Carbonic Anhydrase VA Deficiency

Mendelian MONDO:0014332 Pathograph 6 Show in embeddings browser Inborn Error of Metabolism Inherited Hyperammonemia

Carbonic anhydrase VA (CA-VA) deficiency is an autosomal recessive inborn error of metabolism caused by biallelic loss-of-function variants in CA5A, which encodes the mitochondrial carbonic anhydrase isoform VA. CA-VA supplies bicarbonate to four bicarbonate-dependent mitochondrial liver enzymes — carbamoyl phosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis and gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched-chain amino acid catabolism). Deficient bicarbonate provision impairs all four reactions simultaneously, producing an early-onset, life-threatening metabolic crisis with hyperammonemia, hyperlactatemia, ketonuria, metabolic acidosis, hypoglycemia, and urinary excretion of carboxylase substrates. Presentation is typically in the neonatal period or early childhood with lethargy and hyperammonemic encephalopathy. Unlike most causes of neonatal hyperammonemia, CA-VA deficiency is treatable, and prompt recognition with carglumic acid and ammonia-lowering measures can resolve hyperammonemia and prevent neurologic sequelae.

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4
Pathophys.
6
Phenotypes
6
Pathograph
1
Genes
2
Medical Actions
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
urea cycle and hyperammonemias
⚙

Pathophysiology

4
Mitochondrial carbonic anhydrase VA deficiency
Biallelic loss-of-function CA5A variants reduce or abolish mitochondrial carbonic anhydrase VA activity in hepatocytes. CA-VA catalyzes the reversible hydration of carbon dioxide to bicarbonate, and its loss depletes the intramitochondrial bicarbonate pool required by downstream carboxylases.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
CA5A hgnc:1377 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CA5A (hgnc:1377). hgnc:1377 is a gene from the HUGO Gene Nomenclature Committee.
carbonate dehydratase activity GO:0004089 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased carbonate dehydratase activity (GO:0004089). GO:0004089 is a molecular function from the Gene Ontology. ↓ DECREASED
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired bicarbonate supply to mitochondrial carboxylases Loss of CA-VA depletes mitochondrial bicarbonate needed by bicarbonate-dependent carboxylases.
Show evidence (2 references)
PMID:26913920 SUPPORT Human Clinical
"Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB)."
Establishes CA-VA as the source of bicarbonate for four mitochondrial liver enzymes, so its deficiency is the initiating lesion.
PMID:24530203 SUPPORT Human Clinical
"Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion."
Directly demonstrates loss of hepatic CA-VA protein as the molecular consequence of a CA5A null allele.
Impaired bicarbonate supply to mitochondrial carboxylases
Bicarbonate depletion simultaneously impairs four mitochondrial carboxylation reactions: carbamoyl phosphate synthetase 1 (the entry step of the urea cycle), pyruvate carboxylase (anaplerosis and gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched-chain amino acid catabolism). Reduced ureagenesis allows ammonia to accumulate, reduced gluconeogenesis and anaplerosis promote hypoglycemia and lactate accumulation, and impaired carboxylases lead to excretion of their substrates — the biochemical signature of the disorder unmasked by catabolic stress.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
urea cycle GO:0000050 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased urea cycle (GO:0000050). GO:0000050 is a biological process from the Gene Ontology. ↓ DECREASED gluconeogenesis GO:0006094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gluconeogenesis (GO:0006094). GO:0006094 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Acute hyperammonemic metabolic crisis Combined carboxylase impairment converts to an acute biochemical crisis under catabolic stress.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain..."
Enumerates the four bicarbonate-dependent carboxylases whose combined impairment produces the multi-metabolite crisis.
Acute hyperammonemic metabolic crisis
The biochemical crisis of CA-VA deficiency is a distinctive combination of hyperammonemia (impaired CPS1-dependent ureagenesis), hyperlactatemia and ketosis (impaired pyruvate carboxylase anaplerosis), metabolic acidosis, and hypoglycemia (impaired gluconeogenesis). Hyperammonemia, hyperlactatemia, and ketonuria are described as apparently obligate signs.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
urea cycle GO:0000050 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased urea cycle (GO:0000050). GO:0000050 is a biological process from the Gene Ontology. ↓ DECREASED glucose homeostasis GO:0042593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal glucose homeostasis (GO:0042593). GO:0042593 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Hyperammonemic encephalopathy Rising ammonia crosses into the brain and produces acute encephalopathy.
Hyperammonemia Impaired ureagenesis manifests clinically as hyperammonemia.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
Defines the acute decompensation of CA-VA deficiency and its obligate biochemical signs.
Hyperammonemic encephalopathy
Circulating ammonia crosses the blood-brain barrier and is detoxified in astrocytes to glutamine, the brain's principal intracellular osmole; its accumulation drives astrocyte swelling and cytotoxic cerebral edema. The result is acute encephalopathy presenting as lethargy and depressed consciousness. Because the underlying lesion is treatable, prompt ammonia-lowering therapy can prevent neurologic sequelae.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae."
Frames the encephalopathy as ammonia-driven and preventable with early treatment.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Carbonic Anhydrase VA Deficiency 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

