Pyruvate Carboxylase Deficiency Disease

Metabolic Disorder MONDO:0009949 Pathograph 25 hereditary disease metabolic disorder

Pyruvate carboxylase deficiency disease is a rare autosomal recessive mitochondrial neurometabolic disorder caused by biallelic PC variants. The core lesion is failure of pyruvate-to-oxaloacetate conversion, which impairs gluconeogenesis and anaplerosis and produces lactic acidosis, metabolic decompensation, and neurologic dysfunction.

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7
Pathophys.
13
Phenotypes
25
Pathograph
1
Genes
1
Treatments
3
Subtypes
1
Deep Research
◆

Subtypes

3
Type A pyruvate carboxylase deficiency MONDO:0018141
Infantile pyruvate carboxylase deficiency with substantial neurologic and metabolic morbidity but generally less fulminant disease than type B.
Show evidence (1 reference)
DOI:10.1515/almed-2023-0102 SUPPORT Human Clinical
"The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A."
This directly supports type A as a recognized biochemical and clinical subtype.
Type B pyruvate carboxylase deficiency MONDO:0018142
Severe neonatal pyruvate carboxylase deficiency with early respiratory distress, profound metabolic decompensation, and high mortality.
Show evidence (1 reference)
DOI:10.1515/almed-2023-0102 SUPPORT Human Clinical
"Two siblings displayed typical biochemical findings reported in type B."
This directly supports type B as a severe neonatal biochemical subtype.
Type C pyruvate carboxylase deficiency MONDO:0018143
A comparatively milder form with episodic metabolic decompensation and a more favorable developmental course.
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis."
This directly supports type C as the attenuated pyruvate carboxylase deficiency subtype.
⚙

Pathophysiology

7
Pyruvate Carboxylase Deficiency
Biallelic PC dysfunction impairs the mitochondrial pyruvate carboxylase complex, reducing the conversion of pyruvate to oxaloacetate.
PC link
pyruvate carboxylase activity link ↓ DECREASED
mitochondrial matrix link
Downstream
Impaired Gluconeogenesis Loss of pyruvate carboxylase activity compromises glucose production.
Impaired Anaplerosis Loss of pyruvate carboxylase activity compromises oxaloacetate-dependent metabolic flux.
Lactate Accumulation Pyruvate carboxylase deficiency causes pyruvate/lactate accumulation.
Show evidence (2 references)
PMID:37207470 SUPPORT Human Clinical
"Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options."
This directly supports pyruvate carboxylase deficiency as the proximal molecular lesion.
PMID:20598931 SUPPORT Other
"Pyruvate carboxylase (PC) is a regulated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, a critical transition that replenishes citric acid cycle intermediates and facilitates other biosynthetic reactions that drive anabolism."
This review summarizes the proximal biochemical function of PC and supports the decreased pyruvate carboxylase activity annotation.
Impaired Gluconeogenesis
Pyruvate carboxylase normally supports gluconeogenesis, so deficiency impairs glucose production during metabolic stress.
PC link
gluconeogenesis link ⚠ ABNORMAL
Downstream
Hypoglycemia Impaired gluconeogenesis contributes to hypoglycemia in metabolically unstable presentations.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis."
This directly supports gluconeogenesis as a pyruvate carboxylase-dependent process disrupted by deficiency.
Impaired Anaplerosis
Pyruvate carboxylase replenishes oxaloacetate and other TCA-cycle intermediates, so deficiency impairs anaplerotic mitochondrial flux.
PC link
tricarboxylic acid cycle link ⚠ ABNORMAL
Downstream
Mitochondrial Energy Deficit TCA-cycle flux failure reduces mitochondrial energy production.
Neurologic Dysfunction Anaplerotic failure contributes to CNS metabolic dysfunction.
Urea Cycle Perturbation Mitochondrial metabolic imbalance is associated with secondary nitrogen-disposal abnormalities.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis."
This directly supports impaired gluconeogenesis and anaplerosis as the central metabolic mechanism.
Mitochondrial Energy Deficit
Failure of pyruvate carboxylase-dependent metabolism produces systemic energy deficit that contributes to growth failure and neurologic dysfunction.
cell redox homeostasis link ⚠ ABNORMAL
Downstream
Failure to Thrive Chronic energy deficit contributes to poor growth and nutritional instability.
Neurologic Dysfunction Energy failure in the CNS contributes to encephalopathy, hypotonia, and seizures.
Ketonuria Metabolic decompensation in PC deficiency is accompanied by ketonuria.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports lactic acidosis and systemic metabolic injury as dominant disease consequences.
Lactate Accumulation
Pyruvate carboxylase deficiency causes recurrent or persistent lactate accumulation as a dominant biochemical disease feature.
cell redox homeostasis link ⚠ ABNORMAL
Downstream
Lactic Acidosis Lactate accumulation is represented clinically as lactic acidosis.
Lactate Lactate accumulation is represented biochemically as increased blood lactate.
Respiratory Distress Neonatal metabolic acidosis from lactate accumulation can present with tachypnea or respiratory distress.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports lactic acidosis as a downstream biochemical consequence of PC deficiency.
Urea Cycle Perturbation
Severe pyruvate carboxylase deficiency can perturb mitochondrial nitrogen handling, contributing to hyperammonemia in some presentations.
urea cycle link ⚠ ABNORMAL
Downstream
Hyperammonemia Urea-cycle perturbation in severe neonatal PC deficiency is associated with elevated ammonia.
Hypercitrullinemia Secondary urea-cycle perturbation in severe PC deficiency includes elevated citrulline.
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably found. Hyperammoniemia, hypernatremia, and high proline and lysine were frequently detected."
This supports secondary nitrogen-disposal abnormalities in severe neonatal pyruvate carboxylase deficiency.
Neurologic Dysfunction
Pyruvate carboxylase deficiency disrupts brain energy metabolism and myelination, producing developmental and structural neurologic abnormalities.
brain link
Downstream
Developmental Delay CNS metabolic dysfunction delays neurodevelopment.
Hypotonia Neurometabolic encephalopathy frequently presents with hypotonia.
Abnormal Movements Severe neonatal neurologic dysfunction can manifest with tremor, hypokinesia, and abnormal ocular movements.
Type A Encephalopathy Severe infantile type A disease is part of the life-limiting encephalopathic spectrum of pyruvate carboxylase deficiency.
Type B Encephalopathy Severe neonatal type B disease is part of the life-limiting encephalopathic spectrum of pyruvate carboxylase deficiency.
Periventricular Leukomalacia Severe neonatal type B neurologic dysfunction includes cystic periventricular leukomalacia on brain MRI.
Seizure Severe neurologic dysfunction can manifest with seizures.
Delayed Myelination CNS metabolic dysfunction in type C disease can include delayed cerebral myelination.
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Speech development was delayed. MRI-brain showed delayed cerebral myelination."
This directly supports developmental and neuroimaging evidence of CNS involvement downstream of the metabolic lesion.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pyruvate Carboxylase Deficiency Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Metabolism 3
Lactic Acidosis VERY_FREQUENT Lactic acidosis (HP:0003128)
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports lactic acidosis as a hallmark phenotype.
Hypoglycemia OCCASIONAL Hypoglycemia (HP:0001943)
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain."
This directly supports hypoglycemia as part of the type C metabolic phenotype.
Hyperammonemia OCCASIONAL Hyperammonemia (HP:0001987)
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Hyperammoniemia, hypernatremia, and high proline and lysine were frequently detected."
This directly supports hyperammonemia in severe neonatal pyruvate carboxylase deficiency.
Musculoskeletal 1
Hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (2 references)
DOI:10.1002/jmd2.12405 PARTIAL Human Clinical
"Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B)."
This supports major neurologic involvement; hypotonia is a frequent component of the encephalopathic presentation in PCD.
PMID:16278852 SUPPORT Human Clinical
"All patients had axial hypotonia and tachypnea during the first hours of life."
This directly supports hypotonia in the severe neonatal pyruvate carboxylase deficiency series.
Nervous System 6
Seizure OCCASIONAL Seizure (HP:0001250)
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre ocular behavior were the most common findings, whereas epilepsy was infrequent."
This supports seizures/epilepsy as an occasional neurologic phenotype in severe pyruvate carboxylase deficiency.
Abnormal Movements FREQUENT Abnormality of movement (HP:0100022)
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre ocular behavior were the most common findings, whereas epilepsy was infrequent."
This directly supports abnormal movements as a frequent type B neurologic phenotype.
Type A Encephalopathy VERY_FREQUENT Encephalopathy (HP:0001298)
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B)."
This supports encephalopathy as a defining severe-form phenotype for type A disease.
Type B Encephalopathy VERY_FREQUENT Encephalopathy (HP:0001298)
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B)."
This supports encephalopathy as a defining severe-form phenotype for type B disease.
Developmental Delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Speech development was delayed. MRI-brain showed delayed cerebral myelination."
This directly supports developmental delay in the attenuated type C spectrum.
Delayed Myelination OCCASIONAL Delayed myelination (HP:0012448)
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"MRI‐brain showed delayed cerebral myelination."
This directly supports delayed myelination as a type C neuroimaging phenotype.
Respiratory 1
Respiratory Distress FREQUENT Respiratory distress (HP:0002098)
Show evidence (1 reference)
DOI:10.1515/almed-2023-0102 SUPPORT Human Clinical
"All three developed respiratory distress within the first few hours of birth."
This directly supports neonatal respiratory distress in the reported pyruvate carboxylase deficiency cases.
Growth 1
Failure to Thrive FREQUENT Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports failure to thrive as a major clinical feature.
Other 1
Periventricular Leukomalacia FREQUENT Periventricular leukomalacia (HP:0006970)
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Brain magnetic resonance imaging mostly disclosed cystic periventricular leukomalacia."
This directly supports periventricular leukomalacia as the predominant type B neuroimaging phenotype.
🧬

Genetic Associations

1
PC (Causal biallelic variant)
Show evidence (1 reference)
DOI:10.1515/almed-2023-0102 SUPPORT Human Clinical
"The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A."
This directly supports PC as the causal gene in molecularly confirmed disease.
💊

Treatments

1
Triheptanoin supplementation
Action: nutritional supplementation MAXO:0000106
Triheptanoin is used as an anaplerotic odd-chain triglyceride therapy, with mixed overall results but apparent benefit in some type C patients.
Mechanism Target:
BYPASSES Impaired Anaplerosis — Triheptanoin supplies odd-chain substrates that can replenish TCA-cycle intermediates despite impaired PC-dependent anaplerosis.
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Triheptanoin is an odd‐chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood–brain‐barrier."
The type C case report explicitly frames triheptanoin as an anaplerotic therapy that can replenish TCA intermediates.
MODULATES Lactate Accumulation — Triheptanoin treatment can lower the lactate-accumulation branch in selected patients, although cohort-level effects are variable.
Show evidence (2 references)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved."
The treated type C patient had resolution of post-exertional hyperlactatemia, supporting modulation of lactate accumulation.
PMID:37207470 PARTIAL Human Clinical
"An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint."
The larger cohort supports a possible lactate-lowering effect but also documents substantial inter-individual variability.
MODULATES Mitochondrial Energy Deficit — In type C disease, triheptanoin may improve energy homeostasis and CNS myelin synthesis.
Show evidence (1 reference)
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Triheptanoin was well‐tolerated and appeared efficacious during 2 years' follow‐up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C."
The type C report supports modulation of the energy-deficit branch and downstream myelin synthesis.
Show evidence (2 references)
PMID:37207470 SUPPORT Human Clinical
"Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results."
This directly supports disease-specific use of triheptanoin in the clinical literature.
DOI:10.1002/jmd2.12405 SUPPORT Human Clinical
"Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved."
This directly supports clinical benefit from triheptanoin in at least one type C patient.
🔬

