Carbonic Anhydrase VA Deficiency

Mendelian MONDO:0014332 Pathograph 24 Show in embeddings browser Inborn Error of Metabolism Inherited Hyperammonemia

Carbonic anhydrase VA (CA-VA) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic CA5A variants. Reduced mitochondrial bicarbonate production limits carbamoyl phosphate synthetase 1 and three biotin-dependent carboxylases, impairing ureagenesis, pyruvate metabolism and organic-acid metabolism. Presentation often involves neonatal or childhood hyperammonemic encephalopathy with variable hyperlactatemia, ketosis, acid-base disturbance and hypoglycemia. These findings are not obligatory: asymptomatic adults and children with developmental difficulties without recognized crises have been reported. Clinical outcomes range from normal development to persistent impairment and rare fatal decompensation. Acute anticatabolic and ammonia-lowering treatment and individualized sick-day management are used; recurrence can extend into later childhood.

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8
Pathophys.
20
Phenotypes
2
Gaps
24
Pathograph
1
Genes
9
Medical Actions
3
Differentials
1
Trials
3
Models
13
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
urea cycle and hyperammonemias
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Discussions and Knowledge Gaps

2
Does CA-VB compensation explain variable penetrance and age-dependent recurrence?
KNOWLEDGE GAP OPEN cavb_modifier
Attached to
pathophysiology#Reduced mitochondrial bicarbonate availability
Mouse double-knockout data support overlapping metabolic function. Developmental changes in human CA-VB activity and a role in interindividual prognosis remain unproven.
Show evidence (2 references)
PMID:23589845 SUPPORT Model Organism
"The contribution of Car5B to ureagenesis and gluconeogenesis was evident only on a Car5A null background."
Animal experiments support partial functional compensation.
PMID:38974611 SUPPORT Human Clinical
"We argue that the role of CA‐VB as a potential genetic modifier in patients with CA‐VA deficiency deserves further study."
Human modifier activity remains a hypothesis.
How much of the developmental phenotype is attributable to CA5A independently of metabolic crises and other variants?
KNOWLEDGE GAP OPEN developmental_attribution
Attached to
phenotypes#Global developmental delay
The 2026 deletion series contains no recognized hyperammonemic crises. Two siblings also carried homozygous SYT2 variants, with differing SYNE4 genotypes. The authors regarded these as secondary findings but acknowledged that definitive attribution to CA5A requires larger studies and functional work. No causal edge from acute hyperammonemic encephalopathy to all developmental findings is asserted.
Show evidence (2 references)
PMID:41736722 SUPPORT Human Clinical
"Furthermore, definitively attributing the developmental delay to CA5A deletion needs a larger number of cases and functional studies."
The original report explicitly limits causal attribution.
PMID:41736722 SUPPORT Human Clinical
"index (#2) had SYT2 (homozygous) and SYNE4 (heterozygous); affected sister (#3) had SYT2 (homozygous) and SYNE4 (homozygous)"
Other potentially relevant genotypes complicate interpretation.
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Pathophysiology

8
Mitochondrial carbonic anhydrase VA deficiency
Biallelic pathogenic CA5A variants cause absent or reduced mitochondrial carbonic anhydrase VA activity. Mechanisms include reduced protein abundance, catalytic impairment and variant-dependent thermal instability. Patient liver and heterologous expression studies provide complementary evidence; residual activity is not a reliable predictor of clinical severity.
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 ↓ DECREASED 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.
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.
Experimental models
COS-7 expression of CA5A p.Ser233Pro CELL LINE Measures the variant-associated loss of enzyme function.
Sf9 expression of recombinant human CA-VA variants CELL LINE Measures activity and stability of disease-associated enzyme forms.
Downstream
Reduced mitochondrial bicarbonate availability Reduced CA-VA activity limits locally generated mitochondrial bicarbonate.
Show evidence (3 references)
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.
PMID:24530203 SUPPORT In Vitro
"A marked reduction was observed in the steady-state levels of CA-VA p.Ser233Pro compared with wild-type protein despite similar transfection efficiencies"
COS-7 expression shows reduced mutant protein abundance.
PMID:26913920 SUPPORT In Vitro
"Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect."
Recombinant enzyme studies distinguish loss of activity and stability from benign control variants.
Reduced mitochondrial bicarbonate availability
Impaired intramitochondrial bicarbonate production restricts the substrate available to CPS1, pyruvate carboxylase, PCC and 3MCC. Secondary enzyme impairment is inferred from the metabolic pattern; its magnitude varies by patient and physiological state.
Downstream
Impaired CPS1-dependent ureagenesis Bicarbonate limitation constrains the first step of the urea cycle.
Secondary pyruvate carboxylase dysfunction Bicarbonate limitation reduces pyruvate carboxylation.
Secondary propionyl-CoA carboxylase dysfunction Reduced bicarbonate supply limits PCC-dependent metabolism.
Secondary 3-methylcrotonyl-CoA carboxylase dysfunction Reduced bicarbonate supply limits 3MCC-dependent metabolism.
Show evidence (1 reference)
PMID:24530203 SUPPORT BACKGROUND Human Clinical
"Mitochondria are impermeable to HCO3−, and thus the two intramitochondrial carbonic anhydrases (CA-VA and CA-VB) are pivotal in providing HCO3− for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles"
Explains why reduced mitochondrial bicarbonate production affects the downstream enzymes; this is biochemical background rather than a direct patient bicarbonate measurement.
Impaired CPS1-dependent ureagenesis
Restricted bicarbonate availability limits carbamoyl phosphate formation and nitrogen disposal through the urea cycle. High glutamine with low-to-normal citrulline supports this mechanism in some patients; the pattern is not universal.
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 ↓ DECREASED 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.
Animal models
Car5a-null and Car5a/Car5b double-knockout mice Mouse partially recapitulates Models defective ammonia disposal and the contribution of CA-VB.
Downstream
Hyperammonemia Reduced ureagenesis impairs ammonia disposal.
Hyperammonemic encephalopathy Ammonia accumulation contributes to acute brain dysfunction.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"Given that glutamine was elevated in three of the four affected individuals and that the citrulline was low to normal in all, it appears that an impaired urea cycle, rather than deficient glutamate, was the major cause of hyperammonemia."
The clinical metabolite pattern supports predominant secondary CPS1-dependent ureagenesis impairment, inferred rather than directly measured.
Secondary pyruvate carboxylase dysfunction
Reduced pyruvate-to-oxaloacetate conversion limits anaplerosis and gluconeogenesis. This contributes to lactate elevation and hypoglycemia, which can occur independently of the magnitude of hyperammonemia.
gluconeogenesis GO:0006094 ↓ DECREASED 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.
Downstream
Hypoglycemia Impaired gluconeogenesis reduces glucose production.
Increased circulating lactate concentration Impaired pyruvate metabolism contributes to lactate accumulation.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia, as was observed in our CA-VA-deficient individuals with presumed secondary PC deficiency leading to hypoglycemia through impaired gluconeogenesis."
The authors infer secondary pyruvate carboxylase impairment from the clinical biochemical findings.
Secondary propionyl-CoA carboxylase dysfunction
Reduced bicarbonate provision limits propionyl-CoA carboxylation. Accumulation of related metabolites can produce mild propionic-aciduria-like urinary findings.
Downstream
Organic acid accumulation Secondary PCC impairment contributes to accumulation of organic-acid metabolites.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency."
Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected liver.
Secondary 3-methylcrotonyl-CoA carboxylase dysfunction
Reduced bicarbonate provision limits the 3MCC reaction in leucine catabolism. Urinary metabolites can resemble multiple carboxylase deficiency, often more subtly.
Downstream
Organic acid accumulation Secondary 3MCC impairment contributes to accumulation of organic-acid metabolites.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency."
Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected liver.
Organic acid accumulation
Secondary PCC and 3MCC dysfunction can lead to accumulation and urinary excretion of related organic-acid metabolites. These abnormalities are often mild or absent. Ketonuria is recorded as a variable clinical feature; its generation is not attributed specifically to either carboxylase defect.
Downstream
Metabolic acidosis Accumulating titratable organic acids contribute to acidosis.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency."
Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected liver.
Hyperammonemic encephalopathy
Ammonia-related brain dysfunction can cause altered consciousness and seizures. Severe cerebral injury may progress despite normalization of blood ammonia, so biochemical improvement does not guarantee neurological recovery. Cellular explanations involving energy failure and edema are incompletely resolved in this disorder.
Downstream
Lethargy Acute brain dysfunction manifests as lethargy.
Vomiting Vomiting accompanies hyperammonemic decompensation.
Seizures Metabolic encephalopathy may provoke seizures.
Feeding difficulties Acute hyperammonemic illness impairs feeding.
Coma Severe hyperammonemic encephalopathy may progress to coma.
Cerebral edema Cerebral edema can accompany acute hyperammonemic encephalopathy; the cellular intermediates are not established in this disorder.
Show evidence (2 references)
PMID:26913920 SUPPORT Human Clinical
"including lethargy, poor feeding, and vomiting caused by hyperammonemia"
Clinical decompensations link these acute manifestations to hyperammonemia.
url:https://www.nature.com/articles/s41436-019-0677-9 SUPPORT Human Clinical
"However, encephalopathy and arterial hypertension persisted and worsened even after normalization of metabolic parameters."
The fatal case demonstrates continued brain dysfunction despite biochemical correction.
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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.
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Phenotypes