6
Metabolism 3
Hyperammonemia VERY_FREQUENT HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
Reports hyperammonemia as an obligate sign of CA-VA deficiency.
Metabolic acidosis FREQUENT HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates."
Lists metabolic acidosis among the biochemical findings of the disorder.
Hypoglycemia FREQUENT HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates."
Lists hypoglycemia among the biochemical findings of the disorder.
Nervous System 1
Lethargy FREQUENT HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood."
Reports lethargy as a presenting feature in affected children.
Other 2
Increased circulating lactate concentration VERY_FREQUENT HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
Reports hyperlactatemia as an obligate sign of CA-VA deficiency.
Ketonuria FREQUENT HP:0002919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ketonuria (HP:0002919). HP:0002919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
Reports ketonuria as an obligate sign of CA-VA deficiency.
🧬

Genetic Associations

1
CA5A variants
Gene: CA5A hgnc:1377 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CA5A (hgnc:1377). hgnc:1377 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24530203 SUPPORT Human Clinical
"We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6."
Documents the allelic spectrum of pathogenic CA5A variants.
PMID:24530203 SUPPORT In Vitro
"The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity."
Functional assays confirm pathogenicity of a recurrent CA5A missense variant.
💊

Medical Actions

2
Carglumic acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: carglumic acid CHEBI:71028 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carglumic acid (CHEBI:71028). CHEBI:71028 is a therapeutic agent from Chemical Entities of Biological Interest.
Carglumic acid (N-carbamylglutamate), an N-acetylglutamate synthase analog that stimulates carbamoyl phosphate synthetase 1, resolved hyperammonemia in treated CA-VA-deficient children.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"In the three children who were administered carglumic acid, hyperammonemia resolved."
Direct clinical evidence that carglumic acid resolves hyperammonemia in CA-VA deficiency.
Acute hyperammonemia management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Prompt recognition and treatment of the hyperammonemic crisis — including ammonia-lowering therapy and reversal of catabolism — is the basis for preventing neurologic sequelae in this treatable condition.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae."
Supports early identification and hyperammonemia treatment to prevent neurologic injury.
📊

Prevalence

1
Worldwide
Unknown Rare
Reported in a small number of families since its 2014 description, but a cohort study identified biallelic CA5A variants in 10 of 96 patients investigated for early-onset hyperammonemia, suggesting it may be under-recognized relative to other rare metabolic diseases.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B."
A cohort of early-onset hyperammonemia patients found biallelic CA5A variants in ~10%, supporting the disease occurrence estimate.
{ }