Biochemical Markers

3
Lactate (INCREASED)
Context: High blood lactate is a core laboratory hallmark across pyruvate carboxylase deficiency subtypes.
Pathograph Readouts
Readout Of Lactate Accumulation Positive Diagnostic
Increased lactate reports the lactate-accumulation branch created by impaired pyruvate-to-oxaloacetate flux.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
The patient cohort identifies lactic acidosis as a core biochemical and clinical finding, supporting lactate as the readout of lactate accumulation.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports lactic acidosis/elevated lactate as a core biochemical disease finding.
Ketonuria (PRESENT)
Context: Ketonuria is part of the recurrent biochemical signature of pyruvate carboxylase deficiency.
Pathograph Readouts
Readout Of Mitochondrial Energy Deficit Present Absent Diagnostic
The presence of ketonuria is a biochemical readout of metabolic decompensation accompanying the mitochondrial energy deficit in pyruvate carboxylase deficiency.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
The cohort lists ketonuria with lactic acidosis, failure to thrive, and neurologic dysfunction, supporting it as a diagnostic biochemical readout of the systemic energy-deficit branch.
Show evidence (1 reference)
PMID:37207470 SUPPORT Human Clinical
"The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction."
This directly supports ketonuria as a characteristic biochemical abnormality.
Hypercitrullinemia (INCREASED)
Context: Elevated plasma citrulline can occur in severe neonatal type B disease as part of the secondary metabolic and nitrogen-disposal abnormalities reported in this presentation.
Pathograph Readouts
Readout Of Urea Cycle Perturbation Positive Diagnostic
Elevated citrulline reports the secondary nitrogen-disposal and urea-cycle perturbation seen in severe neonatal pyruvate carboxylase deficiency.
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably found."
The severe neonatal series reports invariant hypercitrullinemia, supporting elevated citrulline as the biochemical readout of the urea-cycle perturbation branch.
Show evidence (1 reference)
PMID:16278852 SUPPORT Human Clinical
"Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably found."
This directly supports hypercitrullinemia as a severe neonatal biochemical abnormality.
{ }