20
Digestive 2
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26913920 SUPPORT Human Clinical
"including lethargy, poor feeding, and vomiting caused by hyperammonemia"
Clinical decompensations link these acute manifestations to hyperammonemia.
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25834911 SUPPORT Human Clinical
"hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma)."
GeneReviews identifies feeding intolerance among presenting symptoms.
Genitourinary 1
Ketonuria 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 (2 references)
PMID:26913920 SUPPORT Human Clinical
"hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent studies broadened the spectrum.
PMID:38974611 REFUTE Human Clinical
"ketosis was reported in 3/12 (25%) patients."
The later cohort refutes universal ketosis; the denominator is the assessed subset.
Head and Neck 1
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38974611 SUPPORT Human Clinical
"3/18 (16.7%) patients had microcephaly"
Cohort-specific observation supports this manifestation.
Metabolism 7
Hyperammonemia 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.
Sequelae: Respiratory alkalosis
Show evidence (2 references)
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."
The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent studies broadened the spectrum.
PMID:38974611 REFUTE Human Clinical
"the two asymptomatic patients had normal ammonia"
Normal ammonia in these two homozygous adults counters the claim that hyperammonemia is obligatory in every affected individual.
Increased circulating lactate concentration 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 (2 references)
PMID:26913920 SUPPORT Human Clinical
"hyperammonemia, hyperlactatemia, and ketonuria as apparently obligate signs."
The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent studies broadened the spectrum.
PMID:38974611 REFUTE Human Clinical
"2/14 (14.3%) had normal lactate"
Refutes obligatory hyperlactatemia in all symptomatic patients.
Metabolic acidosis 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 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.
Respiratory alkalosis HP:0001950 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory alkalosis (HP:0001950). HP:0001950 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25834911 SUPPORT Human Clinical
"complex acid-base status including respiratory alkalosis and metabolic acidosis"
Defines the mixed acid-base pattern.
Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38974611 SUPPORT Human Clinical
"Creatine kinase (CK) was measured in 11 patients, and 9/11 (81.8%) patients had mildly elevated CK"
Shows frequent CK elevation among tested members of one cohort; selection prevents a general frequency estimate.
PMID:42371568 SUPPORT Human Clinical
"However, concurrent myositis in the context of febrile illnesses cannot be excluded."
Qualifies interpretation of CK elevations during febrile decompensations.
Cerebral edema HP:0002181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral edema (HP:0002181). HP:0002181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38974611 SUPPORT Human Clinical
"MRI brain in patient 1 showed mild brain edema with focal areas of diffusion restriction in the right lentiform nucleus and right thalamus in keeping with acute infarcts"
Direct neuroimaging evidence during neonatal hyperammonemic encephalopathy.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41736722 SUPPORT Human Clinical
"neurological examination revealed axial hypotonia."
Observed in the first child with the exon 3–7 deletion.
Nervous System 6
Lethargy 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.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25834911 SUPPORT Human Clinical
"hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma)."
GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating individual frequencies.
Coma HP:0001259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coma (HP:0001259). HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25834911 SUPPORT Human Clinical
"hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma)."
GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating individual frequencies.
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38974611 SUPPORT Human Clinical
"7/18 patients developed variable degree of developmental delay"
Provides the cohort-specific frequency; it is not a population-wide estimate.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41736722 SUPPORT Human Clinical
"She had mild developmental delay, predominantly affecting speech, but otherwise exhibited normal gross motor development."
Case-level language-predominant delay; not a population frequency estimate.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41736722 SUPPORT Human Clinical
"Brain MRI demonstrated moderately marked thinning of the corpus callosum along with mild periventricular leukomalacia"
Supports the imaging finding in a single case.
Respiratory 1
Tachypnea HP:0002789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachypnea (HP:0002789). HP:0002789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25834911 SUPPORT Human Clinical
"hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma)."
GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating individual frequencies.
Growth 1
Failure to thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38974611 SUPPORT Human Clinical
"Failure to thrive was encountered in 7/18 (38.9%) patients"
The frequency applies to this single founder cohort.
🧬

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 (7 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.
PMID:24530203 SUPPORT Human Clinical
"Sanger sequencing of the ∼550 bp band revealed an in-frame deletion of exon 4 from the index RNA"
Patient white-blood-cell RNA confirms abnormal splicing from the synonymous terminal-exon variant.
+ 4 more references
💊

Medical Actions

9
Carglumic acid
Category: Therapeutic 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.
Platform: Small molecule
Carglumic acid is an N-acetylglutamate analogue that activates CPS1. It has been used off-label for acute hyperammonemia in CA-VA deficiency, with rapid biochemical responses in uncontrolled clinical reports. Activation of residual CPS1 flux despite bicarbonate limitation is proposed; benefit cannot always be separated from concurrent caloric support and other ammonia-lowering measures.
Mechanism Target:
RESTORES Impaired CPS1-dependent ureagenesis — Enhances CPS1 activity; compensation for reduced bicarbonate availability is proposed.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"consistent with the suggestion that enhanced CPS1 activity can partially compensate for reduced HCO3− resulting from CA-VA deficiency."
Mechanistic interpretation of observed clinical responses, not direct flux measurement.
Show evidence (3 references)
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.
PMID:24530203 SUPPORT Human Clinical
"This hypothesis should be tested in the Car5A-null mouse model ... especially given the high cost of this medication and uncontrolled circumstances in which these children were managed with multiple therapeutic modalities."
The authors qualify the proposed CA-VA-specific rescue mechanism and the uncontrolled treatment evidence.
PMID:38974611 SUPPORT Human Clinical
"When carglumic acid was used alone in three patients to treat hyperammonemia based on knowledge of founder effect or family history, ammonia normalized in less than 24 h."
Provides additional uncontrolled clinical response data.
Acute anticatabolic support
Category: Therapeutic Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Hospital care uses glucose-containing fluids and additional caloric support, temporary protein adjustment when hyperammonemia is present, and close biochemical monitoring. This reverses catabolism while ammonia-lowering treatment is instituted. Management is individualized by metabolic specialists.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated."
GeneReviews expert management recommendations; not evidence from a controlled CA-VA trial.
Nitrogen scavengers
Category: Therapeutic 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: sodium benzoate CHEBI:113455 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium benzoate (CHEBI:113455). CHEBI:113455 is a therapeutic agent from Chemical Entities of Biological Interest. sodium phenylbutyrate CHEBI:75316 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium phenylbutyrate (CHEBI:75316). CHEBI:75316 is a therapeutic agent from Chemical Entities of Biological Interest. sodium phenylacetate CHEBI:749228 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium phenylacetate (CHEBI:749228). CHEBI:749228 is a therapeutic agent from Chemical Entities of Biological Interest.
Sodium benzoate and phenylbutyrate or phenylacetate have been used to lower ammonia during crises, sometimes with arginine and other measures. Disease-specific comparative efficacy remains uncertain.
Show evidence (2 references)
PMID:38974611 SUPPORT Human Clinical
"Medications used included the ammonia scavengers sodium benzoate and sodium phenylbutyrate"
Documents scavenger use in the founder cohort.
url:https://www.nature.com/articles/s41436-019-0677-9 SUPPORT Human Clinical
"These included sodium benzoate, sodium phenylacetate, L-arginine, as well as carglumic acid."
Documents multimodal treatment in the severe case, without implying treatment success.
Extracorporeal ammonia removal
Category: Therapeutic Action: HemodialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hemodialysis (NCIT:C15248). NCIT:C15248 is a clinical intervention from the NCI Thesaurus. NCIT:C15248
Severe hyperammonemic crises have required hemodialysis or hemofiltration as part of acute specialist management.
Show evidence (2 references)
PMID:41737902 SUPPORT Human Clinical
"The proband, their older brother, had presented on day four of life with marked lactic acidosis, hyperammonaemia and encephalopathy requiring haemofiltration due to CAVA deficiency."
The presenting sibling required extracorporeal support during the neonatal crisis.
PMID:26913920 SUPPORT Human Clinical
"extracorporeal detoxification in the case of severe hyperammonemia"
Supports extracorporeal treatment for severe biochemical decompensation.
Sick-day nutrition and fasting avoidance
Category: Therapeutic Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
An individualized emergency plan supplies additional carbohydrate and fat calories during illness, avoids fasting, and specifies temporary protein adjustment and criteria for hospital care. Long-term dietary or drug treatment during wellness is individualized; universal lifelong protein restriction is not established.
Show evidence (2 references)
PMID:42371568 SUPPORT Human Clinical
"All patients should be provided with a personalized sick‐day protocol during periods of febrile illness and catabolic states, consisting of high‐calorie intake from fats and carbohydrates, temporary protein restriction, strict avoidance of fasting, and clear criteria for hospital admission"
Current expert synthesis supports individualized prevention.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations."
Avoids presenting prophylactic dietary restriction or zinc as established treatment.
Planned neonatal care after familial diagnosis
Category: Therapeutic 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. NCIT:C15747
Antenatal or familial diagnosis allows planned delivery with metabolic support, regular feeding and biochemical observation. Two prenatally identified siblings remained stable after short-course prophylactic carglumic acid plus feeding support. The uncontrolled report does not establish which intervention prevented decompensation; one familial allele remained a VUS.
Show evidence (1 reference)
PMID:41737902 SUPPORT Human Clinical
"Carglumic acid was used for each sibling infant and outcomes may have been due to its use, regular feeding and monitoring, or all of these factors."
The authors explicitly acknowledge confounding between preventive interventions.
Avoidance of carbonic anhydrase inhibitors
Category: Therapeutic
GeneReviews recommends avoiding acetazolamide and topiramate because further carbonic anhydrase inhibition may aggravate the metabolic defect. This is disease-specific expert advice rather than a quantified drug-risk estimate.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity."
Expert avoidance recommendation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"If anti-seizure medication is necessary, avoid topiramate based on its action as a carbonic anhydrase inhibitor."
Expert avoidance recommendation despite isolated published use.
Metabolic and developmental surveillance
Category: Monitoring
Follow metabolic stability, growth and neurodevelopment, with reassessment during illness. Recurrence into later childhood supports retaining an emergency plan even after prolonged stability.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations."
GeneReviews expert surveillance recommendation.
PMID:42371568 SUPPORT Human Clinical
"ongoing surveillance is recommended given the risk of MDE recurrence into later childhood and potential neurodevelopmental sequelae."
Long-term follow-up supports continued clinical surveillance.
Genetic counseling and family testing
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
For two heterozygous parents, each pregnancy has a one-in-four chance of a child inheriting both CA5A variants. Carrier and reproductive testing are possible once familial variants are known. Clinical penetrance and severity cannot be predicted reliably from genotype, and asymptomatic relatives may be homozygous.
Show evidence (2 references)
PMID:25834911 SUPPORT Human Clinical
"a 25% chance of inheriting two CA5A pathogenic variants and usually being affected"
Supports Mendelian recurrence risk while retaining incomplete clinical penetrance.
PMID:25834911 SUPPORT Human Clinical
"The results of prenatal testing cannot be used to predict with certainty whether or not an individual will be affected"
Separates genotype prediction from clinical prognosis.
🔬

