe hypoglycemic/metabolic crises and may
    lead to neuroregression.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Acute encephalopathy
    term:
      id: HP:0006846
      label: Acute encephalopathy
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two out of the seven patients presented with episodes of encephalopathy that
      resulted in seizures and neuroregression leading to global developmental
      delay
    explanation: >-
      Documents encephalopathy episodes and their neurodevelopmental consequences.
- name: Cerebral edema
  description: >-
    Cerebral edema can complicate severe hypoglycemic crises and has been fatal.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:33445193
    reference_title: "Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Cause of Hypoglycemia-Induced Seizure and Death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the child died on the 5th day of admission due to progressive cerebral edema
    explanation: >-
      Fatal progressive cerebral edema in a child with molecularly confirmed
      disease.
- name: Global developmental delay
  description: >-
    Global developmental delay is a lasting sequela in severely affected patients,
    following repeated encephalopathic crises and neuroregression.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      episodes of encephalopathy that resulted in seizures and neuroregression
      leading to global developmental delay
    explanation: >-
      Documents global developmental delay as the lasting neurodevelopmental
      outcome of encephalopathic crises.
- name: Failure to thrive
  description: >-
    Growth failure can occur, driven by reduced fasting tolerance and inadequate
    caloric intake, and improves with nutritional support.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41549939
    reference_title: "Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A severe phenotype with failure to thrive, short fasting tolerance, liver
      dysfunction, and tubulopathy was noted in one individual harboring compound
      heterozygous splicing and nonsense variants.
    explanation: >-
      Documents failure to thrive in a severely affected individual.
- name: Proximal tubulopathy
  description: >-
    Renal proximal tubular dysfunction, including bicarbonate wasting, is a
    recently recognized manifestation reflecting PEPCK-C's role in renal proximal
    tubule metabolism.
  phenotype_term:
    preferred_term: Proximal tubulopathy
    term:
      id: HP:0000114
      label: Proximal tubulopathy
  evidence:
  - reference: PMID:41549939
    reference_title: "Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five Non-Finnish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prominent renal manifestations were noted in two, including proximal
      tubulopathy with bicarbonate wasting, and acute renal failure, respectively,
      with markedly elevated plasma glutamine in both.
    explanation: >-
      Directly reports proximal tubulopathy with bicarbonate wasting.
biochemical:
- name: Glucose
  presence: DECREASED
  context: >-
    Low blood glucose during fasting or catabolic stress is the cardinal
    biochemical abnormality.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typical biochemical pattern was hypoglycemia triggered by catabolic
      situations
    explanation: >-
      Catabolism-triggered hypoglycemia is the core biochemical finding.
- name: Lactate
  presence: INCREASED
  context: >-
    Elevated blood lactate accompanies crises and reflects accumulation of a
    gluconeogenic substrate behind the block.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mildly elevated alanine and aspartate aminotransferase and elevated lactate
      concentrations in serum
    explanation: >-
      Reports elevated serum lactate as part of the typical pattern.
  readouts:
  - target: Lactate Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Rising lactate reports accumulation of gluconeogenic carbon proximal to the
      PEPCK-C step.
- name: Plasma glutamine
  presence: INCREASED
  context: >-
    Elevated plasma glutamine has been proposed as a newborn-screening marker and
    reflects nitrogen handling around the metabolic block.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Newborn screening can identify at least a sub-cohort of affected individuals
      through elevated glutamine concentrations in dry blood.
    explanation: >-
      Supports elevated glutamine as a measurable marker usable in newborn
      screening.
  readouts:
  - target: TCA Cycle Intermediate Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Hyperglutaminemia reports the nitrogen load buffered around the cataplerotic
      block.
genetic:
- name: PCK1
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PCK1
    term:
      id: hgnc:8724
      label: PCK1
  notes: >-
    Cytosolic PEPCK deficiency is caused by biallelic pathogenic variants in
    PCK1. The recurrent missense variant c.925G>A (p.Gly309Arg) is a Finnish
    founder allele and the predominant reported genotype; missense, frameshift,
    splice-site, and nonsense variants are all described. In silico modeling of
    missense variants suggests altered manganese- and substrate-binding.
  variants:
  - name: c.925G>A (p.Gly309Arg)
    description: >-
      Recurrent missense founder variant, endemic in the Finnish population and
      the predominant reported genotype; also seen in the compound-heterozygous
      state.
    evidence:
    - reference: PMID:35868242
      reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are
        predominant and appear to be endemic in the Finnish population
      explanation: >-
        Identifies the recurrent Finnish founder variant as the predominant
        allele.
  - name: c.978delC
    description: >-
      Novel homozygous single-base (C) frameshift deletion, the first frameshift
      variant reported in PCK1; presented as neonatal transient hypoglycemia and
      acute liver failure.