Source YAML

click to show 
name: Pyruvate Carboxylase Deficiency Disease
creation_date: "2026-04-23T00:00:00Z"
updated_date: "2026-05-21T05:22:02Z"
description: >-
  Pyruvate carboxylase deficiency disease is a rare autosomal recessive
  mitochondrial neurometabolic disorder caused by biallelic PC variants. The
  core lesion is failure of pyruvate-to-oxaloacetate conversion, which impairs
  gluconeogenesis and anaplerosis and produces lactic acidosis, metabolic
  decompensation, and neurologic dysfunction.
category: Metabolic Disorder
parents:
- hereditary disease
- metabolic disorder
disease_term:
  preferred_term: pyruvate carboxylase deficiency disease
  term:
    id: MONDO:0009949
    label: pyruvate carboxylase deficiency disease
has_subtypes:
- name: Type A
  display_name: Type A pyruvate carboxylase deficiency
  subtype_term:
    preferred_term: pyruvate carboxylase deficiency, infantile form
    term:
      id: MONDO:0018141
      label: pyruvate carboxylase deficiency, infantile form
  description: >-
    Infantile pyruvate carboxylase deficiency with substantial neurologic and
    metabolic morbidity but generally less fulminant disease than type B.
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other proband with normal citrulline, lysine, moderate lactate,
      paraventricular cystic lesions, bony deformities, and a novel
      missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC
      gene, biochemically favoured type A.
    explanation: >-
      This directly supports type A as a recognized biochemical and
      clinical subtype.
- name: Type B
  display_name: Type B pyruvate carboxylase deficiency
  subtype_term:
    preferred_term: pyruvate carboxylase deficiency, severe neonatal type
    term:
      id: MONDO:0018142
      label: pyruvate carboxylase deficiency, severe neonatal type
  description: >-
    Severe neonatal pyruvate carboxylase deficiency with early respiratory
    distress, profound metabolic decompensation, and high mortality.
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings displayed typical biochemical findings reported in type
      B.
    explanation: >-
      This directly supports type B as a severe neonatal biochemical
      subtype.
- name: Type C
  display_name: Type C pyruvate carboxylase deficiency
  subtype_term:
    preferred_term: pyruvate carboxylase deficiency, benign type
    term:
      id: MONDO:0018143
      label: pyruvate carboxylase deficiency, benign type
  description: >-
    A comparatively milder form with episodic metabolic decompensation and a
    more favorable developmental course.
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate carboxylase deficiency (PCD) mostly presents with
      life-limiting encephalopathy (types A/B). A milder type C
      presentation is rare, with a comparatively favourable prognosis.
    explanation: >-
      This directly supports type C as the attenuated pyruvate carboxylase
      deficiency subtype.
pathophysiology:
- name: Pyruvate Carboxylase Deficiency
  description: >-
    Biallelic PC dysfunction impairs the mitochondrial pyruvate carboxylase
    complex, reducing the conversion of pyruvate to oxaloacetate.
  genes:
  - preferred_term: PC
    term:
      id: hgnc:8636
      label: PC
  molecular_functions:
  - preferred_term: pyruvate carboxylase activity
    term:
      id: GO:0004736
      label: pyruvate carboxylase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive
      mitochondrial neurometabolic disorder of energy deficit resulting in
      high morbidity and mortality, with limited therapeutic options.
    explanation: >-
      This directly supports pyruvate carboxylase deficiency as the
      proximal molecular lesion.
  - reference: PMID:20598931
    reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pyruvate carboxylase (PC) is a regulated mitochondrial enzyme that
      catalyzes the conversion of pyruvate to oxaloacetate, a critical
      transition that replenishes citric acid cycle intermediates and
      facilitates other biosynthetic reactions that drive anabolism.
    explanation: >-
      This review summarizes the proximal biochemical function of PC and
      supports the decreased pyruvate carboxylase activity annotation.
  downstream:
  - target: Impaired Gluconeogenesis
    causal_link_type: DIRECT
    description: Loss of pyruvate carboxylase activity compromises glucose production.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The PC homotetramer has a critical role in gluconeogenesis,
        anaplerosis, neurotransmitter synthesis, and lipogenesis.
      explanation: >-
        The patient cohort paper identifies gluconeogenesis as a critical
        PC-dependent process, supporting this direct graph edge.
  - target: Impaired Anaplerosis
    causal_link_type: DIRECT
    description: Loss of pyruvate carboxylase activity compromises oxaloacetate-dependent metabolic flux.
    evidence:
    - reference: PMID:20598931
      reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Pyruvate carboxylase (PC) is a regulated mitochondrial enzyme that
        catalyzes the conversion of pyruvate to oxaloacetate, a critical
        transition that replenishes citric acid cycle intermediates and
        facilitates other biosynthetic reactions that drive anabolism.
      explanation: >-
        The review directly links PC activity to replenishment of citric
        acid cycle intermediates, supporting impaired anaplerosis when PC
        activity is deficient.
  - target: Lactate Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Pyruvate carboxylase deficiency causes pyruvate/lactate accumulation.
    intermediate_mechanisms:
    - Reduced pyruvate-to-oxaloacetate conversion leaves pyruvate available for lactate production.
    evidence:
    - reference: PMID:20598931
      reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Its deficiency causes multiorgan metabolic imbalance that
        predominantly manifests with lactic acidemia and neurological
        dysfunction at an early age.
      explanation: >-
        The review supports lactic acidemia as a dominant downstream
        consequence of PC deficiency.
- name: Impaired Gluconeogenesis
  description: >-
    Pyruvate carboxylase normally supports gluconeogenesis, so deficiency
    impairs glucose production during metabolic stress.
  genes:
  - preferred_term: PC
    term:
      id: hgnc:8636
      label: PC
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PC homotetramer has a critical role in gluconeogenesis,
      anaplerosis, neurotransmitter synthesis, and lipogenesis.
    explanation: >-
      This directly supports gluconeogenesis as a pyruvate
      carboxylase-dependent process disrupted by deficiency.
  downstream:
  - target: Hypoglycemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired gluconeogenesis contributes to hypoglycemia in metabolically unstable presentations.
    intermediate_mechanisms:
    - Reduced endogenous glucose production during fasting or illness.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypoglycemia, lactic acidosis, and hypercitrullinemia were
        invariably found.
      explanation: >-
        Severe neonatal PC deficiency patients had invariant hypoglycemia,
        supporting hypoglycemia as a downstream metabolic outcome.
- name: Impaired Anaplerosis
  description: >-
    Pyruvate carboxylase replenishes oxaloacetate and other TCA-cycle
    intermediates, so deficiency impairs anaplerotic mitochondrial flux.
  genes:
  - preferred_term: PC
    term:
      id: hgnc:8636
      label: PC
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PC homotetramer has a critical role in gluconeogenesis,
      anaplerosis, neurotransmitter synthesis, and lipogenesis.
    explanation: >-
      This directly supports impaired gluconeogenesis and anaplerosis as
      the central metabolic mechanism.
  downstream:
  - target: Mitochondrial Energy Deficit
    causal_link_type: DIRECT
    description: TCA-cycle flux failure reduces mitochondrial energy production.
    evidence:
    - reference: PMID:20598931
      reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Pyruvate carboxylase (PC) is a regulated mitochondrial enzyme that
        catalyzes the conversion of pyruvate to oxaloacetate, a critical
        transition that replenishes citric acid cycle intermediates and
        facilitates other biosynthetic reactions that drive anabolism.
      explanation: >-
        Oxaloacetate-dependent replenishment of citric acid cycle
        intermediates directly supports mitochondrial energy flux.
  - target: Neurologic Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Anaplerotic failure contributes to CNS metabolic dysfunction.
    intermediate_mechanisms:
    - Citric-acid-cycle substrate limitation and neurometabolic energy imbalance.
    evidence:
    - reference: PMID:20598931
      reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Three clinical forms of PC deficiency have been identified: an
        infantile form (Type A), a severe neonatal form (Type B), and a
        benign form (Type C), all of which exhibit clinical or biochemical
        correlates of impaired anaplerosis.
      explanation: >-
        The review links clinical PC deficiency presentations to impaired
        anaplerosis, supporting neurologic dysfunction downstream of this
        metabolic branch.
  - target: Urea Cycle Perturbation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial metabolic imbalance is associated with secondary nitrogen-disposal abnormalities.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypoglycemia, lactic acidosis, and hypercitrullinemia were
        invariably found. Hyperammoniemia, hypernatremia, and high proline
        and lysine were frequently detected.
      explanation: >-
        The severe neonatal PC deficiency series supports consistent
        citrulline and frequent ammonia abnormalities downstream of the
        mitochondrial metabolic lesion.
- name: Mitochondrial Energy Deficit
  description: >-
    Failure of pyruvate carboxylase-dependent metabolism produces systemic
    energy deficit that contributes to growth failure and neurologic
    dysfunction.
  biological_processes:
  - preferred_term: cell redox homeostasis
    term:
      id: GO:0045454
      label: cell redox homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports lactic acidosis and systemic metabolic injury
      as dominant disease consequences.
  downstream:
  - target: Failure to Thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Chronic energy deficit contributes to poor growth and nutritional instability.
    intermediate_mechanisms:
    - Systemic energy deficit and recurrent metabolic decompensation.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        The cohort abstract lists failure to thrive among the main
        clinical findings of PC deficiency.
  - target: Neurologic Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Energy failure in the CNS contributes to encephalopathy, hypotonia, and seizures.
    intermediate_mechanisms:
    - Brain energy substrate deficiency and neurometabolic decompensation.
    evidence:
    - reference: PMID:20598931
      reference_title: "Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Its deficiency causes multiorgan metabolic imbalance that
        predominantly manifests with lactic acidemia and neurological
        dysfunction at an early age.
      explanation: >-
        This supports neurologic dysfunction as a dominant manifestation
        of PC-deficiency metabolic imbalance.
  - target: Ketonuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Metabolic decompensation in PC deficiency is accompanied by ketonuria.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        The cohort paper supports ketonuria as a main biochemical finding;
        the exact intermediate pathway is left compressed here.
- name: Lactate Accumulation
  description: >-
    Pyruvate carboxylase deficiency causes recurrent or persistent lactate
    accumulation as a dominant biochemical disease feature.
  biological_processes:
  - preferred_term: cell redox homeostasis
    term:
      id: GO:0045454
      label: cell redox homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports lactic acidosis as a downstream biochemical
      consequence of PC deficiency.
  downstream:
  - target: Lactic Acidosis
    causal_link_type: DIRECT
    description: Lactate accumulation is represented clinically as lactic acidosis.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        This supports lactic acidosis as the clinical expression of
        lactate accumulation in PC deficiency.
  - target: Lactate
    causal_link_type: DIRECT
    description: Lactate accumulation is represented biochemically as increased blood lactate.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        Lactic acidosis in the patient cohort supports increased lactate
        as the biochemical readout of the lactate-accumulation node.
  - target: Respiratory Distress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Neonatal metabolic acidosis from lactate accumulation can present with tachypnea or respiratory distress.
    intermediate_mechanisms:
    - Metabolic acidosis with compensatory tachypnea in early neonatal disease.
    evidence:
    - reference: DOI:10.1515/almed-2023-0102
      reference_title: >-
        Clinical, biochemical, and molecular profiles of three Sri Lankan
        neonates with pyruvate carboxylase deficiency
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings indicate the necessity of prompt laboratory
        investigations in a tachypneic neonate with coexisting metabolic
        acidosis, as early recognition is essential for patient management and
        family counselling.
      explanation: >-
        The neonatal case series links tachypnea/respiratory presentation
        with metabolic acidosis in pyruvate carboxylase deficiency.
- name: Urea Cycle Perturbation
  description: >-
    Severe pyruvate carboxylase deficiency can perturb mitochondrial nitrogen
    handling, contributing to hyperammonemia in some presentations.
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably
      found. Hyperammoniemia, hypernatremia, and high proline and lysine
      were frequently detected.
    explanation: >-
      This supports secondary nitrogen-disposal abnormalities in severe
      neonatal pyruvate carboxylase deficiency.
  downstream:
  - target: Hyperammonemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Urea-cycle perturbation in severe neonatal PC deficiency is associated with elevated ammonia.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hyperammoniemia, hypernatremia, and high proline and lysine were
        frequently detected.
      explanation: >-
        The severe neonatal series reports frequent hyperammonemia,
        supporting this endpoint downstream of nitrogen-disposal
        perturbation.
  - target: Hypercitrullinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Secondary urea-cycle perturbation in severe PC deficiency includes elevated citrulline.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypoglycemia, lactic acidosis, and hypercitrullinemia were
        invariably found.
      explanation: >-
        The severe neonatal series reports invariant hypercitrullinemia,
        supporting this biochemical endpoint.
- name: Neurologic Dysfunction
  description: >-
    Pyruvate carboxylase deficiency disrupts brain energy metabolism and
    myelination, producing developmental and structural neurologic
    abnormalities.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Speech development was delayed. MRI-brain showed delayed cerebral
      myelination.
    explanation: >-
      This directly supports developmental and neuroimaging evidence of CNS
      involvement downstream of the metabolic lesion.
  downstream:
  - target: Developmental Delay
    causal_link_type: DIRECT
    description: CNS metabolic dysfunction delays neurodevelopment.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Speech development was delayed. MRI-brain showed delayed cerebral
        myelination.
      explanation: >-
        The type C case report directly supports developmental delay as a
        neurologic manifestation.
  - target: Hypotonia
    causal_link_type: DIRECT
    description: Neurometabolic encephalopathy frequently presents with hypotonia.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients had axial hypotonia and tachypnea during the first
        hours of life.
      explanation: >-
        The severe neonatal series directly supports hypotonia as an early
        neurologic manifestation.
  - target: Abnormal Movements
    causal_link_type: DIRECT
    description: Severe neonatal neurologic dysfunction can manifest with tremor, hypokinesia, and abnormal ocular movements.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Abnormal movements (high-amplitude tremor and hypokinesia) and
        bizarre ocular behavior were the most common findings, whereas
        epilepsy was infrequent.
      explanation: >-
        The severe neonatal type B series identifies abnormal movements as the
        most common neurologic findings.
  - target: Type A Encephalopathy
    causal_link_type: DIRECT
    description: Severe infantile type A disease is part of the life-limiting encephalopathic spectrum of pyruvate carboxylase deficiency.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pyruvate carboxylase deficiency (PCD) mostly presents with
        life-limiting encephalopathy (types A/B).
      explanation: >-
        The type C report contrasts attenuated type C disease with the
        life-limiting encephalopathy of types A and B.
  - target: Type B Encephalopathy
    causal_link_type: DIRECT
    description: Severe neonatal type B disease is part of the life-limiting encephalopathic spectrum of pyruvate carboxylase deficiency.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pyruvate carboxylase deficiency (PCD) mostly presents with
        life-limiting encephalopathy (types A/B).
      explanation: >-
        The type C report contrasts attenuated type C disease with the
        life-limiting encephalopathy of types A and B.
  - target: Periventricular Leukomalacia
    causal_link_type: DIRECT
    description: Severe neonatal type B neurologic dysfunction includes cystic periventricular leukomalacia on brain MRI.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance imaging mostly disclosed cystic
        periventricular leukomalacia.
      explanation: >-
        The severe neonatal type B series identifies cystic periventricular
        leukomalacia as the predominant neuroimaging finding.
  - target: Seizure
    causal_link_type: DIRECT
    description: Severe neurologic dysfunction can manifest with seizures.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Abnormal movements (high-amplitude tremor and hypokinesia) and
        bizarre ocular behavior were the most common findings, whereas
        epilepsy was infrequent.
      explanation: >-
        The series supports epilepsy/seizures as an infrequent neurologic
        manifestation, consistent with an occasional endpoint.
  - target: Delayed Myelination
    causal_link_type: DIRECT
    description: CNS metabolic dysfunction in type C disease can include delayed cerebral myelination.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Speech development was delayed. MRI-brain showed delayed cerebral
        myelination.
      explanation: >-
        The type C case report directly links neurologic involvement to
        delayed cerebral myelination.
phenotypes:
- name: Lactic Acidosis
  description: >-
    Recurrent or persistent lactic acidosis is the dominant biochemical
    abnormality across pyruvate carboxylase deficiency phenotypes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports lactic acidosis as a hallmark phenotype.
- name: Failure to Thrive
  description: >-
    Poor growth and nutritional instability are common manifestations of the
    chronic metabolic deficit.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports failure to thrive as a major clinical feature.
- name: Hypotonia
  description: >-
    Hypotonia is a frequent early neurologic sign, especially in the more
    severe infantile and neonatal presentations.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate carboxylase deficiency (PCD) mostly presents with
      life-limiting encephalopathy (types A/B).
    explanation: >-
      This supports major neurologic involvement; hypotonia is a frequent
      component of the encephalopathic presentation in PCD.
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had axial hypotonia and tachypnea during the first hours
      of life.
    explanation: >-
      This directly supports hypotonia in the severe neonatal pyruvate
      carboxylase deficiency series.
- name: Seizure
  description: >-
    Seizures occur in severe pyruvate carboxylase deficiency as part of the
    neurometabolic encephalopathy.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre
      ocular behavior were the most common findings, whereas epilepsy was
      infrequent.
    explanation: >-
      This supports seizures/epilepsy as an occasional neurologic phenotype
      in severe pyruvate carboxylase deficiency.
- name: Abnormal Movements
  subtype: Type B
  description: >-
    High-amplitude tremor, hypokinesia, and bizarre ocular behavior are the most
    common neurologic findings reported in severe neonatal type B disease.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: abnormal movements
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre
      ocular behavior were the most common findings, whereas epilepsy was
      infrequent.
    explanation: >-
      This directly supports abnormal movements as a frequent type B neurologic
      phenotype.
- name: Type A Encephalopathy
  subtype: Type A
  description: >-
    Life-limiting encephalopathy is a dominant clinical feature of the severe
    infantile type A form of pyruvate carboxylase deficiency.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate carboxylase deficiency (PCD) mostly presents with
      life-limiting encephalopathy (types A/B).
    explanation: >-
      This supports encephalopathy as a defining severe-form phenotype for type
      A disease.
- name: Type B Encephalopathy
  subtype: Type B
  description: >-
    Life-limiting encephalopathy is a dominant clinical feature of the severe
    neonatal type B form of pyruvate carboxylase deficiency.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyruvate carboxylase deficiency (PCD) mostly presents with
      life-limiting encephalopathy (types A/B).
    explanation: >-
      This supports encephalopathy as a defining severe-form phenotype for type
      B disease.
- name: Periventricular Leukomalacia
  subtype: Type B
  description: >-
    Cystic periventricular leukomalacia is the predominant brain MRI finding in
    severe neonatal type B pyruvate carboxylase deficiency.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: periventricular leukomalacia
    term:
      id: HP:0006970
      label: Periventricular leukomalacia
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging mostly disclosed cystic periventricular
      leukomalacia.
    explanation: >-
      This directly supports periventricular leukomalacia as the predominant
      type B neuroimaging phenotype.
- name: Developmental Delay
  description: >-
    Neurodevelopmental delay ranges from speech delay in type C to severe
    encephalopathy in types A and B.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Speech development was delayed. MRI-brain showed delayed cerebral
      myelination.
    explanation: >-
      This directly supports developmental delay in the attenuated type C
      spectrum.
- name: Hypoglycemia
  description: >-
    Hypoglycemia occurs in some patients, especially in the attenuated but
    still metabolically unstable type C presentation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia
      and hypoglycaemia at 2 years of age, with gross motor delay and mild
      global volume loss on MRI brain.
    explanation: >-
      This directly supports hypoglycemia as part of the type C metabolic
      phenotype.
- name: Respiratory Distress
  description: >-
    Severe neonatal pyruvate carboxylase deficiency may present with
    respiratory distress in the first hours of life.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three developed respiratory distress within the first few hours of
      birth.
    explanation: >-
      This directly supports neonatal respiratory distress in the reported
      pyruvate carboxylase deficiency cases.
- name: Delayed Myelination
  subtype: Type C
  description: >-
    Delayed cerebral myelination has been reported in attenuated type C
    pyruvate carboxylase deficiency.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI‐brain showed delayed cerebral myelination.
    explanation: >-
      This directly supports delayed myelination as a type C neuroimaging
      phenotype.
- name: Hyperammonemia
  description: >-
    Hyperammonemia may occur in severe pyruvate carboxylase deficiency
    through secondary urea-cycle perturbation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperammoniemia, hypernatremia, and high proline and lysine were
      frequently detected.
    explanation: >-
      This directly supports hyperammonemia in severe neonatal pyruvate
      carboxylase deficiency.
biochemical:
- name: Lactate
  presence: INCREASED
  context: >-
    High blood lactate is a core laboratory hallmark across pyruvate
    carboxylase deficiency subtypes.
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports lactic acidosis/elevated lactate as a core
      biochemical disease finding.
  readouts:
  - target: Lactate Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased lactate reports the lactate-accumulation branch created by impaired pyruvate-to-oxaloacetate flux.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        The patient cohort identifies lactic acidosis as a core biochemical and
        clinical finding, supporting lactate as the readout of lactate
        accumulation.
- name: Ketonuria
  presence: PRESENT
  context: >-
    Ketonuria is part of the recurrent biochemical signature of pyruvate
    carboxylase deficiency.
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main biochemical and clinical findings in PC deficiency (PCD)
      include lactic acidosis, ketonuria, failure to thrive, and
      neurological dysfunction.
    explanation: >-
      This directly supports ketonuria as a characteristic biochemical
      abnormality.
  readouts:
  - target: Mitochondrial Energy Deficit
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: The presence of ketonuria is a biochemical readout of metabolic decompensation accompanying the mitochondrial energy deficit in pyruvate carboxylase deficiency.
    evidence:
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The main biochemical and clinical findings in PC deficiency (PCD)
        include lactic acidosis, ketonuria, failure to thrive, and
        neurological dysfunction.
      explanation: >-
        The cohort lists ketonuria with lactic acidosis, failure to thrive, and
        neurologic dysfunction, supporting it as a diagnostic biochemical
        readout of the systemic energy-deficit branch.
- name: Hypercitrullinemia
  presence: INCREASED
  subtype: Type B
  context: >-
    Elevated plasma citrulline can occur in severe neonatal type B disease as
    part of the secondary metabolic and nitrogen-disposal abnormalities
    reported in this presentation.
  evidence:
  - reference: PMID:16278852
    reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably
      found.
    explanation: >-
      This directly supports hypercitrullinemia as a severe neonatal
      biochemical abnormality.
  readouts:
  - target: Urea Cycle Perturbation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated citrulline reports the secondary nitrogen-disposal and urea-cycle perturbation seen in severe neonatal pyruvate carboxylase deficiency.
    evidence:
    - reference: PMID:16278852
      reference_title: "Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably
        found.
      explanation: >-
        The severe neonatal series reports invariant hypercitrullinemia,
        supporting elevated citrulline as the biochemical readout of the
        urea-cycle perturbation branch.
genetic:
- name: PC
  association: Causal biallelic variant
  gene_term:
    preferred_term: PC
    term:
      id: hgnc:8636
      label: PC
  notes: >-
    Pyruvate carboxylase deficiency disease is caused by biallelic pathogenic
    variants in the PC gene.
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other proband with normal citrulline, lysine, moderate lactate,
      paraventricular cystic lesions, bony deformities, and a novel
      missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC
      gene, biochemically favoured type A.
    explanation: >-
      This directly supports PC as the causal gene in molecularly confirmed
      disease.
environmental: []
treatments:
- name: Triheptanoin supplementation
  description: >-
    Triheptanoin is used as an anaplerotic odd-chain triglyceride therapy,
    with mixed overall results but apparent benefit in some type C patients.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
  target_mechanisms:
  - target: Impaired Anaplerosis
    treatment_effect: BYPASSES
    description: Triheptanoin supplies odd-chain substrates that can replenish TCA-cycle intermediates despite impaired PC-dependent anaplerosis.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Triheptanoin is an odd‐chain triglyceride, with the potential to
        replenish TCA intermediates (anaplerosis), and its metabolites cross
        the blood–brain‐barrier.
      explanation: >-
        The type C case report explicitly frames triheptanoin as an
        anaplerotic therapy that can replenish TCA intermediates.
  - target: Lactate Accumulation
    treatment_effect: MODULATES
    description: Triheptanoin treatment can lower the lactate-accumulation branch in selected patients, although cohort-level effects are variable.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Subsequently, hospitalisations during intercurrent illnesses
        decreased, post-exertional hyperlactataemia resolved and exercise
        tolerance improved.
      explanation: >-
        The treated type C patient had resolution of post-exertional
        hyperlactatemia, supporting modulation of lactate accumulation.
    - reference: PMID:37207470
      reference_title: >-
        Clinical, biochemical and molecular characterization of 12 patients
        with pyruvate carboxylase deficiency treated with triheptanoin.
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An overall trend of lactate reduction with time on triheptanoin
        was noted, but with significant variability among subjects and
        only one subject reaching close to statistical significance for
        this endpoint.
      explanation: >-
        The larger cohort supports a possible lactate-lowering effect but
        also documents substantial inter-individual variability.
  - target: Mitochondrial Energy Deficit
    treatment_effect: MODULATES
    description: In type C disease, triheptanoin may improve energy homeostasis and CNS myelin synthesis.
    evidence:
    - reference: DOI:10.1002/jmd2.12405
      reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Triheptanoin was well‐tolerated and appeared efficacious during
        2 years' follow‐up, and has potential to restore energy
        homeostasis and myelin synthesis in PCD type C.
      explanation: >-
        The type C report supports modulation of the energy-deficit branch
        and downstream myelin synthesis.
  evidence:
  - reference: PMID:37207470
    reference_title: >-
      Clinical, biochemical and molecular characterization of 12 patients
      with pyruvate carboxylase deficiency treated with triheptanoin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use of the anaplerotic agent triheptanoin on a limited number of
      individuals with PCD has had mixed results.
    explanation: >-
      This directly supports disease-specific use of triheptanoin in the
      clinical literature.
  - reference: DOI:10.1002/jmd2.12405
    reference_title: Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, hospitalisations during intercurrent illnesses
      decreased, post-exertional hyperlactataemia resolved and exercise
      tolerance improved.
    explanation: >-
      This directly supports clinical benefit from triheptanoin in at least
      one type C patient.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Molecular testing confirms biallelic PC variants and distinguishes among
    subtype presentations.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The other proband with normal citrulline, lysine, moderate lactate,
      paraventricular cystic lesions, bony deformities, and a novel
      missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC
      gene, biochemically favoured type A.
    explanation: >-
      This directly supports molecular confirmation through PC variant
      detection.
- name: Clinical whole-exome sequencing
  description: >-
    Whole-exome sequencing is used in current diagnostic workups for pyruvate
    carboxylase deficiency.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: MAXO:0009004
      label: clinical whole-exome sequencing
- name: Prompt metabolic laboratory evaluation
  description: >-
    Rapid biochemical assessment of tachypneic neonates with metabolic
    acidosis is emphasized for early recognition.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: DOI:10.1515/almed-2023-0102
    reference_title: >-
      Clinical, biochemical, and molecular profiles of three Sri Lankan
      neonates with pyruvate carboxylase deficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings indicate the necessity of prompt laboratory
      investigations in a tachypneic neonate with coexisting metabolic
      acidosis, as early recognition is essential for patient management and
      family counselling.
    explanation: >-
      This directly supports prompt diagnostic laboratory evaluation in
      suspected neonatal disease.
differential_diagnoses: []
clinical_trials: []
datasets: []
📚