Diagnosis

4
Biochemical investigation during decompensation
Assess ammonia, lactate, glucose, blood gases, plasma amino acids and urine organic acids. Elevated glutamine and alanine with low-to-normal citrulline and mild carboxylase-substrate elevations can suggest CA-VA deficiency. Results vary and may normalize between episodes.
Show evidence (2 references)
PMID:25834911 SUPPORT Human Clinical
"elevated plasma glutamine and alanine and low-to-normal citrulline"
Identifies an informative amino-acid pattern.
PMID:24530203 SUPPORT Human Clinical
"Furthermore, these abnormalities may be present only during symptomatic episodes."
Normal interval testing cannot exclude the disorder.
CA5A sequence and deletion analysis
Identify biallelic pathogenic or likely pathogenic CA5A variants, using sequence and exon-level copy-number analysis as appropriate. Whole-exome or genome sequencing can detect atypical presentations. The homologous CA5AP1 pseudogene complicates assay design. VUS findings require interpretation and do not independently establish the diagnosis.
Molecular Diagnosis NCIT:C20826 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:25834911 SUPPORT Human Clinical
"biallelic pathogenic variants in CA5A identified by molecular genetic testing."
Supports molecular confirmation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/ SUPPORT Human Clinical
"If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted ... deletion/duplication analysis ... to detect exon and whole-gene deletions or duplications."
GeneReviews recommends copy-number analysis after incomplete sequence results; ellipses skip glossary markup.
PMID:24530203 SUPPORT Human Clinical
"the CA5A variant was confirmed by targeted Sanger sequencing via carefully designed primers to avoid amplification of the pseudogene sequences"
Demonstrates the need for pseudogene-aware confirmation.
+ 1 more reference
Newborn screening limitations
A normal standard tandem-mass-spectrometry newborn screen does not exclude CA-VA deficiency. The characteristic C3 and C5OH elevations may be absent even during crises; genomic screening is being evaluated separately.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"Newborn screening profiles (Tandem MS/MS), specifically C3 and C5OH levels, were unremarkable in all four cases"
Direct evidence of normal screening in affected children.
Neurological assessment
Developmental assessment and brain MRI help characterize injury; EEG is relevant when seizures are suspected. MRI may be normal or show cortical, deep-gray or white-matter injury. No imaging pattern independently establishes CA-VA deficiency.
Show evidence (2 references)
PMID:38974611 SUPPORT Human Clinical
"MRI brain in patient 2 at the age of 9 days showed abnormal T2 signal intensity and diffusion restriction in the perirolandic cortex, insula, and basal ganglia in keeping with hyperammonemic encephalopathy"
Documents an observed acute imaging pattern.
PMID:24530203 SUPPORT Human Clinical
"in the female sibling, both MRI and EEG were unremarkable."
Normal neurodiagnostic tests also occur.
📈

Progression

1
Clinical course
Initial crises often occur in the neonatal period, but onset and recurrence can occur later in childhood. Normal development is possible even after recurrent episodes, while severe neurological impairment and rare fatal outcomes are also reported. In follow-up of the original siblings, one had her last crisis at eight years and the other remained stable; both had favorable adolescent outcomes.
Show evidence (3 references)
PMID:42371568 SUPPORT Human Clinical
"Case 1 experienced three additional MDEs at ages 2 years 6 months, 3 years 6 months, and 8 years, all triggered by febrile illnesses."
Extends the documented recurrence window into later childhood.
PMID:42371568 SUPPORT Human Clinical
"Currently, both cases show normal growth, development, and neurological outcomes"
Longitudinal follow-up of the original siblings supports favorable outcomes in these individuals, not a universal prognosis.
url:https://www.nature.com/articles/s41436-019-0677-9 SUPPORT Human Clinical
"this case demonstrates that the disease course can be fulminant and fatal despite rapid initiation of adequate treatment and despite quick normalization of ammonia and lactate levels during metabolic crisis."
Rare fatal disease counters an unconditional benign prognosis.
📊

Prevalence

1
Worldwide
Unknown Rare
Population prevalence is unknown. Identification of biallelic CA5A variants in 10 of 96 selected patients investigated for unexplained early-onset hyperammonemia is a diagnostic yield in a referred cohort, not a population prevalence estimate.
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."
The denominator comprises selected hyperammonemia referrals; this finding supports under-recognition but cannot estimate population prevalence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Carbonic Anhydrase VA Deficiency:

Proximal urea cycle disorders
Overlapping Features CPS1 and NAGS deficiencies share hyperammonemia, high glutamine, low citrulline and little orotic acid excretion. Lactate and carboxylase-related urinary metabolites can favor CA-VA deficiency, although their absence does not exclude it.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child."
The primary study establishes the differential diagnosis.
Multiple carboxylase deficiency
Overlapping Features Biotinidase and holocarboxylase synthetase deficiencies can produce overlapping urinary metabolites. Secondary CPS1 impairment and milder PCC/3MCC metabolites can help distinguish CA-VA deficiency.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"the significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation"
The primary study compares biotinidase and holocarboxylase synthetase defects with CA-VA deficiency.
Pyruvate carboxylase deficiency
Overlapping Features Shares lactic acidosis, hypoglycemia and hyperammonemia; molecular and biochemical investigation distinguishes primary PC deficiency from secondary impairment in CA-VA deficiency.
Show evidence (1 reference)
PMID:24530203 SUPPORT Human Clinical
"Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia"
The overlapping biochemical profile requires differential testing.
🔬

Clinical Trials

1
NCT03655223 NOT_APPLICABLE ACTIVE_NOT_RECRUITING
Early Check is a prospective observational newborn-screening study whose registered condition list includes carbonic anhydrase VA deficiency. It evaluates expanded screening and its impact on families; it is not a CA5A-targeted treatment trial. The registry was last updated July 1, 2026.
Show evidence (1 reference)
clinicaltrials:NCT03655223 SUPPORT Human Clinical
"Early Check provides voluntary screening of newborns for a selected panel of conditions."
Registry summary establishes the screening purpose; the official API condition list explicitly includes this disease.
🧫