Source YAML

click to show 
name: Carbonic Anhydrase VA Deficiency
creation_date: '2026-07-07T00:00:00Z'
category: Mendelian
synonyms:
- CA-VA deficiency
- CA5A deficiency
- Mitochondrial carbonic anhydrase VA deficiency
- Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
- CA5AD
description: >
  Carbonic anhydrase VA (CA-VA) deficiency is an autosomal recessive inborn
  error of metabolism caused by biallelic loss-of-function variants in CA5A,
  which encodes the mitochondrial carbonic anhydrase isoform VA. CA-VA supplies
  bicarbonate to four bicarbonate-dependent mitochondrial liver enzymes —
  carbamoyl phosphate synthetase 1 (urea cycle), pyruvate carboxylase
  (anaplerosis and gluconeogenesis), propionyl-CoA carboxylase, and
  3-methylcrotonyl-CoA carboxylase (branched-chain amino acid catabolism).
  Deficient bicarbonate provision impairs all four reactions simultaneously,
  producing an early-onset, life-threatening metabolic crisis with
  hyperammonemia, hyperlactatemia, ketonuria, metabolic acidosis, hypoglycemia,
  and urinary excretion of carboxylase substrates. Presentation is typically in
  the neonatal period or early childhood with lethargy and hyperammonemic
  encephalopathy. Unlike most causes of neonatal hyperammonemia, CA-VA
  deficiency is treatable, and prompt recognition with carglumic acid and
  ammonia-lowering measures can resolve hyperammonemia and prevent neurologic
  sequelae.
classifications:
  icimd_category:
  - classification_value: urea_cycle_and_hyperammonemias
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Urea cycle &
      hyperammonemias" under category "Disorders of amino acid metabolism".
      CA-VA deficiency is an inherited hyperammonemia acting upstream of the
      urea cycle through impaired bicarbonate supply to carbamoyl phosphate
      synthetase 1. MONDO:0014332 is classified is_a "urea cycle disorder or
      inherited hyperammonemia".
disease_term:
  preferred_term: hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
  term:
    id: MONDO:0014332
    label: hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
parents:
- Inborn Error of Metabolism
- Inherited Hyperammonemia
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Reported in a small number of families since its 2014 description, but a
    cohort study identified biallelic CA5A variants in 10 of 96 patients
    investigated for early-onset hyperammonemia, suggesting it may be
    under-recognized relative to other rare metabolic diseases.
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B."
    explanation: A cohort of early-onset hyperammonemia patients found biallelic CA5A variants in ~10%, supporting the disease occurrence estimate.
pathophysiology:
- name: Mitochondrial carbonic anhydrase VA deficiency
  conforms_to: "metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism"
  description: >
    Biallelic loss-of-function CA5A variants reduce or abolish mitochondrial
    carbonic anhydrase VA activity in hepatocytes. CA-VA catalyzes the reversible
    hydration of carbon dioxide to bicarbonate, and its loss depletes the
    intramitochondrial bicarbonate pool required by downstream carboxylases.
  genes:
  - preferred_term: CA5A
    term:
      id: hgnc:1377
      label: CA5A
  molecular_functions:
  - preferred_term: carbonate dehydratase activity
    term:
      id: GO:0004089
      label: carbonate dehydratase activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: hydrogencarbonate
    term:
      id: CHEBI:17544
      label: hydrogencarbonate
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four mitochondrial metabolic liver enzymes require bicarbonate, which is provided by the carbonic anhydrase isoforms VA (CAVA) and VB (CAVB)."
    explanation: Establishes CA-VA as the source of bicarbonate for four mitochondrial liver enzymes, so its deficiency is the initiating lesion.
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion."
    explanation: Directly demonstrates loss of hepatic CA-VA protein as the molecular consequence of a CA5A null allele.
  downstream:
  - target: Impaired bicarbonate supply to mitochondrial carboxylases
    description: Loss of CA-VA depletes mitochondrial bicarbonate needed by bicarbonate-dependent carboxylases.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24530203
      reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism"
      explanation: Links CA-VA deficiency to impaired bicarbonate delivery to the downstream carboxylases.
- name: Impaired bicarbonate supply to mitochondrial carboxylases