References & Deep Research

Deep Research

1
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Pyruvate Carboxylase Deficiency Disease (PCD) — Comprehensive Research Report
Edison Scientific Literature 37 citations 2026-04-23T18:55:40.028191

Pyruvate Carboxylase Deficiency Disease (PCD) — Comprehensive Research Report

Executive summary

Pyruvate carboxylase deficiency (PCD) is an ultra-rare, autosomal recessive mitochondrial neurometabolic disorder caused by biallelic pathogenic variants in PC (pyruvate carboxylase; EC 6.4.1.1) that impair conversion of pyruvate to oxaloacetate, disrupting anaplerosis and gluconeogenesis and leading to lactic acidosis, hypoglycemia, neurodevelopmental impairment, and characteristic neuroimaging abnormalities (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2). Contemporary (2023–2024) case reports and the largest available treatment cohort (n=12) underscore (i) severe neonatal mortality in type B disease, (ii) genotype- and phenotype-dependent variability, and (iii) mixed outcomes for anaplerotic therapy with triheptanoin, with a notable apparent benefit in a type C patient (xue2023casereportprenatal pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, lasio2023clinicalbiochemicaland pages 9-11, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Key identifiers and nomenclature (disease information)

What is the disease? A disorder of intermediary metabolism in which deficiency of the mitochondrial biotin-dependent enzyme pyruvate carboxylase limits formation of oxaloacetate from pyruvate, causing multiorgan metabolic imbalance dominated by lactic acidemia/acidosis and early neurologic dysfunction (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2).

Identifiers available in retrieved evidence - OMIM: 266150 (PCD) (xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2) - MONDO: - MONDO_0018141 (infantile form) - MONDO_0018142 (severe neonatal type) - MONDO_0018143 (benign type) (from OpenTargets disease-target associations evidence) (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) - MeSH term present in ClinicalTrials.gov record: “Pyruvate Carboxylase Deficiency Disease” (NCT01461304 chunk 1)

Not found in accessible full-text evidence for this run: Orphanet/ORPHAcode, ICD-10/ICD-11, and a curated MONDO ID for the umbrella disease beyond subtype MONDO terms.

Common synonyms / alternative names (from literature usage) - “Pyruvate carboxylase (PC) deficiency” (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2) - “PCD type A / infantile / North American form” (xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2) - “PCD type B / severe neonatal / French form” (xue2023casereportprenatal pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2) - “PCD type C / intermittent / benign form” (xue2023casereportprenatal pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2)

Evidence provenance: For this rare disease, much of the clinical description derives from individual cases and small series rather than large registries; a notable aggregated cohort is the 12-patient triheptanoin-treated series (lasio2023clinicalbiochemicaland pages 1-3, lasio2023clinicalbiochemicaland pages 9-11).