Experimental Models

2
COS-7 expression of CA5A p.Ser233Pro CELL_LINE
Heterologous expression demonstrates lower mutant CA-VA abundance and temperature-sensitive enzyme activity. These assays do not reproduce the integrated human liver metabolic phenotype.
Cell source
Transfected COS-7 cells
Publication
PMID:24530203
Pathograph links
Mitochondrial carbonic anhydrase VA deficiency recapitulates Measures the variant-associated loss of enzyme function.
Show evidence (1 reference)
PMID:24530203 SUPPORT In Vitro
"A marked reduction was observed in the steady-state levels of CA-VA p.Ser233Pro compared with wild-type protein despite similar transfection efficiencies"
COS-7 expression shows reduced mutant protein abundance.
Show evidence (1 reference)
PMID:24530203 SUPPORT In Vitro
"After a 30 min preincubation, the mutant enzyme had lost 80% of its activity at 30°C and almost all its activity at 40°C."
Direct thermal-inactivation measurements in the COS-7 expression system.
Sf9 expression of recombinant human CA-VA variants CELL_LINE
Purified recombinant proteins permit comparison of catalytic activity and thermal stability. Missense and exon-deletion alleles show different activity and stability defects; cellular proteostasis and clinical severity are not fully captured.
Cell source
Baculovirus-transduced Sf9 insect cells
Publication
PMID:26913920
Pathograph links
Mitochondrial carbonic anhydrase VA deficiency recapitulates Measures activity and stability of disease-associated enzyme forms.
Show evidence (1 reference)
PMID:26913920 SUPPORT In Vitro
"Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect."
Recombinant enzyme studies distinguish loss of activity and stability from benign control variants.
Show evidence (1 reference)
PMID:26913920 SUPPORT In Vitro
"developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues."
Establishes the heterologous protein assay system.
🐁

Animal Models

1
Car5a-null and Car5a/Car5b double-knockout mice
Car5a-null mice show hyperammonemia and impaired growth, with normal fasting glucose. Double knockout worsens hyperammonemia, growth and survival and reduces fasting glucose. Sodium-potassium citrate improved breeding and neonatal survival but did not improve growth or post-weaning mortality; efficacy in humans is unestablished.
Species
Mouse
Genotype
Car5a knockout; Car5a/Car5b double knockout
Publication
PMID:23589845
Pathograph links
Impaired CPS1-dependent ureagenesis partially recapitulates Models defective ammonia disposal and the contribution of CA-VB.
Limitations: Whole-animal gene deletion does not establish age-dependent compensation or clinical prognosis in humans.
Show evidence (1 reference)
PMID:23589845 SUPPORT Model Organism
"The enhanced hyperammonemia and lower fasting blood sugar, which are both seen in the DKO mice, indicate that both Car5A and Car5B contribute to both ammonia detoxification (ureagenesis) and regulation of fasting blood sugar (gluconeogenesis)."
Genetic perturbation connects mitochondrial carbonic anhydrases with whole-animal metabolism.
Show evidence (2 references)
PMID:23589845 SUPPORT Model Organism
"Their blood ammonia concentrations were markedly elevated, but their fasting blood sugars were normal."
Car5a single knockout does not reproduce every human biochemical feature.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645511/ SUPPORT Model Organism
"citrate salt supplementation improved breeding and reduced the neonatal mortality of the ... null and DKO mice, but we did not observe that it improved growth or reduced mortality after weaning."
Full-text results distinguish neonatal benefit from absent growth or post-weaning benefit.
{ }