    evidence:
    - reference: PMID:40092582
      reference_title: Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The deletion of C at position 978 (chr20:56139240, hg19) results in
        frameshift of the open reading frame culminating in termination 15
        amino-acids downstream.
      explanation: >-
        Describes the homozygous c.978 single-base deletion and its frameshift
        consequence.
  evidence:
  - reference: PMID:32908218
    reference_title: Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is caused by biallelic pathogenic variants in the PCK1 gene.
    explanation: >-
      Directly states biallelic PCK1 variants as the cause.
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all
      affected individuals.
    explanation: >-
      Original molecular identification of the recurrent homozygous PCK1 variant.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    PEPCK-C deficiency is inherited in an autosomal recessive manner; affected
    individuals carry biallelic pathogenic PCK1 variants.
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PEPCK-C deficiency is a rare childhood-onset autosomal recessive metabolic
      disease caused by PCK1 genetic defects.
    explanation: >-
      States the autosomal recessive mode of inheritance directly.
environmental:
- name: Fasting and catabolic stress
  description: >-
    Catabolic states precipitate the metabolic crises of PEPCK-C deficiency by
    raising demand for endogenous glucose output. Identified triggers include
    infections, fasting or poor intake, heavy exercise, alcohol, and
    breastfeeding.
  evidence:
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infections, fasting or poor food intake, heavy exercise, alcohol
      consumption, and breastfeeding were identified as triggering factors.
    explanation: >-
      Establishes that catabolic/fasting exposures are the documented triggers of
      metabolic crises in cytosolic PEPCK deficiency.
  influences_mechanisms:
  - target: Fasting Hypoglycemia
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Increased gluconeogenic demand during catabolic stress converts the
      compensated state into symptomatic hypoglycemia.
    evidence:
    - reference: PMID:34622459
      reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Infections, fasting or poor food intake, heavy exercise, alcohol
        consumption, and breastfeeding were identified as triggering factors.
      explanation: >-
        Lists the catabolic exposures that trigger hypoglycemic episodes.
treatments:
- name: Acute intravenous glucose
  description: >-
    Acute hypoglycemic crises are treated with intravenous glucose, supplying the
    glucose that the blocked gluconeogenic pathway cannot produce.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: glucose
      term:
        id: CHEBI:17234
        label: glucose
  target_mechanisms:
  - target: Fasting Hypoglycemia
    treatment_effect: BYPASSES
    description: >-
      Exogenous glucose substitutes for the absent endogenous glucose production.
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoglycemia, ketonuria, and mild lactic acidosis that were corrected by
      intravenous (IV) dextrose treatment
    explanation: >-
      Documents acute intravenous dextrose correcting the hypoglycemia of a
      metabolic crisis, directly supporting this treatment.
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is a treatable disease and early diagnosis is important to prevent
      metabolic derailment and morbidity.
    explanation: >-
      Supports treatability and the importance of preventing metabolic
      decompensation.
- name: Avoidance of fasting
  description: >-
    Preventive management centers on avoiding fasting and catabolic triggers,
    with a sick-day regimen and prompt carbohydrate during illness, exercise, and
    other fasting stress.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Fasting Hypoglycemia
    treatment_effect: INHIBITS
    description: >-
      Preventing the catabolic state removes the trigger that converts the
      compensated gluconeogenic block into symptomatic hypoglycemia.
  evidence:
  - reference: PMID:37924129
    reference_title: "Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prompt reversal of the catabolic state is mandatory to avoid metabolic
      insult to the brain, which is achievable through gluconeogenesis prevention
      by the avoidance of fasting and the administration of glucose polymer
      emergency regimen to patients under metabolic attack
    explanation: >-
      States that avoidance of fasting (with an emergency glucose regimen) is the
      management strategy, directly supporting this preventive treatment.
  - reference: PMID:34622459
    reference_title: "Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infections, fasting or poor food intake, heavy exercise, alcohol
      consumption, and breastfeeding were identified as triggering factors.
    explanation: >-
      Identifying the triggers defines the avoidance targets of preventive
      management.
- name: Nutritional support for growth failure
  description: >-
    Growth failure driven by inadequate caloric intake responds to nutritional
    intervention.
  therapeutic_modality: BEHAVIORAL
  notes: >-
    therapeutic_modality is BEHAVIORAL because this is a caloric/feeding
    intervention ensuring adequate intake, not supplementation of a specific
    chemical compound (which would be SMALL_MOLECULE).
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Chronic Energy Deficit
    treatment_effect: BYPASSES
    description: >-
      Adequate caloric intake offsets the reduced fasting tolerance that drives
      the chronic energy shortfall.
  evidence:
  - reference: PMID:32908218
    reference_title: Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth restriction happened due to insufficient caloric intake, and it was
      improved with nutritional intervention.