  conforms_to: "metabolic_intoxication_decompensation#Toxic Metabolite Accumulation and Energy Deficit"
  description: >
    Bicarbonate depletion simultaneously impairs four mitochondrial
    carboxylation reactions: carbamoyl phosphate synthetase 1 (the entry step of
    the urea cycle), pyruvate carboxylase (anaplerosis and gluconeogenesis),
    propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched-chain
    amino acid catabolism). Reduced ureagenesis allows ammonia to accumulate,
    reduced gluconeogenesis and anaplerosis promote hypoglycemia and lactate
    accumulation, and impaired carboxylases lead to excretion of their substrates
    — the biochemical signature of the disorder unmasked by catabolic stress.
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
    modifier: DECREASED
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism)."
    explanation: Enumerates the four bicarbonate-dependent carboxylases whose combined impairment produces the multi-metabolite crisis.
  downstream:
  - target: Acute hyperammonemic metabolic crisis
    description: Combined carboxylase impairment converts to an acute biochemical crisis under catabolic stress.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26913920
      reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates."
      explanation: Directly links impaired bicarbonate production to the combined biochemical decompensation.
- name: Acute hyperammonemic metabolic crisis
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  description: >
    The biochemical crisis of CA-VA deficiency is a distinctive combination of
    hyperammonemia (impaired CPS1-dependent ureagenesis), hyperlactatemia and
    ketosis (impaired pyruvate carboxylase anaplerosis), metabolic acidosis, and
    hypoglycemia (impaired gluconeogenesis). Hyperammonemia, hyperlactatemia, and
    ketonuria are described as apparently obligate signs.
  chemical_entities:
  - preferred_term: ammonium
    term:
      id: CHEBI:28938
      label: ammonium
    modifier: INCREASED
  - preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
    modifier: INCREASED
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
    modifier: DECREASED
  - preferred_term: glucose homeostasis
    term:
      id: GO:0042593
      label: glucose homeostasis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
    explanation: Defines the acute decompensation of CA-VA deficiency and its obligate biochemical signs.
  downstream:
  - target: Hyperammonemic encephalopathy
    description: Rising ammonia crosses into the brain and produces acute encephalopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Brain ammonia entry
    - Astrocytic glutamine accumulation
    evidence:
    - reference: PMID:24530203
      reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood."
      explanation: Documents the presenting hyperammonemia with lethargy, the clinical bridge to encephalopathy.
  - target: Hyperammonemia
    description: Impaired ureagenesis manifests clinically as hyperammonemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26913920
      reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
      explanation: Hyperammonemia is an obligate clinical sign of the crisis.
- name: Hyperammonemic encephalopathy
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Encephalopathy"
  description: >
    Circulating ammonia crosses the blood-brain barrier and is detoxified in
    astrocytes to glutamine, the brain's principal intracellular osmole; its
    accumulation drives astrocyte swelling and cytotoxic cerebral edema. The
    result is acute encephalopathy presenting as lethargy and depressed
    consciousness. Because the underlying lesion is treatable, prompt
    ammonia-lowering therapy can prevent neurologic sequelae.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae."
    explanation: Frames the encephalopathy as ammonia-driven and preventable with early treatment.
phenotypes:
- name: Hyperammonemia
  frequency: VERY_FREQUENT
  description: Elevated plasma ammonia, the cardinal and apparently obligate biochemical sign.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAVA deficiency is a differential diagnosis of early-onset and life-threatening metabolic crisis, with hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
    explanation: Reports hyperammonemia as an obligate sign of CA-VA deficiency.
- name: Increased circulating lactate concentration
  frequency: VERY_FREQUENT