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 metabolic disorder caused by biallelic
  pathogenic CA5A variants. Reduced mitochondrial bicarbonate production limits carbamoyl phosphate synthetase
  1 and three biotin-dependent carboxylases, impairing ureagenesis, pyruvate metabolism and organic-acid
  metabolism. Presentation often involves neonatal or childhood hyperammonemic encephalopathy with variable
  hyperlactatemia, ketosis, acid-base disturbance and hypoglycemia. These findings are not obligatory:
  asymptomatic adults and children with developmental difficulties without recognized crises have been
  reported. Clinical outcomes range from normal development to persistent impairment and rare fatal decompensation.
  Acute anticatabolic and ammonia-lowering treatment and individualized sick-day management are used;
  recurrence can extend into later childhood.
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: >-
    Population prevalence is unknown. Identification of biallelic CA5A variants in 10 of 96 selected patients
    investigated for unexplained early-onset hyperammonemia is a diagnostic yield in a referred cohort,
    not a population prevalence estimate.
  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: >-
      The denominator comprises selected hyperammonemia referrals; this finding supports under-recognition
      but cannot estimate population prevalence.
pathophysiology:
- name: Mitochondrial carbonic anhydrase VA deficiency
  conforms_to: metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism
  description: >-
    Biallelic pathogenic CA5A variants cause absent or reduced mitochondrial carbonic anhydrase VA activity.
    Mechanisms include reduced protein abundance, catalytic impairment and variant-dependent thermal instability.
    Patient liver and heterologous expression studies provide complementary evidence; residual activity
    is not a reliable predictor of clinical severity.
  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
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  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: 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.
  - 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: A marked reduction was observed in the steady-state levels of CA-VA p.Ser233Pro compared with wild-type protein despite similar transfection efficiencies
    explanation: >-
      COS-7 expression shows reduced mutant protein abundance.
  - 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: IN_VITRO
    snippet: Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect.
    explanation: >-
      Recombinant enzyme studies distinguish loss of activity and stability from benign control variants.
  downstream:
  - target: Reduced mitochondrial bicarbonate availability
    description: >-
      Reduced CA-VA activity limits locally generated mitochondrial bicarbonate.
    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: Mitochondria are impermeable to HCO3−, and thus the two intramitochondrial carbonic anhydrases (CA-VA and CA-VB) are pivotal in providing HCO3− for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles
      explanation: >-
        Explains why reduced mitochondrial bicarbonate production affects the downstream enzymes; this
        is biochemical background rather than a direct patient bicarbonate measurement.
      quote_role: BACKGROUND
- name: Reduced mitochondrial bicarbonate availability
  description: >-
    Impaired intramitochondrial bicarbonate production restricts the substrate available to CPS1, pyruvate
    carboxylase, PCC and 3MCC. Secondary enzyme impairment is inferred from the metabolic pattern; its
    magnitude varies by patient and physiological state.
  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: Mitochondria are impermeable to HCO3−, and thus the two intramitochondrial carbonic anhydrases (CA-VA and CA-VB) are pivotal in providing HCO3− for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles
    explanation: >-
      Explains why reduced mitochondrial bicarbonate production affects the downstream enzymes; this is
      biochemical background rather than a direct patient bicarbonate measurement.
    quote_role: BACKGROUND
  chemical_entities:
  - preferred_term: hydrogencarbonate
    term:
      id: CHEBI:17544
      label: hydrogencarbonate
    modifier: DECREASED
  downstream:
  - target: Impaired CPS1-dependent ureagenesis
    description: >-
      Bicarbonate limitation constrains the first step of the urea cycle.
    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: Given that glutamine was elevated in three of the four affected individuals and that the citrulline was low to normal in all, it appears that an impaired urea cycle, rather than deficient glutamate, was the major cause of hyperammonemia.
      explanation: >-
        The clinical metabolite pattern supports predominant secondary CPS1-dependent ureagenesis impairment,
        inferred rather than directly measured.
  - target: Secondary pyruvate carboxylase dysfunction
    description: >-
      Bicarbonate limitation reduces pyruvate carboxylation.
    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: Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia, as was observed in our CA-VA-deficient individuals with presumed secondary PC deficiency leading to hypoglycemia through impaired gluconeogenesis.
      explanation: >-
        The authors infer secondary pyruvate carboxylase impairment from the clinical biochemical findings.
  - target: Secondary propionyl-CoA carboxylase dysfunction
    description: >-
      Reduced bicarbonate supply limits PCC-dependent metabolism.
    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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
      explanation: >-
        Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in
        affected liver.
  - target: Secondary 3-methylcrotonyl-CoA carboxylase dysfunction
    description: >-
      Reduced bicarbonate supply limits 3MCC-dependent metabolism.
    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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
      explanation: >-
        Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in
        affected liver.
- name: Impaired CPS1-dependent ureagenesis
  description: >-
    Restricted bicarbonate availability limits carbamoyl phosphate formation and nitrogen disposal through
    the urea cycle. High glutamine with low-to-normal citrulline supports this mechanism in some patients;
    the pattern is not universal.
  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: Given that glutamine was elevated in three of the four affected individuals and that the citrulline was low to normal in all, it appears that an impaired urea cycle, rather than deficient glutamate, was the major cause of hyperammonemia.
    explanation: >-
      The clinical metabolite pattern supports predominant secondary CPS1-dependent ureagenesis impairment,
      inferred rather than directly measured.
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Hyperammonemia
    description: >-
      Reduced ureagenesis impairs ammonia disposal.
    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: Given that glutamine was elevated in three of the four affected individuals and that the citrulline was low to normal in all, it appears that an impaired urea cycle, rather than deficient glutamate, was the major cause of hyperammonemia.
      explanation: >-
        The clinical metabolite pattern supports predominant secondary CPS1-dependent ureagenesis impairment,
        inferred rather than directly measured.
  - target: Hyperammonemic encephalopathy
    description: >-
      Ammonia accumulation contributes to acute brain dysfunction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
      explanation: >-
        Links hyperammonemia to the clinical encephalopathy; intermediary cellular mechanisms are not
        directly demonstrated in this cohort.
- name: Secondary pyruvate carboxylase dysfunction
  description: >-
    Reduced pyruvate-to-oxaloacetate conversion limits anaplerosis and gluconeogenesis. This contributes
    to lactate elevation and hypoglycemia, which can occur independently of the magnitude of hyperammonemia.
  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: Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia, as was observed in our CA-VA-deficient individuals with presumed secondary PC deficiency leading to hypoglycemia through impaired gluconeogenesis.
    explanation: >-
      The authors infer secondary pyruvate carboxylase impairment from the clinical biochemical findings.
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  downstream:
  - target: Hypoglycemia
    description: >-
      Impaired gluconeogenesis reduces glucose production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia, as was observed in our CA-VA-deficient individuals with presumed secondary PC deficiency leading to hypoglycemia through impaired gluconeogenesis.
      explanation: >-
        The authors infer secondary pyruvate carboxylase impairment from the clinical biochemical findings.
  - target: Increased circulating lactate concentration
    description: >-
      Impaired pyruvate metabolism contributes to lactate accumulation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia, as was observed in our CA-VA-deficient individuals with presumed secondary PC deficiency leading to hypoglycemia through impaired gluconeogenesis.
      explanation: >-
        The authors infer secondary pyruvate carboxylase impairment from the clinical biochemical findings.
- name: Secondary propionyl-CoA carboxylase dysfunction
  description: >-
    Reduced bicarbonate provision limits propionyl-CoA carboxylation. Accumulation of related metabolites
    can produce mild propionic-aciduria-like urinary findings.
  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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
    explanation: >-
      Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected
      liver.
  downstream:
  - target: Organic acid accumulation
    description: >-
      Secondary PCC impairment contributes to accumulation of organic-acid metabolites.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
      explanation: >-
        Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in
        affected liver.
- name: Secondary 3-methylcrotonyl-CoA carboxylase dysfunction
  description: >-
    Reduced bicarbonate provision limits the 3MCC reaction in leucine catabolism. Urinary metabolites
    can resemble multiple carboxylase deficiency, often more subtly.
  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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
    explanation: >-
      Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected
      liver.
  downstream:
  - target: Organic acid accumulation
    description: >-
      Secondary 3MCC impairment contributes to accumulation of organic-acid metabolites.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
      explanation: >-
        Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in
        affected liver.
- name: Organic acid accumulation
  description: >-
    Secondary PCC and 3MCC dysfunction can lead to accumulation and urinary excretion of related organic-acid
    metabolites. These abnormalities are often mild or absent. Ketonuria is recorded as a variable clinical
    feature; its generation is not attributed specifically to either carboxylase defect.
  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: The observed moderate increase of urinary 3-OH propionic acid, propionyl glycine, and methylcitrate along with traces of 3-methylcrotonylglycine are consistent with the expected reduced activities of PCC and 3MCC in CA-VA deficiency.
    explanation: >-
      Urinary metabolites support secondary PCC and 3MCC dysfunction without direct enzyme assays in affected
      liver.
  downstream:
  - target: Metabolic acidosis
    description: >-
      Accumulating titratable organic acids contribute to acidosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
      reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Complex acid-base status that includes respiratory alkalosis and metabolic acidosis ... reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
      explanation: >-
        GeneReviews distinguishes the respiratory alkalosis of hyperammonemia from metabolic acidosis
        caused by organic acids.
- name: Hyperammonemic encephalopathy
  description: >-
    Ammonia-related brain dysfunction can cause altered consciousness and seizures. Severe cerebral injury
    may progress despite normalization of blood ammonia, so biochemical improvement does not guarantee
    neurological recovery. Cellular explanations involving energy failure and edema are incompletely resolved
    in this disorder.
  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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
    explanation: >-
      Clinical decompensations link these acute manifestations to hyperammonemia.
  - reference: url:https://www.nature.com/articles/s41436-019-0677-9
    reference_title: Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia | Genetics in Medicine
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, encephalopathy and arterial hypertension persisted and worsened even after normalization of metabolic parameters.
    explanation: >-
      The fatal case demonstrates continued brain dysfunction despite biochemical correction.
  conforms_to: metabolic_intoxication_decompensation#Acute Metabolic Encephalopathy
  downstream:
  - target: Lethargy
    description: >-