    explanation: >-
      Documents nutritional intervention reversing the growth failure.
diagnosis:
- name: Molecular genetic testing of PCK1
  description: >-
    Identification of biallelic pathogenic PCK1 variants establishes the
    diagnosis; given nonspecific clinical manifestations, sequencing is the
    practical diagnostic route.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all
      affected individuals.
    explanation: >-
      Molecular identification of biallelic PCK1 variants is the diagnostic
      confirmation.
- name: Urine organic acid analysis
  description: >-
    A recognizable urine organic acid pattern — elevated tricarboxylic acid cycle
    intermediates (especially fumarate) and lactate, with inadequate ketones
    during hypoglycemia — is the practical trigger for targeted PCK1 testing.
  diagnosis_term:
    preferred_term: urine organic acid analysis
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytosolic PEPCK deficiency should be considered in the differential
      diagnosis of children presenting with hypoglycemia, hepatic dysfunction and
      elevated tricarboxylic acid intermediates in urinary organic acid analysis.
    explanation: >-
      Identifies the urine organic acid pattern that should prompt testing.
differential_diagnoses:
- name: Mitochondrial PEPCK (PCK2) deficiency
  description: >-
    PCK2 encodes the mitochondrial isoform of phosphoenolpyruvate carboxykinase
    (PEPCK-M), a separate entity from the cytosolic (PCK1) form curated here; the
    two share the Orphanet umbrella concept (ORPHA:2880) but are genetically and
    biochemically distinct.
  evidence:
  - reference: PMID:35868242
    reference_title: Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic biallelic variants in PCK1 coding for the cytosolic
      phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency
    explanation: >-
      Establishes that the cytosolic form is specifically a PCK1 disorder,
      distinguishing it from the mitochondrial PCK2 form.
- name: Other gluconeogenesis and fasting disorders
  description: >-
    Because hypoglycemia with lactic acidosis and hepatopathy is shared with
    other gluconeogenesis defects (fructose-1,6-bisphosphatase deficiency),
    glycogen storage diseases, and mitochondrial disorders, these are routinely
    considered first.
  evidence:
  - reference: PMID:28216384
    reference_title: >-
      Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate
      carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal
      pattern of urine metabolites and liver dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytosolic PEPCK deficiency should be considered in the differential
      diagnosis of children presenting with hypoglycemia, hepatic dysfunction and
      elevated tricarboxylic acid intermediates in urinary organic acid analysis.
    explanation: >-
      Situates the disorder within the differential diagnosis of childhood
      hypoglycemia with hepatic dysfunction.
animal_models:
- name: Pck1 del/del mouse (whole-body PEPCK-C knockout)
  species: Mouse
  genotype: Pck1 del/del (whole-body cytosolic PEPCK knockout)
  publication: PMID:27785616
  description: >-
    Whole-body cytosolic PEPCK knockout mice die early after birth with profound
    hypoglycemia. Early postnatal hepatic reexpression partially rescues
    hypoglycemia and allows survival, identifying the liver as the critical organ
    and hypoglycemia as the critical pathomechanism.
  modeled_mechanisms:
  - target: Failure of Hepatic Gluconeogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Hepatic PEPCK-C loss produces the hypoglycemia of gluconeogenic failure,
      and liver-specific reexpression rescues it.
    limitations: >-
      The whole-body knockout is neonatally lethal with profound hypoglycemia,
      unlike the viable, episodic, catabolism-triggered human disease, so the
      model reproduces the severe hepatic-gluconeogenesis phenotype but not the
      human clinical spectrum.
    evidence:
    - reference: PMID:27785616
      reference_title: >-
        PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1
        (del/del) mice, unmasking role in non-gluconeogenic tissues.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This maneuver was sufficient to partially rescue hypoglycemia and allow
        the pups to survive and identifies the liver as a critical organ, and
        hypoglycemia as the critical pathomechanism, leading to early postnatal
        death in the whole-body PEPCK-C knockout mice.
      explanation: >-
        Liver reexpression rescuing hypoglycemia supports the model as informative
        for hepatic gluconeogenic failure.
  evidence:
  - reference: PMID:27785616
    reference_title: >-
      PEPCK-C reexpression in the liver counters neonatal hypoglycemia in Pck1
      (del/del) mice, unmasking role in non-gluconeogenic tissues.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO)
      mice die early after birth with profound hypoglycemia therefore masking the
      role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed.
    explanation: >-
      Establishes the whole-body knockout phenotype of neonatal lethal
      hypoglycemia.
notes: >-
  Lump/split: this entry is the cytosolic (PCK1) form only, matching MONDO:0009866
  and OMIM:261680. The mitochondrial form (PCK2, encoding mitochondrial PEPCK-M;
  OMIM:261650) is a distinct disease and is not covered here; Orphanet lumps both
  under ORPHA:2880, which cross-references OMIM:261680 as broader, and the
  cytosolic-specific ORPHA:79316 was obsoleted and redirected to ORPHA:2880.
  Molecular confirmation of isolated cytosolic PEPCK deficiency is recent — first
  reported with biallelic PCK1 variants in 2014 and functionally established in
  2017 — and roughly 32 individuals were in the literature at the 2022 systematic
  review; the earlier pre-molecular history of "PEPCK deficiency" is not relied on
  here.
clinical_trials: []
datasets: []