Artifact: identifiers and subtype snapshot

Disease MONDO ID(s) in evidence OMIM Inheritance Clinical subtype Typical onset Hallmark biochemical features Hallmark clinical features Quantitative epidemiology Key recent source(s) 2023–2024
Pyruvate carboxylase deficiency (PCD) / pyruvate carboxylase deficiency disease MONDO_0018141 = pyruvate carboxylase deficiency, infantile form; MONDO_0018142 = pyruvate carboxylase deficiency, severe neonatal type; MONDO_0018143 = pyruvate carboxylase deficiency, benign type; disease-level association also noted as EFO_1001142 “pyruvate carboxylase deficiency disease” (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) 266150 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, habarou2015pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Autosomal recessive; caused by biallelic/bi-allelic PC variants (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, habarou2015pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Disease-level summary Congenital to infancy; variable by subtype (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Lactic acidosis/hyperlactataemia, ketonuria or ketoacidosis, elevated alanine; severe forms may show hyperammonemia, hypercitrullinemia, elevated lysine/proline, abnormal lactate:pyruvate and acetoacetate:β-hydroxybutyrate ratios (lasio2023clinicalbiochemicaland pages 3-4, xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2) Neurometabolic disorder with hypotonia, seizures, developmental delay, failure to thrive, encephalopathy; MRI may show delayed myelination/white-matter abnormalities/cysts (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, lasio2023clinicalbiochemicaland pages 3-4, xue2023casereportprenatal pages 1-2, xue2023casereportprenatal pages 5-7, lasio2023clinicalbiochemicaland pages 1-3) Estimated incidence/prevalence reported as ~1 in 250,000 live births/births (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, habarou2015pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, tsygankova2022expandingthegenetic pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2) Lasio et al., Mol Genet Metab, Jun 2023, DOI 10.1016/j.ymgme.2023.107605, https://doi.org/10.1016/j.ymgme.2023.107605 (lasio2023clinicalbiochemicaland pages 3-4, lasio2023clinicalbiochemicaland pages 1-3); Xue, Front Endocrinol, Jul 2023, DOI 10.3389/fendo.2023.1199590, https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2, xue2023casereportprenatal pages 5-7); Maryami et al., Iran Biomed J, Sep 2023, DOI 10.61186/ibj.27.5.307, https://doi.org/10.61186/ibj.27.5.307 (maryami2023insilicoanalysis pages 1-2, maryami2023insilicoanalysis pages 2-4); Jasinge et al., Adv Lab Med, Jan 2024, DOI 10.1515/almed-2023-0102, https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 5-7); Bernhardt et al., JIMD Rep, Dec 2024, DOI 10.1002/jmd2.12405, https://doi.org/10.1002/jmd2.12405 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2)
PCD type A (infantile / North American form) MONDO_0018141 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) 266150 (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2) Autosomal recessive (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2) Type A Infancy; can present after neonatal period, but neonatal overlap reported (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2) Lactic acidosis/hyperlactataemia, ketosis, hyperalaninemia, hyperprolinemia; generally less severe than type B; citrulline may be normal in A/C (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4) Developmental delay, hypotonia, seizures, failure to thrive; often death in infancy/early childhood, though survival is longer than type B (lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2) Included within overall estimate ~1 in 250,000; no subtype-specific rate available in evidence (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, jasinge2024clinicalbiochemicaland pages 1-2) Jasinge et al., Jan 2024: one proband with moderate lactate, normal citrulline/lysine, paraventricular cystic lesions, novel homozygous c.2746G>C p.Asp916His, biochemically favoring type A, DOI/URL above (jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4)
PCD type B (severe neonatal / French form) MONDO_0018142 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) 266150 (xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2) Autosomal recessive (xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2) Type B Neonatal, often within first 72 h or first hours of life (xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, maryami2023insilicoanalysis pages 2-4) Severe lactic acidosis, ketoacidosis, hyperammonemia, hypercitrullinemia, elevated alanine/proline/lysine, abnormal redox ratios; high plasma lactate often >10 mmol/L (lasio2023clinicalbiochemicaland pages 3-4, xue2023casereportprenatal pages 1-2, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, maryami2023insilicoanalysis pages 2-4) Tachypnea/respiratory distress, truncal hypotonia, seizures, abnormal movements, liver failure/hepatomegaly, severe encephalopathy; usually early death, often within weeks to months (xue2023casereportprenatal pages 1-2, xue2023casereportprenatal pages 5-7, lasio2023clinicalbiochemicaland pages 1-3, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, maryami2023insilicoanalysis pages 2-4) No subtype-specific population rate; prognosis poor with survival often <3 months in reports/reviews (xue2023casereportprenatal pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2) Xue, Jul 2023: first reported Chinese type B case, compound heterozygous c.1154_1155del and c.152G>A, death at 26 days, DOI/URL above (xue2023casereportprenatal pages 1-2); Maryami et al., Sep 2023: novel p.G303Afs40 and p.R156P associated with severe/type B disease, DOI/URL above (maryami2023insilicoanalysis pages 1-2, maryami2023insilicoanalysis pages 2-4); Jasinge et al., Jan 2024: two siblings with typical type B biochemical findings, truncating c.2514G>A p.Trp838, DOI/URL above (jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 5-7)
PCD type C (benign / intermittent form) MONDO_0018143 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) 266150 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Autosomal recessive (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Type C Later onset or intermittent; reported from infancy to childhood (e.g., 2 years) with episodic crises (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Episodic hyperlactataemia, ketoacidosis, hypoglycaemia; milder/intermittent biochemical abnormalities (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, lasio2023clinicalbiochemicaland pages 3-4, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2) Relatively favorable prognosis, mild developmental delay, exercise intolerance, recurrent hospitalizations during illness; MRI may show delayed myelination or mild volume loss (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) Only 11 type C patients reported, 7 molecularly confirmed, in Bernhardt et al. 2024 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) Bernhardt et al., Dec 2024: 2 new type C cases; triheptanoin up-titrated to 35 mL/day (~25% daily energy) in one patient was associated with fewer hospitalizations, resolution of post-exertional hyperlactataemia, improved exercise tolerance, and improved myelination over 18 months to 2 years, DOI/URL above (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2)

Table: This table summarizes core disease identifiers, inheritance, subtype-defining features, epidemiology, and recent 2023–2024 primary literature for pyruvate carboxylase deficiency. It is designed as a compact reference for rapid evidence-grounded review.

Etiology

Disease causal factors

Genetic cause: Biallelic pathogenic variants in PC cause PCD (autosomal recessive) (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Molecular function: PC catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate (OAA), supporting gluconeogenesis and replenishing tricarboxylic acid (TCA) cycle intermediates (anaplerosis) (mochel2005pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).

Risk factors

  • Family history / autosomal recessive inheritance (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2)
  • Consanguinity is highlighted in recent neonatal series from Sri Lanka (two consanguineous families) (jasinge2024clinicalbiochemicaland pages 2-4).

Protective factors

No validated genetic “protective variants” or environmental protective factors were identified in the retrieved evidence.

Gene–environment interactions

No direct gene–environment interaction studies were retrieved; however, metabolic stress/infections can precipitate decompensation episodes in infantile forms (wang2008themolecularbasis pages 1-2).

Phenotypes (clinical spectrum)

PCD is classically divided into three overlapping phenotypes (A/B/C) (xue2023casereportprenatal pages 1-2, wang2008themolecularbasis pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).

Type B (severe neonatal) — high mortality

  • Onset: within hours to first 72 hours of life (xue2023casereportprenatal pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).
  • Key manifestations: severe lactic acidosis with metabolic acidosis, hyperammonemia and hypercitrullinemia, hypotonia, seizures, abnormal movements, and frequent early death (xue2023casereportprenatal pages 1-2, wang2008themolecularbasis pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).
  • Quantitative examples:
  • In the Chinese type B case: arterial pH 7.24, HCO3− 5.2 mM, urine lactic acid 7262 nmol/mg creatinine, urine pyruvate 1416.8 nmol/mg creatinine, urine 3-hydroxybutyrate 1725.3 nmol/mg creatinine (xue2023casereportprenatal pages 1-2).
  • In the Sri Lankan neonatal series: example lactate 18.75 mmol/L, pH 7.12, HCO3− 4.2 mmol/L, glucose 38 mg/dL (jasinge2024clinicalbiochemicaland pages 2-4).

Type A (infantile)

  • Onset: infancy; neonatal overlap reported (lasio2023clinicalbiochemicaland pages 1-3, jasinge2024clinicalbiochemicaland pages 1-2).
  • Key manifestations: lactic acidosis/hyperlactataemia, ketosis, hypotonia, seizures, developmental delay; death often in infancy/early childhood (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2).

Type C (intermittent/benign/attenuated)

  • Onset/course: episodic metabolic decompensation; comparatively favorable prognosis (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).
  • Clinical pattern: episodic hyperlactataemia and ketoacidosis with milder developmental delay and variable myelination changes (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).
  • Quantitative example: persistent lactate 4.1–5.9 mmol/L with lactate:pyruvate ratio 24–29 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Suggested HPO terms (non-exhaustive; based on phenotypes repeatedly described)

  • Metabolic/biochemical: Lactic acidosis (HP:0003128), Metabolic acidosis (HP:0001942), Hypoglycemia (HP:0001943), Hyperammonemia (HP:0001987), Ketonuria (HP:0002919), Ketoacidosis (HP:0001993)
  • Neurologic: Hypotonia (HP:0001252), Seizures (HP:0001250), Developmental delay (HP:0001263), Encephalopathy (HP:0001298), Abnormal movement (HP:0001270)
  • Respiratory: Tachypnea/Respiratory distress (HP:0002094/HP:0002098)
  • Neuroimaging: Delayed myelination (HP:0003429), Ventriculomegaly (HP:0002119), Subependymal cysts (HP:0010629) (supported by case descriptions) (xue2023casereportprenatal pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Genetic / molecular information

Causal gene

  • PC (pyruvate carboxylase), nuclear-encoded mitochondrial enzyme; gene maps to 11q13 region and encodes a ~125 kDa protein; multiple transcripts exist (wang2008themolecularbasis pages 1-2).

Pathogenic variant spectrum (classes and recent examples)

Variant classes include missense, nonsense/frameshift, small deletions/insertions, splice-site variants, and (importantly for diagnostics) deep intronic and structural variants (reciprocal translocation disrupting PC) (tsygankova2022expandingthegenetic pages 1-2, wang2008themolecularbasis pages 1-2).

Recent (2023–2024) examples - Type B: compound heterozygous variants c.1154_1155del and c.152G>A (China case report) (xue2023casereportprenatal pages 1-2). - Type B: homozygous frameshift c.908delG:p.G303Afs40 (likely pathogenic) and homozygous missense p.R156P (VUS in paper but argued damaging by in silico modeling) (maryami2023insilicoanalysis pages 1-2, maryami2023insilicoanalysis pages 2-4). - Sri Lankan neonates: homozygous nonsense c.2514G>A (p.Trp838) in one proband; novel homozygous missense c.2746G>C (p.Asp916His) in another (jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 1-2).