      Acute brain dysfunction manifests as lethargy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
      explanation: >-
        Clinical decompensations link these acute manifestations to hyperammonemia.
  - target: Vomiting
    description: >-
      Vomiting accompanies hyperammonemic decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
      explanation: >-
        Clinical decompensations link these acute manifestations to hyperammonemia.
  - target: Seizures
    description: >-
      Metabolic encephalopathy may provoke seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42371568
      reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Seizures and epileptic encephalopathy have been documented in cases with CA‐VA deficiency during MDE (n = 9/67), mostly provoked by hyperammonemic crises
      explanation: >-
        The literature synthesis links seizures to metabolic crises; chronic epilepsy occurs in only some
        cases.
  - target: Feeding difficulties
    description: >-
      Acute hyperammonemic illness impairs feeding.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
      explanation: >-
        Clinical decompensations link these acute manifestations to hyperammonemia.
  - target: Coma
    description: Severe hyperammonemic encephalopathy may progress to coma.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25834911
      reference_title: Carbonic Anhydrase VA Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma).
      explanation: >-
        GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating
        individual frequencies.
  - target: Cerebral edema
    description: Cerebral edema can accompany acute hyperammonemic encephalopathy; the cellular intermediates are not established in this disorder.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38974611
      reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: During the first episode of hyperammonemic encephalopathy at the age of 3 days, MRI brain in patient 1 showed mild brain edema with focal areas of diffusion restriction in the right lentiform nucleus and right thalamus in keeping with acute infarcts
      explanation: >-
        The founder cohort documents cerebral edema during acute hyperammonemic encephalopathy. This supports
        the clinical link without establishing the cellular mechanism.
phenotypes:
- name: Hyperammonemia
  description: >-
    Prominent during many acute crises, but not obligatory in all biallelic CA5A carriers. Ammonia can
    be normal between episodes and in asymptomatic adults.
  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: >-
      The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent
      studies broadened the spectrum.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: the two asymptomatic patients had normal ammonia
    explanation: >-
      Normal ammonia in these two homozygous adults counters the claim that hyperammonemia is obligatory
      in every affected individual.
  category: Biochemical
  sequelae:
  - target: Respiratory alkalosis
    description: Hyperammonemia can provoke a respiratory disturbance with alkalosis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
      reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Complex acid-base status that includes respiratory alkalosis and metabolic acidosis ... reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
      explanation: >-
        GeneReviews distinguishes the respiratory alkalosis of hyperammonemia from metabolic acidosis
        caused by organic acids.
- name: Increased circulating lactate concentration
  description: >-
    Often elevated during decompensation but normal lactate has also been documented.
  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: >-
      The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent
      studies broadened the spectrum.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 2/14 (14.3%) had normal lactate
    explanation: >-
      Refutes obligatory hyperlactatemia in all symptomatic patients.
  category: Biochemical
- name: Ketonuria
  description: >-
    Variable ketone excretion during crises. Early hyperammonemia-selected series suggested universality,
    whereas the 2024 founder cohort reported ketosis in only 3 of 12 assessed patients.
  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: >-
      The early hyperammonemia-selected cohort described this feature as apparently obligatory; subsequent
      studies broadened the spectrum.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: ketosis was reported in 3/12 (25%) patients.
    explanation: >-
      The later cohort refutes universal ketosis; the denominator is the assessed subset.
  category: Biochemical
- name: Metabolic acidosis
  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.
  category: Biochemical
- name: Hypoglycemia
  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.
  category: Biochemical
- name: Lethargy
  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.
  category: Neurological
- name: Vomiting
  category: Gastrointestinal
  description: >-
    Vomiting can occur during metabolic decompensation.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  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: including lethargy, poor feeding, and vomiting caused by hyperammonemia
    explanation: >-
      Clinical decompensations link these acute manifestations to hyperammonemia.
- name: Tachypnea
  category: Respiratory
  description: >-
    Tachypnea accompanies some acute episodes.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma).
    explanation: >-
      GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating
      individual frequencies.
- name: Seizures
  category: Neurological
  description: >-
    Seizures occur during some metabolic crises; persistent epilepsy is less common.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma).
    explanation: >-
      GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating
      individual frequencies.
- name: Coma
  category: Neurological
  description: >-
    Severe encephalopathy may progress to coma.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma).
    explanation: >-
      GeneReviews identifies these manifestations of acute metabolic encephalopathy without estimating
      individual frequencies.
- name: Respiratory alkalosis
  category: Biochemical
  description: >-
    Respiratory alkalosis may coexist with metabolic acidosis.
  phenotype_term:
    preferred_term: Respiratory alkalosis
    term:
      id: HP:0001950
      label: Respiratory alkalosis
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: complex acid-base status including respiratory alkalosis and metabolic acidosis
    explanation: >-
      Defines the mixed acid-base pattern.
- name: Global developmental delay
  category: Neurological
  description: >-
    Development ranges from normal to severe delay. In the 2024 founder cohort, 7 of 18 had developmental
    delay; co-inherited disorders and metabolic injury may contribute.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 7/18 patients developed variable degree of developmental delay
    explanation: >-
      Provides the cohort-specific frequency; it is not a population-wide estimate.
  frequency: FREQUENT
  context: 2024 c.59G>A founder cohort
- name: Microcephaly
  category: Neurological
  description: >-
    Reported in three of eighteen patients in the 2024 founder cohort. Attribution can be complicated
    by consanguinity and additional genetic conditions.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3/18 (16.7%) patients had microcephaly
    explanation: >-
      Cohort-specific observation supports this manifestation.
  frequency: OCCASIONAL
  context: 2024 c.59G>A founder cohort
- name: Failure to thrive
  category: Growth
  description: >-
    Poor growth occurred in seven of eighteen patients in the 2024 founder cohort.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Failure to thrive was encountered in 7/18 (38.9%) patients
    explanation: >-
      The frequency applies to this single founder cohort.
  frequency: FREQUENT
  context: 2024 c.59G>A founder cohort
- name: Elevated circulating creatine kinase activity
  category: Biochemical
  description: >-
    HyperCKemia was found in nine of eleven tested patients in the founder cohort and during crises in
    long-term follow-up. The mechanism is uncertain; illness-associated myositis is a competing explanation.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Creatine kinase (CK) was measured in 11 patients, and 9/11 (81.8%) patients had mildly elevated CK
    explanation: >-
      Shows frequent CK elevation among tested members of one cohort; selection prevents a general frequency
      estimate.
  - reference: PMID:42371568
    reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, concurrent myositis in the context of febrile illnesses cannot be excluded.
    explanation: >-
      Qualifies interpretation of CK elevations during febrile decompensations.
- name: Hypotonia
  category: Neurological
  description: >-
    Axial hypotonia has been reported with developmental impairment without recognized metabolic crisis.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: neurological examination revealed axial hypotonia.
    explanation: >-
      Observed in the first child with the exon 3–7 deletion.
- name: Delayed speech and language development
  category: Neurological
  description: >-
    Speech delay has been described in children with biallelic CA5A deletions and no recognized hyperammonemic
    crisis. Additional variants in some children complicate causal attribution.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She had mild developmental delay, predominantly affecting speech, but otherwise exhibited normal gross motor development.
    explanation: >-
      Case-level language-predominant delay; not a population frequency estimate.
- name: Thin corpus callosum
  category: Neurological
  description: >-
    Callosal thinning was reported in one child with the exon 3–7 deletion; it is not a defining radiological
    signature.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI demonstrated moderately marked thinning of the corpus callosum along with mild periventricular leukomalacia
    explanation: >-
      Supports the imaging finding in a single case.
- name: Cerebral edema
  category: Neurological
  description: >-
    Brain edema and acute injury may accompany severe metabolic encephalopathy.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MRI brain in patient 1 showed mild brain edema with focal areas of diffusion restriction in the right lentiform nucleus and right thalamus in keeping with acute infarcts
    explanation: >-
      Direct neuroimaging evidence during neonatal hyperammonemic encephalopathy.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Poor feeding or feeding intolerance can accompany neonatal metabolic encephalopathy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma).
    explanation: >-
      GeneReviews identifies feeding intolerance among presenting symptoms.
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.
    - reference: PMID:38974611
      reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 2/18 (11.1%) patients were asymptomatic adults with normal intellect who were identified during familial segregation studies
      explanation: >-
        Directly demonstrates incomplete clinical penetrance in this founder cohort.
    description: >-
      Autosomal recessive inheritance with variable clinical penetrance. Asymptomatic homozygous adults
      and affected relatives with different courses are documented.
  features: >-
    Pathogenic alleles include missense, nonsense, splice-altering synonymous variants and exon deletions,
    in homozygous or compound-heterozygous states. The synonymous c.555G>A change causes exon 4 skipping;
    exon 6 deletion can abolish detectable hepatic protein. The c.59G>A p.Trp20Ter allele occurs in an
    Arabian Peninsula founder cohort with marked intrafamilial variability. Missense effects differ between
    assay systems and do not establish a clinical severity ranking.
  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.
  - 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: Sanger sequencing of the ∼550 bp band revealed an in-frame deletion of exon 4 from the index RNA
    explanation: >-
      Patient white-blood-cell RNA confirms abnormal splicing from the synonymous terminal-exon variant.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A.
    explanation: >-
      Defines the founder allele and cohort.
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A pathogenic homozygous loss of 16.5 kb (exons 3-7) in CA5A gene
    explanation: >-
      Documents the larger deletion; transcript effects were not experimentally demonstrated.
  - reference: PMID:41113665
    reference_title: Carbonic anhydrase VA deficiency due to a novel CA5A variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Rapid trio genome sequencing revealed a biparentally inherited, homozygous variant of uncertain significance (VUS) in CA5A NM_001739.1:c.475T>C p.(Trp159Arg).
    explanation: >-
      Preserves the authors’ VUS classification despite supportive clinical and computational observations.
  - reference: PMID:41737902
    reference_title: Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The maternally‐inherited variant has not been reported in the medical literature to date.
    explanation: >-
      The maternal allele in the antenatal report remained a VUS, as recorded in its Table 3.
  notes: >-
    The 2025 p.Trp159Arg report retained a variant-of-uncertain-significance classification despite a
    clinically compatible presentation. The 2026 antenatal series carried a pathogenic paternal frameshift