📚

References & Deep Research

References

2

PMID:35868242

Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

No top-level findings curated for this source.

PMID:34622459

Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Phosphoenolpyruvate Carboxykinase Deficiency, Cytosolic · 2026-10-16T04:09:34Z · View source

New de-novo curation of cytosolic PEPCK (PCK1) deficiency, MONDO:0009866. Deep research run with the claude_code provider (3 web searches, 7 citations, 4 on-topic) was thin and used only as leads; the backbone was independent PubMed work. Backbone PMIDs: 35868242 (Goetz 2022 systematic review of 32 individuals), 34622459 (Vieira 2022 Finnish cohort of 24), 28216384 (Vieira 2017 first molecular/functional confirmation, COS-1), 32908218 (Oishi 2021 growth failure without hypoglycemia), 33445193 (Becker 2021 fatal cerebral edema), 41549939 (Bernhardt 2026 five non-Finnish, renal manifestations), 37924129 (Al Busaidi 2023 Arabian Gulf), 27785616 (Semakova 2017 Pck1 del/del mouse). Built a 10-node atomic pathophysiology chain with all 16 phenotypes causally connected (100%). No GeneReviews chapter exists (verified offline). No ClinGen PCK1 record, so no gene_disease_validity block. Validated: just validate (50 snippets, 52 titles, 0 issues), validate-terms passed, entity-refs/causal-targets/qualifier-terms/duplicate-keys/block-scalar OK, count-verified 50/50, and validate-disorders passed.

Claude Code ▸

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

claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-16T03:45:35.905230

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.