Deep intronic / structural findings (diagnostic expansion) - Homozygous deep intronic c.1983-116C>T caused exonization (residual WT transcript present) (tsygankova2022expandingthegenetic pages 1-2). - Reciprocal translocation disrupting PC discovered by WGS and validated by FISH/Sanger (tsygankova2022expandingthegenetic pages 1-2).

Variant counts (HGMD snapshot as of 2022-06-12) A 2022 report states 62 PC variants in HGMD, with distribution: 42 missense/nonsense, 7 splicing, 7 small deletions, 5 small insertions, 1 small duplication; and noted that large structural or deep intronic variants had not been reported at that time—their paper then contributed such variant classes (tsygankova2022expandingthegenetic pages 1-2).

Modifier-like genetic factors

Somatic mosaicism: In an 8-patient molecular series (1 type A, 5 type B, 2 type C), mosaicism was found in 5 cases and 4 had prolonged survival; authors concluded survival correlated better with mosaicism than with classical phenotype labels or residual protein (wang2008themolecularbasis pages 1-2).

Environmental information

No specific environmental toxins, lifestyle factors, or infectious agents as causal contributors were identified. Intercurrent infections/illnesses are repeatedly described as triggers for metabolic decompensation (e.g., type C and type A/B overlap cases) (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2).

Mechanism / pathophysiology

Core biochemical lesion and causal chain

  1. PC loss-of-function reduces conversion of pyruvate → oxaloacetate (OAA) in mitochondria (mochel2005pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).
  2. OAA deficit impairs replenishment of TCA intermediates (anaplerosis) and compromises gluconeogenesis (mochel2005pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).
  3. Energy failure and redox imbalance promote lactic acidosis (often severe in type B) and can lead to hypoglycemia (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).
  4. Disruption of aspartate/OAA-dependent processes contributes to urea-cycle perturbation, manifesting as hypercitrullinemia and hyperammonemia in severe neonatal disease (wang2008themolecularbasis pages 1-2, xue2023casereportprenatal pages 1-2).
  5. CNS vulnerability: PC activity is robust in glia but absent in neurons; glial anaplerosis supports glutamine supply for neuronal glutamate/GABA, providing a mechanistic basis for neurologic dysfunction and encephalopathy (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).

Pathways and ontology suggestions

  • Pathways: TCA cycle / Krebs cycle; gluconeogenesis; anaplerotic reactions (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2).
  • GO biological process (suggested): anaplerotic reaction; gluconeogenesis; tricarboxylic acid cycle; regulation of cellular redox homeostasis.
  • GO molecular function (suggested): pyruvate carboxylase activity.
  • Cell types (CL suggested): astrocyte (glial PC activity emphasized) (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).
  • Anatomy (UBERON suggested): liver, brain, kidney, pancreatic islet (high PC activity tissues) (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, wang2008themolecularbasis pages 1-2).
  • CHEBI suggested: pyruvate, oxaloacetate, lactate, alanine, citrate, aspartate, ammonia.

Anatomical structures affected

  • Primary systems/organs: CNS/brain (encephalopathy, seizures, myelination abnormalities), liver (hepatic failure in severe neonatal cases), metabolic homeostasis broadly (mochel2005pyruvatecarboxylasedeficiency pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).
  • Neuroimaging localizations: delayed cerebral myelination and cystic white matter/ventricular abnormalities have been documented, including prenatal onset as early as 22w5d gestation (xue2023casereportprenatal pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).
  • Subcellular (GO cellular component suggested): mitochondrial matrix (PC localization) (tsygankova2022expandingthegenetic pages 1-2).

Temporal development

  • Type B: acute neonatal presentation; often death within weeks to months. A specific case died at 26 days (xue2023casereportprenatal pages 1-2). A 2024 series notes two neonates died within the first six weeks (jasinge2024clinicalbiochemicaland pages 2-4).
  • Type A: onset in infancy with variable course; death often in infancy/early childhood (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2).
  • Type C: episodic course with comparatively favorable prognosis and longer survival; symptomatic crises can be triggered by illness/exertion (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Inheritance and population

  • Inheritance: autosomal recessive (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2).
  • Epidemiology: multiple sources cite an estimate of ~1 in 250,000 live births/births (lasio2023clinicalbiochemicaland pages 1-3, xue2023casereportprenatal pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, tsygankova2022expandingthegenetic pages 1-2).
  • Population clusters: 2010 review notes higher reporting in specific groups (Algonquian-speaking Amerindians and Arabs) (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).

Diagnostics

Biochemical testing (core real-world implementation)

  • Blood gases / lactate: PCD often presents with lactic acidemia; mechanistic review gives typical lactic acid >5 mmol/L and bicarbonate <18 mmol/L (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2). Severe type B often has lactate >10 mmol/L (jasinge2024clinicalbiochemicaland pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2).
  • Redox ratios: elevated lactate:pyruvate and altered ketone ratios (acetoacetate:β-hydroxybutyrate; 3-hydroxybutyrate:acetoacetate) described as characteristic, especially in type B (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2).
  • Plasma amino acids: elevations can include alanine, citrulline, proline, lysine (especially type B) (lasio2023clinicalbiochemicaland pages 1-3, wang2008themolecularbasis pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).
  • Urine organic acids: elevated lactate and ketone bodies; some reports describe reduced excretion of TCA intermediates (jasinge2024clinicalbiochemicaland pages 2-4, mochel2005pyruvatecarboxylasedeficiency pages 1-2).

Imaging

  • Brain MRI features include delayed myelination/hypomyelination and cystic/ventricular abnormalities; prenatal imaging abnormalities can occur (xue2023casereportprenatal pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Enzyme assays

  • Definitive diagnosis may require enzymatic assay; a 2010 review states enzymatic assay is “still often required” (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).
  • Enzyme activity can be assessed in cultured fibroblasts (also referenced as a definitive approach in 2022 genetic paper) (tsygankova2022expandingthegenetic pages 1-2, habarou2015pyruvatecarboxylasedeficiency pages 2-3).
  • Prenatal confirmation can include PC activity measurement in chorionic villi or cultured amniotic fluid cells (xue2023casereportprenatal pages 5-7).

Genetic testing approach

  • WES used in multiple recent cases (China type B report; Maryami 2023; Tsygankova 2022) (xue2023casereportprenatal pages 1-2, maryami2023insilicoanalysis pages 2-4, tsygankova2022expandingthegenetic pages 1-2).
  • WGS with deep analysis is recommended when standard testing yields 0–1 pathogenic allele, as deep intronic and structural variants can be missed (tsygankova2022expandingthegenetic pages 1-2).

Differential diagnosis

Several disorders can overlap with lactic acidosis and neurologic dysfunction (e.g., other disorders of pyruvate metabolism/TCA cycle, mitochondrial respiratory chain disorders); misdiagnosis as respiratory chain defect has been documented (habarou2015pyruvatecarboxylasedeficiency pages 1-2).

Screening

No evidence in the retrieved corpus supports routine newborn screening for PCD.

Outcome / prognosis

  • Mechanistic review: “There is no effective treatment… most, except those affected by the benign form, die in early life” (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2).
  • Type B neonatal cases frequently die early despite supportive care (e.g., death at 26 days) (xue2023casereportprenatal pages 1-2).
  • Prognostic modifier: somatic mosaicism correlates with prolonged survival (wang2008themolecularbasis pages 1-2).

Treatment

Acute management (real-world implementation)

  • Anti-catabolic therapy (e.g., dextrose-containing IV fluids) and correction of acidosis (bicarbonate) are repeatedly used in severe neonatal presentations and reviews (lasio2023clinicalbiochemicaland pages 3-4, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2, xue2023casereportprenatal pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4).

Cofactors / supplements (supportive)

  • Biotin is frequently trialed (minimal effect in A/B; occasional benefit reported in C) (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).
  • Thiamine, riboflavin, carnitine, CoQ10 and other supportive measures are commonly administered in case management (xue2023casereportprenatal pages 1-2, mochel2005pyruvatecarboxylasedeficiency pages 1-2, habarou2015pyruvatecarboxylasedeficiency pages 2-3, jasinge2024clinicalbiochemicaland pages 2-4).
  • Citrate/aspartate supplementation may stabilize systemic biochemical derangements but may not normalize CSF abnormalities or neurologic outcome (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Anaplerotic therapy: triheptanoin

Concept: triheptanoin (odd-chain triglyceride) yields acetyl-CoA and propionyl-CoA; propionyl-CoA → succinyl-CoA replenishes TCA intermediates (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Evidence and outcomes - Largest cohort (n=12; 2023): overall trend toward lactate reduction in 4 of 6 analyzable subjects; only one approached statistical significance; HRQoL outcomes were mixed (lasio2023clinicalbiochemicaland pages 9-11). Authors propose possible genotype-dependent response patterns (lasio2023clinicalbiochemicaland pages 9-11). - Type C case with apparent benefit (2024): triheptanoin up-titrated to 35 mL/day (~25% daily energy) was associated with fewer hospitalizations, resolution of post-exertional hyperlactataemia, improved exercise tolerance, and improved myelination on repeat MRI at 18 months, with apparent efficacy over 2 years (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2). - Severe neonatal report (2005): a type B infant showed “immediate reversal (less than 48 h) of major hepatic failure” on triheptanoin-based anaplerotic management, but later died from severe infection (mochel2005pyruvatecarboxylasedeficiency pages 1-2).

Transplantation

Liver transplantation is referenced in the triheptanoin cohort paper as having produced partial biochemical improvement in some reports, but detailed outcomes were not extractable in the provided excerpt (lasio2023clinicalbiochemicaland pages 3-4).

Clinical trials / expanded access

ClinicalTrials.gov expanded access: NCT01461304 (“Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism”) explicitly includes PCD as an eligible condition. Key operational details from the record include: - First posted: 2011-10-28; last update posted: 2021-12-10 (NCT01461304 chunk 1). - Dosing described as up to 2 g/kg/24 h (up to 4 g/kg/24 h in cardiomyopathy), divided doses, with 12-month period and extension option (NCT01461304 chunk 1).

MAXO term suggestions (treatments/interventions)

  • Intravenous glucose administration; correction of metabolic acidosis; dietary management; triheptanoin supplementation (anaplerotic therapy); biotin supplementation; genetic counseling; prenatal diagnosis.

Prevention

  • Primary prevention: not applicable beyond carrier screening strategies.
  • Secondary/tertiary prevention: rapid recognition and early metabolic management in tachypneic neonates with metabolic acidosis is emphasized (jasinge2024clinicalbiochemicaland pages 1-2).
  • Genetic counseling and prenatal diagnosis: strongly emphasized; prenatal neuroradiologic abnormalities can be detected early (22w5d) and prenatal molecular testing (amniotic fluid sequencing) is feasible (xue2023casereportprenatal pages 1-2, xue2023casereportprenatal pages 5-7).

Other species / natural disease

No naturally occurring veterinary cases were retrieved in the available evidence.

Model organisms and experimental models

No PCD-specific animal model papers were retrieved in this run. Human cellular models used for diagnosis/research include patient-derived skin fibroblasts (enzyme activity assays; expression studies) and prenatal cell sources (chorionic villi/amniocytes) (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, tsygankova2022expandingthegenetic pages 1-2, xue2023casereportprenatal pages 5-7).