    and maternal p.Ala142Thr VUS. Neither should be recast as two experimentally proven pathogenic alleles.
    The 2026 exon 3–7 deletion series reported additional SYT2 and SYNE4 variants in two siblings and
    acknowledged that causal attribution of developmental delay requires further cases and functional
    studies.
treatments:
- name: Carglumic acid
  description: >-
    Carglumic acid is an N-acetylglutamate analogue that activates CPS1. It has been used off-label for
    acute hyperammonemia in CA-VA deficiency, with rapid biochemical responses in uncontrolled clinical
    reports. Activation of residual CPS1 flux despite bicarbonate limitation is proposed; benefit cannot
    always be separated from concurrent caloric support and other ammonia-lowering measures.
  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.
  - 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: This hypothesis should be tested in the Car5A-null mouse model ... especially given the high cost of this medication and uncontrolled circumstances in which these children were managed with multiple therapeutic modalities.
    explanation: >-
      The authors qualify the proposed CA-VA-specific rescue mechanism and the uncontrolled treatment
      evidence.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: When carglumic acid was used alone in three patients to treat hyperammonemia based on knowledge of founder effect or family history, ammonia normalized in less than 24 h.
    explanation: >-
      Provides additional uncontrolled clinical response data.
  target_mechanisms:
  - target: Impaired CPS1-dependent ureagenesis
    treatment_effect: RESTORES
    description: >-
      Enhances CPS1 activity; compensation for reduced bicarbonate availability is proposed.
    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: consistent with the suggestion that enhanced CPS1 activity can partially compensate for reduced HCO3− resulting from CA-VA deficiency.
      explanation: >-
        Mechanistic interpretation of observed clinical responses, not direct flux measurement.
  action_category: THERAPEUTIC
- name: Acute anticatabolic support
  action_category: THERAPEUTIC
  description: >-
    Hospital care uses glucose-containing fluids and additional caloric support, temporary protein adjustment
    when hyperammonemia is present, and close biochemical monitoring. This reverses catabolism while ammonia-lowering
    treatment is instituted. Management is individualized by metabolic specialists.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
    explanation: >-
      GeneReviews expert management recommendations; not evidence from a controlled CA-VA trial.
- name: Nitrogen scavengers
  action_category: THERAPEUTIC
  description: >-
    Sodium benzoate and phenylbutyrate or phenylacetate have been used to lower ammonia during crises,
    sometimes with arginine and other measures. Disease-specific comparative efficacy remains uncertain.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium benzoate
      term:
        id: CHEBI:113455
        label: sodium benzoate
    - preferred_term: sodium phenylbutyrate
      term:
        id: CHEBI:75316
        label: sodium phenylbutyrate
    - preferred_term: sodium phenylacetate
      term:
        id: CHEBI:749228
        label: sodium phenylacetate
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Medications used included the ammonia scavengers sodium benzoate and sodium phenylbutyrate
    explanation: >-
      Documents scavenger use in the founder cohort.
  - reference: url:https://www.nature.com/articles/s41436-019-0677-9
    reference_title: Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia | Genetics in Medicine
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These included sodium benzoate, sodium phenylacetate, L-arginine, as well as carglumic acid.
    explanation: >-
      Documents multimodal treatment in the severe case, without implying treatment success.
- name: Extracorporeal ammonia removal
  action_category: THERAPEUTIC
  description: >-
    Severe hyperammonemic crises have required hemodialysis or hemofiltration as part of acute specialist
    management.
  treatment_term:
    preferred_term: Hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  evidence:
  - reference: PMID:41737902
    reference_title: Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband, their older brother, had presented on day four of life with marked lactic acidosis, hyperammonaemia and encephalopathy requiring haemofiltration due to CAVA deficiency.
    explanation: >-
      The presenting sibling required extracorporeal support during the neonatal crisis.
  - 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: extracorporeal detoxification in the case of severe hyperammonemia
    explanation: >-
      Supports extracorporeal treatment for severe biochemical decompensation.
- name: Sick-day nutrition and fasting avoidance
  action_category: THERAPEUTIC
  description: >-
    An individualized emergency plan supplies additional carbohydrate and fat calories during illness,
    avoids fasting, and specifies temporary protein adjustment and criteria for hospital care. Long-term
    dietary or drug treatment during wellness is individualized; universal lifelong protein restriction
    is not established.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:42371568
    reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients should be provided with a personalized sick‐day protocol during periods of febrile illness and catabolic states, consisting of high‐calorie intake from fats and carbohydrates, temporary protein restriction, strict avoidance of fasting, and clear criteria for hospital admission
    explanation: >-
      Current expert synthesis supports individualized prevention.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.
    explanation: >-
      Avoids presenting prophylactic dietary restriction or zinc as established treatment.
- name: Planned neonatal care after familial diagnosis
  action_category: THERAPEUTIC
  description: >-
    Antenatal or familial diagnosis allows planned delivery with metabolic support, regular feeding and
    biochemical observation. Two prenatally identified siblings remained stable after short-course prophylactic
    carglumic acid plus feeding support. The uncontrolled report does not establish which intervention
    prevented decompensation; one familial allele remained a VUS.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41737902
    reference_title: Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Carglumic acid was used for each sibling infant and outcomes may have been due to its use, regular feeding and monitoring, or all of these factors.
    explanation: >-
      The authors explicitly acknowledge confounding between preventive interventions.
- name: Avoidance of carbonic anhydrase inhibitors
  action_category: THERAPEUTIC
  description: >-
    GeneReviews recommends avoiding acetazolamide and topiramate because further carbonic anhydrase inhibition
    may aggravate the metabolic defect. This is disease-specific expert advice rather than a quantified
    drug-risk estimate.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity.
    explanation: >-
      Expert avoidance recommendation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: If anti-seizure medication is necessary, avoid topiramate based on its action as a carbonic anhydrase inhibitor.
    explanation: >-
      Expert avoidance recommendation despite isolated published use.
- name: Metabolic and developmental surveillance
  action_category: MONITORING
  description: >-
    Follow metabolic stability, growth and neurodevelopment, with reassessment during illness. Recurrence
    into later childhood supports retaining an emergency plan even after prolonged stability.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Follow up during infancy and early childhood with a metabolic disease specialist every three to six months for physical and neurologic examinations.
    explanation: >-
      GeneReviews expert surveillance recommendation.
  - reference: PMID:42371568
    reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ongoing surveillance is recommended given the risk of MDE recurrence into later childhood and potential neurodevelopmental sequelae.
    explanation: >-
      Long-term follow-up supports continued clinical surveillance.
- name: Genetic counseling and family testing
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    For two heterozygous parents, each pregnancy has a one-in-four chance of a child inheriting both CA5A
    variants. Carrier and reproductive testing are possible once familial variants are known. Clinical
    penetrance and severity cannot be predicted reliably from genotype, and asymptomatic relatives may
    be homozygous.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a 25% chance of inheriting two CA5A pathogenic variants and usually being affected
    explanation: >-
      Supports Mendelian recurrence risk while retaining incomplete clinical penetrance.
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The results of prenatal testing cannot be used to predict with certainty whether or not an individual will be affected
    explanation: >-
      Separates genotype prediction from clinical prognosis.
notes: >-
  CA5A deficiency is a variable clinical spectrum rather than a set of established molecular subtypes.
  A 2026 report of developmental delay without recognized metabolic crises is limited by small numbers
  and additional potentially relevant variants in two siblings; developmental findings should not automatically
  be attributed to CA5A alone. Genotype does not reliably predict crisis recurrence or neurological outcome.
progression:
- phase: Clinical course
  evidence:
  - reference: PMID:42371568
    reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Case 1 experienced three additional MDEs at ages 2 years 6 months, 3 years 6 months, and 8 years, all triggered by febrile illnesses.
    explanation: >-
      Extends the documented recurrence window into later childhood.
  - reference: PMID:42371568
    reference_title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Currently, both cases show normal growth, development, and neurological outcomes
    explanation: >-
      Longitudinal follow-up of the original siblings supports favorable outcomes in these individuals,
      not a universal prognosis.
  - reference: url:https://www.nature.com/articles/s41436-019-0677-9
    reference_title: Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia | Genetics in Medicine
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: this case demonstrates that the disease course can be fulminant and fatal despite rapid initiation of adequate treatment and despite quick normalization of ammonia and lactate levels during metabolic crisis.
    explanation: >-
      Rare fatal disease counters an unconditional benign prognosis.
  notes: >-
    Initial crises often occur in the neonatal period, but onset and recurrence can occur later in childhood.
    Normal development is possible even after recurrent episodes, while severe neurological impairment
    and rare fatal outcomes are also reported. In follow-up of the original siblings, one had her last
    crisis at eight years and the other remained stable; both had favorable adolescent outcomes.
diagnosis:
- name: Biochemical investigation during decompensation
  description: >-
    Assess ammonia, lactate, glucose, blood gases, plasma amino acids and urine organic acids. Elevated
    glutamine and alanine with low-to-normal citrulline and mild carboxylase-substrate elevations can
    suggest CA-VA deficiency. Results vary and may normalize between episodes.
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: elevated plasma glutamine and alanine and low-to-normal citrulline
    explanation: >-
      Identifies an informative amino-acid pattern.
  - 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: Furthermore, these abnormalities may be present only during symptomatic episodes.
    explanation: >-
      Normal interval testing cannot exclude the disorder.
- name: CA5A sequence and deletion analysis
  diagnosis_term:
    preferred_term: Molecular Diagnosis
    term:
      id: NCIT:C20826
      label: Molecular Diagnosis
  description: >-
    Identify biallelic pathogenic or likely pathogenic CA5A variants, using sequence and exon-level copy-number
    analysis as appropriate. Whole-exome or genome sequencing can detect atypical presentations. The homologous
    CA5AP1 pseudogene complicates assay design. VUS findings require interpretation and do not independently
    establish the diagnosis.
  evidence:
  - reference: PMID:25834911
    reference_title: Carbonic Anhydrase VA Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: biallelic pathogenic variants in CA5A identified by molecular genetic testing.
    explanation: >-
      Supports molecular confirmation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted ... deletion/duplication analysis ... to detect exon and whole-gene deletions or duplications.
    explanation: >-
      GeneReviews recommends copy-number analysis after incomplete sequence results; ellipses skip glossary
      markup.
  - 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: the CA5A variant was confirmed by targeted Sanger sequencing via carefully designed primers to avoid amplification of the pseudogene sequences
    explanation: >-
      Demonstrates the need for pseudogene-aware confirmation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