  description: Hyperlactatemia from impaired pyruvate carboxylase anaplerosis, an obligate sign.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
    explanation: Reports hyperlactatemia as an obligate sign of CA-VA deficiency.
- name: Ketonuria
  frequency: FREQUENT
  description: Ketonuria accompanying the metabolic crisis, an obligate sign in reported cases.
  phenotype_term:
    preferred_term: Ketonuria
    term:
      id: HP:0002919
      label: Ketonuria
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
    explanation: Reports ketonuria as an obligate sign of CA-VA deficiency.
- name: Metabolic acidosis
  frequency: FREQUENT
  description: High-anion-gap metabolic acidosis during decompensation.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates."
    explanation: Lists metabolic acidosis among the biochemical findings of the disorder.
- name: Hypoglycemia
  frequency: FREQUENT
  description: Hypoglycemia from impaired gluconeogenesis.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective hepatic bicarbonate production leads to a unique combination of biochemical findings: hyperammonemia, elevated lactate and ketone bodies, metabolic acidosis, hypoglycemia, and excretion of carboxylase substrates."
    explanation: Lists hypoglycemia among the biochemical findings of the disorder.
- name: Lethargy
  frequency: FREQUENT
  description: Reduced arousal at presentation, reflecting hyperammonemic encephalopathy.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood."
    explanation: Reports lethargy as a presenting feature in affected children.
genetic:
- name: CA5A variants
  gene_term:
    preferred_term: CA5A
    term:
      id: hgnc:1377
      label: CA5A
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:26913920
      reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 10 of 96 patients, mutations in CA5A were identified on both alleles but none in CA5B."
      explanation: Biallelic CA5A variants in affected patients support autosomal recessive inheritance.
  features: >
    Reported pathogenic CA5A variants include missense, splice-site, and
    whole-exon deletion alleles, all biallelic. Functional characterization
    demonstrated reduced enzymatic activity and increased thermal sensitivity for
    a recurrent missense allele.
  evidence:
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6."
    explanation: Documents the allelic spectrum of pathogenic CA5A variants.
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity."
    explanation: Functional assays confirm pathogenicity of a recurrent CA5A missense variant.
treatments:
- name: Carglumic acid
  description: >
    Carglumic acid (N-carbamylglutamate), an N-acetylglutamate synthase analog
    that stimulates carbamoyl phosphate synthetase 1, resolved hyperammonemia in
    treated CA-VA-deficient children.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carglumic acid
      term:
        id: CHEBI:71028
        label: carglumic acid
  evidence:
  - reference: PMID:24530203
    reference_title: "Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the three children who were administered carglumic acid, hyperammonemia resolved."
    explanation: Direct clinical evidence that carglumic acid resolves hyperammonemia in CA-VA deficiency.
- name: Acute hyperammonemia management
  description: >
    Prompt recognition and treatment of the hyperammonemic crisis — including
    ammonia-lowering therapy and reversal of catabolism — is the basis for
    preventing neurologic sequelae in this treatable condition.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26913920
    reference_title: "Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early identification may allow specific treatment of hyperammonemia and ultimately prevent neurologic sequelae."
    explanation: Supports early identification and hyperammonemia treatment to prevent neurologic injury.
notes: >
  First WP-001 (IEMbase metabolic) new-entry increment for issue #5556. CA-VA
  deficiency is one of the true new-entry gaps identified in the WP-001 coverage
  triage (row 1.1.09.01, CA5A/OMIM:615751/ORPHA:401948). Dietary protein
  management and long-term follow-up are established for the broader
  hyperammonemia/organic-aciduria class but were not added here because the two
  primary CA-VA references do not provide quotable disease-specific snippets for
  them; they can be added in a follow-up pass. This entry conforms to the
  metabolic_intoxication_decompensation module across its enzymatic-block,
  toxic-accumulation, decompensation, and encephalopathy nodes.