Phenotype	HPO (verify by lookup)	Notes and source
Hypoglycemia, fasting- or illness-triggered	Hypoglycemia (HP:0001943)	Core feature. Glucose 21–25 mg/dL in Burg 2024.
Lactic acidosis	Lactic acidosis (HP:0003128)	Seen during decompensation (Burg 2024; AJCR).
Ketotic acidosis	Metabolic acidosis (HP:0001942)	Burg 2024.
Elevated transaminases / hepatic dysfunction	Elevated hepatic transaminase (HP:0002910)	AJCR; Vieira 2017.
Acute liver failure with coagulopathy	Acute hepatic failure (HP:0006554)	Neonatal in Burg 2024. Transient in Vasiļevska 2026, where the proband met pediatric ALF criteria.
Hepatic steatosis	Hepatic steatosis (HP:0001397)	Fatty infiltration on ultrasound at 7 months (Burg 2024).
Hyperferritinemia (extreme)	Hyperferritinemia (HP:0003281)	More than 40,000 ng/ml in the neonate. Normalized to 108 ng/ml. Mechanism speculative.
Hyperammonemia	Hyperammonemia (HP:0001987)	Reported in Burg 2024 and in the OJRD literature. Mild or normal in the Vasiļevska proband.
Elevated plasma/urine glutamine	Hyperglutaminemia (HP:0033360)	Vasiļevska 2026.
Seizures, cerebral edema, death	Seizure (HP:0001250)	Becker 2021 (PMID 33445193): hypoglycemia-induced seizure and death in a 3-year-old.
Growth failure	Failure to thrive (HP:0001508)	Oishi 2021 (PMID 32908218).
Mild motor delay	Motor delay (HP:0001270)	Burg 2024, at 15 months.
Hypertriglyceridemia, transient	Hypertriglyceridemia (HP:0002155)	298 mg/dL in Burg 2024.
Acute kidney injury, transient	Acute kidney injury (HP:0001919)	Vasiļevska proband.
Urinary TCA intermediates (fumarate), dicarboxylic aciduria, glutaric and α-hydroxyglutaric aciduria	Abnormal urinary organic acid profile (HP:0003110 or similar)	Burg 2024.

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.

Variant	Source and notes
c.925G>A, p.(Gly309Arg)	Vieira 2017 (PMID 28216384). Vasiļevska 2026 reports it in "84% of patients". Cell studies showed the mutant gene could not produce a normally functioning enzyme (Centogene-hosted copy). ClinVar variation ID 338886.
p.Gly430Asp and p.His496Gln	Oishi 2021 (PMID 32908218). Novel compound heterozygous missense variants.
c.978delC (1-bp deletion)	Burg 2024. First homozygous frameshift. Exon 7 of 10; translation terminates 15 amino acids downstream. Classified pathogenic under ACMG.
c.1833_1834del, p.(Glu611AspfsTer16)	Vasiļevska 2026. Last exon; predicted to escape nonsense-mediated decay and alter the last 12 amino acids. Likely pathogenic. Found in compound heterozygosity with p.Gly309Arg.

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

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.
PEPCK-C normally converts oxaloacetate to phosphoenolpyruvate, a rate-limiting gluconeogenic step in liver and kidney. Its loss "impedes cytosolic gluconeogenesis" (Burg 2024).
During fasting or illness, glycogen runs out and gluconeogenesis cannot compensate. The result is fasting or illness-triggered hypoglycemia.
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.
TCA intermediates such as fumarate, along with glutaric and α-hydroxyglutaric acids, accumulate and are excreted in urine (observed; the mechanism is not demonstrated).
Hepatic injury and steatosis follow. The proposed drivers are energy failure and altered substrate flux during decompensation. This is inferred.
Extreme hyperferritinemia was seen in the neonate. The authors only hypothesize iron–glucose cross-talk.
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:

PMID	Source
40092582	Burg 2024 (fetched)
41608521	Vasiļevska 2026 (fetched)
28216384	Vieira 2017
26971250	Santra 2016
32908218	Oishi 2021
33445193	Becker 2021
34622459	Vieira 2022 (expanded phenotype)
24863970	Adams 2014
176867	Hommes 1976
179269	Vidnes and Sovik 1976

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

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	7
On topic	4
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	26
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	19
Terms named correctly	13
Terms named as a different term	3
Terms whose name is worth a second look	3

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

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References & Deep Research

References

Deep Research

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

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Curation notes

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look