    reference_title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Identification of ... biallelic ... CA5A ... variants of ... uncertain significance ... (or identification of one known ... CA5A ... pathogenic variant ... and one ... CA5A ... variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
    explanation: >-
      VUS findings are not diagnostic; ellipses skip glossary markup.
- name: Newborn screening limitations
  description: >-
    A normal standard tandem-mass-spectrometry newborn screen does not exclude CA-VA deficiency. The characteristic
    C3 and C5OH elevations may be absent even during crises; genomic screening is being evaluated separately.
  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: Newborn screening profiles (Tandem MS/MS), specifically C3 and C5OH levels, were unremarkable in all four cases
    explanation: >-
      Direct evidence of normal screening in affected children.
- name: Neurological assessment
  description: >-
    Developmental assessment and brain MRI help characterize injury; EEG is relevant when seizures are
    suspected. MRI may be normal or show cortical, deep-gray or white-matter injury. No imaging pattern
    independently establishes CA-VA deficiency.
  evidence:
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MRI brain in patient 2 at the age of 9 days showed abnormal T2 signal intensity and diffusion restriction in the perirolandic cortex, insula, and basal ganglia in keeping with hyperammonemic encephalopathy
    explanation: >-
      Documents an observed acute imaging pattern.
  - 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 female sibling, both MRI and EEG were unremarkable.
    explanation: >-
      Normal neurodiagnostic tests also occur.
clinical_trials:
- name: NCT03655223
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Early Check is a prospective observational newborn-screening study whose registered condition list
    includes carbonic anhydrase VA deficiency. It evaluates expanded screening and its impact on families;
    it is not a CA5A-targeted treatment trial. The registry was last updated July 1, 2026.
  evidence:
  - reference: clinicaltrials:NCT03655223
    reference_title: 'Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early Check provides voluntary screening of newborns for a selected panel of conditions.
    explanation: >-
      Registry summary establishes the screening purpose; the official API condition list explicitly includes
      this disease.
animal_models:
- name: Car5a-null and Car5a/Car5b double-knockout mice
  species: Mouse
  genotype: Car5a knockout; Car5a/Car5b double knockout
  description: >-
    Car5a-null mice show hyperammonemia and impaired growth, with normal fasting glucose. Double knockout
    worsens hyperammonemia, growth and survival and reduces fasting glucose. Sodium-potassium citrate
    improved breeding and neonatal survival but did not improve growth or post-weaning mortality; efficacy
    in humans is unestablished.
  publication: PMID:23589845
  modeled_mechanisms:
  - target: Impaired CPS1-dependent ureagenesis
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Models defective ammonia disposal and the contribution of CA-VB.
    limitations: >-
      Whole-animal gene deletion does not establish age-dependent compensation or clinical prognosis in
      humans.
    evidence:
    - reference: PMID:23589845
      reference_title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The enhanced hyperammonemia and lower fasting blood sugar, which are both seen in the DKO mice, indicate that both Car5A and Car5B contribute to both ammonia detoxification (ureagenesis) and regulation of fasting blood sugar (gluconeogenesis).
      explanation: >-
        Genetic perturbation connects mitochondrial carbonic anhydrases with whole-animal metabolism.
  evidence:
  - reference: PMID:23589845
    reference_title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Their blood ammonia concentrations were markedly elevated, but their fasting blood sugars were normal.
    explanation: >-
      Car5a single knockout does not reproduce every human biochemical feature.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645511/
    reference_title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: citrate salt supplementation improved breeding and reduced the neonatal mortality of the ... null and DKO mice, but we did not observe that it improved growth or reduced mortality after weaning.
    explanation: >-
      Full-text results distinguish neonatal benefit from absent growth or post-weaning benefit.
experimental_models:
- name: COS-7 expression of CA5A p.Ser233Pro
  experimental_model_type: CELL_LINE
  cell_source: Transfected COS-7 cells
  description: >-
    Heterologous expression demonstrates lower mutant CA-VA abundance and temperature-sensitive enzyme
    activity. These assays do not reproduce the integrated human liver metabolic phenotype.
  publication: PMID:24530203
  modeled_mechanisms:
  - target: Mitochondrial carbonic anhydrase VA deficiency
    relationship: RECAPITULATES
    description: >-
      Measures the variant-associated loss of enzyme function.
    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: IN_VITRO
      snippet: A marked reduction was observed in the steady-state levels of CA-VA p.Ser233Pro compared with wild-type protein despite similar transfection efficiencies
      explanation: >-
        COS-7 expression shows reduced mutant protein abundance.
  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: IN_VITRO
    snippet: After a 30 min preincubation, the mutant enzyme had lost 80% of its activity at 30°C and almost all its activity at 40°C.
    explanation: >-
      Direct thermal-inactivation measurements in the COS-7 expression system.
- name: Sf9 expression of recombinant human CA-VA variants
  experimental_model_type: CELL_LINE
  cell_source: Baculovirus-transduced Sf9 insect cells
  description: >-
    Purified recombinant proteins permit comparison of catalytic activity and thermal stability. Missense
    and exon-deletion alleles show different activity and stability defects; cellular proteostasis and
    clinical severity are not fully captured.
  publication: PMID:26913920
  modeled_mechanisms:
  - target: Mitochondrial carbonic anhydrase VA deficiency
    relationship: RECAPITULATES
    description: >-
      Measures activity and stability of disease-associated enzyme forms.
    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: IN_VITRO
      snippet: Exhibiting decreased enzyme activity or thermal stability, all CAVA mutations were proven to cause disease, whereas the three variants showed no relevant effect.
      explanation: >-
        Recombinant enzyme studies distinguish loss of activity and stability from benign control variants.
  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: IN_VITRO
    snippet: developed an expression system using insect cells, which enabled the characterization of wild-type CAVA, clinical mutations, and three variants that affect functional residues.
    explanation: >-
      Establishes the heterologous protein assay system.
references:
- reference: PMID:23589845
  title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism.
- reference: PMID:24530203
  title: Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.
- reference: PMID:25834911
  title: Carbonic Anhydrase VA Deficiency.
  tags:
  - GeneReviews
- reference: PMID:26913920
  title: Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis.
- reference: PMID:38974611
  title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
- reference: PMID:41113665
  title: Carbonic anhydrase VA deficiency due to a novel CA5A variant.
- reference: PMID:41736722
  title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
- reference: PMID:41737902
  title: Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency.
- reference: PMID:42371568
  title: Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
- reference: clinicaltrials:NCT03655223
  title: 'Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645511/
  title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism - PMC
- reference: url:https://www.nature.com/articles/s41436-019-0677-9
  title: Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia | Genetics in Medicine
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
  title: Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
discussions:
- discussion_id: cavb_modifier
  prompt: Does CA-VB compensation explain variable penetrance and age-dependent recurrence?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced mitochondrial bicarbonate availability
  rationale: >-
    Mouse double-knockout data support overlapping metabolic function. Developmental changes in human
    CA-VB activity and a role in interindividual prognosis remain unproven.
  evidence:
  - reference: PMID:23589845
    reference_title: Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The contribution of Car5B to ureagenesis and gluconeogenesis was evident only on a Car5A null background.
    explanation: >-
      Animal experiments support partial functional compensation.
  - reference: PMID:38974611
    reference_title: A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We argue that the role of CA‐VB as a potential genetic modifier in patients with CA‐VA deficiency deserves further study.
    explanation: >-
      Human modifier activity remains a hypothesis.
- discussion_id: developmental_attribution
  prompt: How much of the developmental phenotype is attributable to CA5A independently of metabolic crises and other variants?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Global developmental delay
  rationale: >-
    The 2026 deletion series contains no recognized hyperammonemic crises. Two siblings also carried homozygous
    SYT2 variants, with differing SYNE4 genotypes. The authors regarded these as secondary findings but
    acknowledged that definitive attribution to CA5A requires larger studies and functional work. No causal
    edge from acute hyperammonemic encephalopathy to all developmental findings is asserted.
  evidence:
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Furthermore, definitively attributing the developmental delay to CA5A deletion needs a larger number of cases and functional studies.
    explanation: >-
      The original report explicitly limits causal attribution.
  - reference: PMID:41736722
    reference_title: A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: index (#2) had SYT2 (homozygous) and SYNE4 (heterozygous); affected sister (#3) had SYT2 (homozygous) and SYNE4 (homozygous)
    explanation: >-
      Other potentially relevant genotypes complicate interpretation.
differential_diagnoses:
- name: Proximal urea cycle disorders
  description: >-
    CPS1 and NAGS deficiencies share hyperammonemia, high glutamine, low citrulline and little orotic
    acid excretion. Lactate and carboxylase-related urinary metabolites can favor CA-VA deficiency, although
    their absence does not exclude it.
  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: CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.
    explanation: >-
      The primary study establishes the differential diagnosis.
- name: Multiple carboxylase deficiency
  description: >-
    Biotinidase and holocarboxylase synthetase deficiencies can produce overlapping urinary metabolites.
    Secondary CPS1 impairment and milder PCC/3MCC metabolites can help distinguish CA-VA deficiency.
  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: the significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation
    explanation: >-
      The primary study compares biotinidase and holocarboxylase synthetase defects with CA-VA deficiency.
- name: Pyruvate carboxylase deficiency
  description: >-
    Shares lactic acidosis, hypoglycemia and hyperammonemia; molecular and biochemical investigation distinguishes
    primary PC deficiency from secondary impairment in CA-VA deficiency.
  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: Primary PC deficiency is biochemically characterized by lactic acidosis, hyperammonemia, and hypoglycemia
    explanation: >-
      The overlapping biochemical profile requires differential testing.
📚

References & Deep Research

References

13
PMID:23589845
Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism.
No top-level findings curated for this source.
PMID:24530203
Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.
No top-level findings curated for this source.
PMID:25834911
Carbonic Anhydrase VA Deficiency.
No top-level findings curated for this source.
PMID:26913920
Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis.
No top-level findings curated for this source.
PMID:38974611
A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.
No top-level findings curated for this source.
PMID:41113665
Carbonic anhydrase VA deficiency due to a novel CA5A variant.
No top-level findings curated for this source.
PMID:41736722
A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis.
No top-level findings curated for this source.
PMID:41737902
Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency.
No top-level findings curated for this source.
PMID:42371568
Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review.
No top-level findings curated for this source.
clinicaltrials:NCT03655223
Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3645511/
Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism - PMC
No top-level findings curated for this source.
url:https://www.nature.com/articles/s41436-019-0677-9
Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia | Genetics in Medicine
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK284774/
Carbonic Anhydrase VA Deficiency - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.