Recent developments (2023–2024 highlights)

  1. Largest treated cohort to date (2023): long-term triheptanoin treatment in 12 PCD patients suggests high inter-individual variability and possible genotype-dependent response, but limited statistical signal overall (lasio2023clinicalbiochemicaland pages 1-3, lasio2023clinicalbiochemicaland pages 9-11).
  2. Prenatal onset documented (2023): neuroradiologic phenotype detected as early as 22w5d gestation in a genetically confirmed type B case, reinforcing prenatal diagnostic value (xue2023casereportprenatal pages 1-2).
  3. New neonatal genotypes (2023–2024): multiple novel PC variants (frameshift, nonsense, missense) reported across diverse populations (Iran; Sri Lanka; China) (maryami2023insilicoanalysis pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, xue2023casereportprenatal pages 1-2).
  4. Type C triheptanoin response (2024): first reported type C triheptanoin response with reduced hospitalizations and improved myelination (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).

Artifact: variants and diagnostic hallmarks with example values

Section Study / case Year Phenotype Variant class / hallmark cDNA Protein Zygosity Example quantitative / descriptive findings DOI / URL Citation
Variant Xue case report, first reported Chinese type B case 2023 Type B Compound heterozygous deletion + missense c.1154_1155del; c.152G>A NA Compound heterozygous Prenatal neuroradiologic abnormalities from 22w5d; infant died at 26 days 10.3389/fendo.2023.1199590 / https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2)
Variant Maryami et al., neonate 1 2023 Type B / severe form Frameshift c.908delG p.G303Afs*40 Homozygous Classified likely pathogenic (ACMG); associated with acute early-onset metabolic derangement and neonatal death 10.61186/ibj.27.5.307 / https://doi.org/10.61186/ibj.27.5.307 (maryami2023insilicoanalysis pages 1-2, maryami2023insilicoanalysis pages 2-4)
Variant Maryami et al., neonate 2 2023 Type B / severe form Missense NA p.R156P Homozygous Classified VUS by ACMG in paper, but authors concluded pathogenicity supported by in silico/ATP-binding destabilization 10.61186/ibj.27.5.307 / https://doi.org/10.61186/ibj.27.5.307 (maryami2023insilicoanalysis pages 1-2, maryami2023insilicoanalysis pages 2-4)
Variant Jasinge et al., Sri Lankan proband 2024 Type A-favoring overlap Missense c.2746G>C p.Asp916His Homozygous Novel variant in neonate with normal citrulline/lysine, moderate lactate, paraventricular cystic lesions, bony deformities 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 5-7)
Variant Jasinge et al., affected siblings 2024 Type B Nonsense / truncating c.2514G>A p.Trp838* Homozygous Severe neonatal presentation; two affected neonates died in first six weeks of life in series 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 5-7)
Variant Tsygankova et al., Patient 1 2022 Type A Missense + structural rearrangement c.1372A>G p.Asn458Asp Heterozygous plus reciprocal translocation disrupting PC WGS found discordant reads mapped to chr11/chr1; diagnosis required structural variant analysis 10.1016/j.ymgmr.2022.100889 / https://doi.org/10.1016/j.ymgmr.2022.100889 (tsygankova2022expandingthegenetic pages 1-2)
Variant Tsygankova et al., Patient 2 2022 Type C Deep intronic splice-altering c.1983-116C>T NA Homozygous mRNA analysis showed exonization of intron 16 sequences with residual WT transcript 10.1016/j.ymgmr.2022.100889 / https://doi.org/10.1016/j.ymgmr.2022.100889 (tsygankova2022expandingthegenetic pages 1-2)
Variant Tsygankova et al., additional patients 2022 Type A / Type B Missense c.1876C>T; c.2606G>C; c.2435C>A p.Arg626Trp; p.Gly869Ala; p.Ala812Asp Compound heterozygous or homozygous Reported in more severe disease; exact patient-level assignment not fully extractable from available evidence 10.1016/j.ymgmr.2022.100889 / https://doi.org/10.1016/j.ymgmr.2022.100889 (tsygankova2022expandingthegenetic pages 1-2)
Variant Wang et al., eight-patient molecular series 2008 Types A/B/C Mixed classes: missense, deletions, splice-site, nonsense NA NA Includes mosaic and non-mosaic cases Eight novel complex mutations in 8 cases; somatic mosaicism in 5 cases, 4 with prolonged survival 10.1016/j.ymgme.2008.06.006 / https://doi.org/10.1016/j.ymgme.2008.06.006 (wang2008themolecularbasis pages 1-2)
Biochemical hallmark General type B pattern from reviews/series 2005-2024 Type B Plasma lactate NA NA NA Often high and severe; “high plasma lactate often >10 mmol/L” in type B NA (mochel2005pyruvatecarboxylasedeficiency pages 1-2, jasinge2024clinicalbiochemicaland pages 1-2)
Biochemical hallmark Xue case report 2023 Type B Plasma / blood gas NA NA NA Arterial pH 7.24; HCO3− 5.2 mM 10.3389/fendo.2023.1199590 / https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2)
Biochemical hallmark Xue case report 2023 Type B Plasma amino acids NA NA NA Citrulline 109.4 mM; tyrosine 223.4 mM; alanine 408.5 mM 10.3389/fendo.2023.1199590 / https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2)
Biochemical hallmark Xue case report 2023 Type B Urine organic acids NA NA NA Lactic acid 7262 nmol/mg creatinine; pyruvate 1416.8 nmol/mg creatinine; 3-hydroxybutyric acid 1725.3 nmol/mg creatinine 10.3389/fendo.2023.1199590 / https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2)
Biochemical hallmark Xue case report 2023 Type B MRI / fetal imaging NA NA NA Widened posterior horns of lateral ventricles, huge subependymal cysts, increased biparietal diameter and head circumference 10.3389/fendo.2023.1199590 / https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2, xue2023casereportprenatal pages 5-7)
Biochemical hallmark Jasinge et al., Patient 1 example 2024 Type B Lactate / acid-base / glucose NA NA NA Plasma lactate 18.75 mmol/L; pH 7.12; HCO3− 4.2 mmol/L; capillary glucose 38 mg/dL 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 2-4)
Biochemical hallmark Jasinge et al. 2024 Type B Plasma amino acids NA NA NA Markedly elevated citrulline, alanine, lysine, and tyrosine 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 2-4)
Biochemical hallmark Jasinge et al. 2024 Type A/B overlap Urine organic acids NA NA NA Very high lactate and ketone bodies (3-hydroxybutyrate, acetoacetate); reduced urinary TCA intermediates including alpha-ketoglutarate, fumarate, oxaloacetate, malate 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 2-4, jasinge2024clinicalbiochemicaland pages 5-7)
Biochemical hallmark Jasinge et al. 2024 Type A/B overlap Neuroimaging NA NA NA Porencephalic cysts, paraventricular cystic lesions, microcephaly; recurrent infections precipitated refractory metabolic acidosis 10.1515/almed-2023-0102 / https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 1-2, jasinge2024clinicalbiochemicaland pages 5-7)
Biochemical hallmark Bernhardt et al., Patient 1 2024 Type C Lactate / lactate:pyruvate NA NA NA Persistent hyperlactataemia 4.1–5.9 mmol/L; lactate:pyruvate ratio 24–29 (normal <25) 10.1002/jmd2.12405 / https://doi.org/10.1002/jmd2.12405 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2)
Biochemical hallmark Bernhardt et al., Patient 1 2024 Type C Glucose / ammonia NA NA NA Severe neonatal lactic acidosis and hypoglycaemia without hyperammonaemia 10.1002/jmd2.12405 / https://doi.org/10.1002/jmd2.12405 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2)
Biochemical hallmark Bernhardt et al. 2024 Type C MRI NA NA NA Delayed cerebral myelination with improvement on follow-up after triheptanoin 10.1002/jmd2.12405 / https://doi.org/10.1002/jmd2.12405 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2)
Biochemical hallmark Hidalgo review/case summary 2021 Types A/B/C Lactate and lactate:pyruvate ranges NA NA NA Type A lactate 2–10 mmol/L; Type B >10 mmol/L; Type C 2–5 mmol/L; lactate:pyruvate ratio usually >20 in type B and <20 in types A/C 10.7759/cureus.15042 / https://doi.org/10.7759/cureus.15042 (hidalgo2021auniquecase pages 4-5)
Biochemical hallmark Lasio et al. review of phenotype 2023 Types A/B/C Signature abnormalities NA NA NA Type B: severe neonatal lactic acidosis, ketoacidosis, hyperammonemia, elevated alanine/citrulline/proline/lysine, elevated lactate:pyruvate and acetoacetate:β-hydroxybutyrate; Type A: lactic acidosis, ketosis, hyperalaninemia, hyperprolinemia 10.1016/j.ymgme.2023.107605 / https://doi.org/10.1016/j.ymgme.2023.107605 (lasio2023clinicalbiochemicaland pages 3-4, lasio2023clinicalbiochemicaland pages 1-3)

Table: This table compiles representative PC variants and core diagnostic biochemical/imaging features for pyruvate carboxylase deficiency using only evidence available in the conversation. It is useful as a quick-reference artifact linking genotype classes to phenotype subtypes and concrete diagnostic values from recent case reports and series.

Evidence-based expert interpretation (authoritative analysis)

  • The field consensus remains that disease-modifying therapy is lacking and supportive care predominates, especially for types A/B where early mortality is common (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2, bernhardt2024pyruvatecarboxylasedeficiency pages 1-2).
  • Anaplerotic therapy is mechanistically attractive because the “primary result of the defect is a major deficit of oxaloacetate for the CAC,” but real-world outcomes are heterogeneous and may depend on genotype/domain effects and phenotype severity (mochel2005pyruvatecarboxylasedeficiency pages 1-2, lasio2023clinicalbiochemicaland pages 9-11).
  • Diagnostic practice is shifting toward genome-wide sequencing plus structural/deep intronic variant analysis, because standard exon-focused approaches can miss causative alleles (tsygankova2022expandingthegenetic pages 1-2).

References (URLs and publication dates where available)

The report citations above include DOI URLs and months/years extracted from the retrieved full texts and records, including: - Lasio et al., Molecular Genetics and Metabolism (Jun 2023): https://doi.org/10.1016/j.ymgme.2023.107605 (lasio2023clinicalbiochemicaland pages 1-3) - Xue, Frontiers in Endocrinology (Jul 2023): https://doi.org/10.3389/fendo.2023.1199590 (xue2023casereportprenatal pages 1-2) - Maryami et al., Iranian Biomedical Journal (Sep 2023): https://doi.org/10.61186/ibj.27.5.307 (maryami2023insilicoanalysis pages 1-2) - Jasinge et al., Advances in Laboratory Medicine (Jan 2024): https://doi.org/10.1515/almed-2023-0102 (jasinge2024clinicalbiochemicaland pages 1-2) - Bernhardt et al., JIMD Reports (published 2024; accepted 2023-12-05; Dec 2024 issue listed): https://doi.org/10.1002/jmd2.12405 (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2) - NCT01461304 (posted 2011-10-28; updated 2021-12-10): ClinicalTrials.gov record as retrieved (NCT01461304 chunk 1)

References

  1. (lasio2023clinicalbiochemicaland pages 1-3): M. Laura Duque Lasio, Angela C. Leshinski, Nicole H. Ducich, Leigh Anne Flore, April Lehman, Natasha Shur, Parul B. Jayakar, Bryan E. Hainline, Alice A. Basinger, William G. Wilson, George A. Diaz, Richard W. Erbe, Dwight D. Koeberl, Jerry Vockley, and Jirair K. Bedoyan. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin. Molecular Genetics and Metabolism, 139:107605, Jun 2023. URL: https://doi.org/10.1016/j.ymgme.2023.107605, doi:10.1016/j.ymgme.2023.107605. This article has 5 citations and is from a peer-reviewed journal.

  2. (marinvalencia2010pyruvatecarboxylasedeficiency pages 1-2): Isaac Marin-Valencia, Charles R. Roe, and Juan M. Pascual. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Molecular genetics and metabolism, 101 1:9-17, Sep 2010. URL: https://doi.org/10.1016/j.ymgme.2010.05.004, doi:10.1016/j.ymgme.2010.05.004. This article has 150 citations and is from a peer-reviewed journal.

  3. (bernhardt2024pyruvatecarboxylasedeficiency pages 1-2): I. Bernhardt, L. Van Dorp, M. Dixon, M. McSweeney, C. Gan, J. Baruteau, and A. Chakrapani. Pyruvate carboxylase deficiency type c; variable presentation and beneficial effect of triheptanoin. JIMD Reports, 65:10-16, Dec 2024. URL: https://doi.org/10.1002/jmd2.12405, doi:10.1002/jmd2.12405. This article has 3 citations and is from a peer-reviewed journal.

  4. (xue2023casereportprenatal pages 1-2): Mei Xue. Case report: prenatal neurological injury in a neonate with pyruvate carboxylase deficiency type b. Frontiers in Endocrinology, Jul 2023. URL: https://doi.org/10.3389/fendo.2023.1199590, doi:10.3389/fendo.2023.1199590. This article has 5 citations.

  5. (jasinge2024clinicalbiochemicaland pages 2-4): Eresha Jasinge, Mihika Fernando, Neluwa-Liyanage Ruwan Indika, Pyara Dilani Ratnayake, Nalin Gamaathige, Ratnanathan Ratnaranjith, Sabine Schroeder, Patricia Jones, Skrahina Volha, Subhashinie Jayasena, Anusha Varuni Gunaratna, Asitha Niroshana Bandara Ekanayake, and Arndt Rolfs. Clinical, biochemical, and molecular profiles of three sri lankan neonates with pyruvate carboxylase deficiency. Advances in Laboratory Medicine, 5:205-212, Jan 2024. URL: https://doi.org/10.1515/almed-2023-0102, doi:10.1515/almed-2023-0102. This article has 0 citations.

  6. (lasio2023clinicalbiochemicaland pages 9-11): M. Laura Duque Lasio, Angela C. Leshinski, Nicole H. Ducich, Leigh Anne Flore, April Lehman, Natasha Shur, Parul B. Jayakar, Bryan E. Hainline, Alice A. Basinger, William G. Wilson, George A. Diaz, Richard W. Erbe, Dwight D. Koeberl, Jerry Vockley, and Jirair K. Bedoyan. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin. Molecular Genetics and Metabolism, 139:107605, Jun 2023. URL: https://doi.org/10.1016/j.ymgme.2023.107605, doi:10.1016/j.ymgme.2023.107605. This article has 5 citations and is from a peer-reviewed journal.

  7. (mochel2005pyruvatecarboxylasedeficiency pages 1-2): Fanny Mochel, Pascale DeLonlay, Guy Touati, Henri Brunengraber, Renee P. Kinman, Daniel Rabier, Charles R. Roe, and Jean-Marie Saudubray. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Molecular genetics and metabolism, 84 4:305-12, Apr 2005. URL: https://doi.org/10.1016/j.ymgme.2004.09.007, doi:10.1016/j.ymgme.2004.09.007. This article has 178 citations and is from a peer-reviewed journal.

  8. (wang2008themolecularbasis pages 1-2): Dong Wang, Hong Yang, Kevin C. De Braganca, Jiesheng Lu, Ling Yu Shih, Paz Briones, Tim Lang, and Darryl C. De Vivo. The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival. Molecular genetics and metabolism, 95 1-2:31-8, Sep 2008. URL: https://doi.org/10.1016/j.ymgme.2008.06.006, doi:10.1016/j.ymgme.2008.06.006. This article has 51 citations and is from a peer-reviewed journal.

  9. (NCT01461304 chunk 1): Jerry Vockley, MD, PhD. Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism. Jerry Vockley, MD, PhD. ClinicalTrials.gov Identifier: NCT01461304

  10. (habarou2015pyruvatecarboxylasedeficiency pages 1-2): F. Habarou, A. Brassier, M. Rio, D. Chrétien, S. Monnot, V. Barbier, R. Barouki, J.P. Bonnefont, N. Boddaert, B. Chadefaux-Vekemans, L. Le Moyec, J. Bastin, C. Ottolenghi, and P. de Lonlay. Pyruvate carboxylase deficiency: an underestimated cause of lactic acidosis. Molecular Genetics and Metabolism Reports, 2:25-31, Mar 2015. URL: https://doi.org/10.1016/j.ymgmr.2014.11.001, doi:10.1016/j.ymgmr.2014.11.001. This article has 32 citations.

  11. (lasio2023clinicalbiochemicaland pages 3-4): M. Laura Duque Lasio, Angela C. Leshinski, Nicole H. Ducich, Leigh Anne Flore, April Lehman, Natasha Shur, Parul B. Jayakar, Bryan E. Hainline, Alice A. Basinger, William G. Wilson, George A. Diaz, Richard W. Erbe, Dwight D. Koeberl, Jerry Vockley, and Jirair K. Bedoyan. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin. Molecular Genetics and Metabolism, 139:107605, Jun 2023. URL: https://doi.org/10.1016/j.ymgme.2023.107605, doi:10.1016/j.ymgme.2023.107605. This article has 5 citations and is from a peer-reviewed journal.

  12. (xue2023casereportprenatal pages 5-7): Mei Xue. Case report: prenatal neurological injury in a neonate with pyruvate carboxylase deficiency type b. Frontiers in Endocrinology, Jul 2023. URL: https://doi.org/10.3389/fendo.2023.1199590, doi:10.3389/fendo.2023.1199590. This article has 5 citations.

  13. (tsygankova2022expandingthegenetic pages 1-2): Polina Tsygankova, Igor Bychkov, Marina Minzhenkova, Natalia Pechatnikova, Lyudmila Bessonova, Galina Buyanova, Irina Naumchik, Nikita Beskorovainiy, Vyacheslav Tabakov, Yulia Itkis, Nadezhda Shilova, and Ekaterina Zakharova. Expanding the genetic spectrum of the pyruvate carboxylase deficiency with novel missense, deep intronic and structural variants. Molecular Genetics and Metabolism Reports, 32:100889, Sep 2022. URL: https://doi.org/10.1016/j.ymgmr.2022.100889, doi:10.1016/j.ymgmr.2022.100889. This article has 3 citations.

  14. (jasinge2024clinicalbiochemicaland pages 1-2): Eresha Jasinge, Mihika Fernando, Neluwa-Liyanage Ruwan Indika, Pyara Dilani Ratnayake, Nalin Gamaathige, Ratnanathan Ratnaranjith, Sabine Schroeder, Patricia Jones, Skrahina Volha, Subhashinie Jayasena, Anusha Varuni Gunaratna, Asitha Niroshana Bandara Ekanayake, and Arndt Rolfs. Clinical, biochemical, and molecular profiles of three sri lankan neonates with pyruvate carboxylase deficiency. Advances in Laboratory Medicine, 5:205-212, Jan 2024. URL: https://doi.org/10.1515/almed-2023-0102, doi:10.1515/almed-2023-0102. This article has 0 citations.

  15. (maryami2023insilicoanalysis pages 1-2): Fereshteh Maryami, Elham Rismani, Elham Davoudi-Dehaghani, Nasrin Khalesi, Saeed Talebi, Reza Mahdian, and Sirous Zeinali. In silico analysis of two novel variants in the pyruvate carboxylase (pc) gene associated with the severe form of pc deficiency. Iranian Biomedical Journal, 27:307-319, Sep 2023. URL: https://doi.org/10.61186/ibj.27.5.307, doi:10.61186/ibj.27.5.307. This article has 3 citations.

  16. (maryami2023insilicoanalysis pages 2-4): Fereshteh Maryami, Elham Rismani, Elham Davoudi-Dehaghani, Nasrin Khalesi, Saeed Talebi, Reza Mahdian, and Sirous Zeinali. In silico analysis of two novel variants in the pyruvate carboxylase (pc) gene associated with the severe form of pc deficiency. Iranian Biomedical Journal, 27:307-319, Sep 2023. URL: https://doi.org/10.61186/ibj.27.5.307, doi:10.61186/ibj.27.5.307. This article has 3 citations.

  17. (jasinge2024clinicalbiochemicaland pages 5-7): Eresha Jasinge, Mihika Fernando, Neluwa-Liyanage Ruwan Indika, Pyara Dilani Ratnayake, Nalin Gamaathige, Ratnanathan Ratnaranjith, Sabine Schroeder, Patricia Jones, Skrahina Volha, Subhashinie Jayasena, Anusha Varuni Gunaratna, Asitha Niroshana Bandara Ekanayake, and Arndt Rolfs. Clinical, biochemical, and molecular profiles of three sri lankan neonates with pyruvate carboxylase deficiency. Advances in Laboratory Medicine, 5:205-212, Jan 2024. URL: https://doi.org/10.1515/almed-2023-0102, doi:10.1515/almed-2023-0102. This article has 0 citations.

  18. (habarou2015pyruvatecarboxylasedeficiency pages 2-3): F. Habarou, A. Brassier, M. Rio, D. Chrétien, S. Monnot, V. Barbier, R. Barouki, J.P. Bonnefont, N. Boddaert, B. Chadefaux-Vekemans, L. Le Moyec, J. Bastin, C. Ottolenghi, and P. de Lonlay. Pyruvate carboxylase deficiency: an underestimated cause of lactic acidosis. Molecular Genetics and Metabolism Reports, 2:25-31, Mar 2015. URL: https://doi.org/10.1016/j.ymgmr.2014.11.001, doi:10.1016/j.ymgmr.2014.11.001. This article has 32 citations.

  19. (hidalgo2021auniquecase pages 4-5): Jessica Hidalgo, Leticia Campoverde, Juan Fernando Ortiz, Samir Ruxmohan, and Ahmed Eissa-Garcés. A unique case of pyruvate carboxylase deficiency. Cureus, May 2021. URL: https://doi.org/10.7759/cureus.15042, doi:10.7759/cureus.15042. This article has 10 citations.