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Carbonic Anhydrase VA Deficiency

Synonym: CA-VA Deficiency

, MD, PhD, FCCMG and , MD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

The four children with carbonic anhydrase VA (CA-VA) deficiency reported to date presented between day two of life and age 20 months with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Data on long-term follow up are limited (the oldest known patient is age 7 years). Two of the four children showed normal psychomotor development and two showed mild learning difficulties and delayed motor skills. Seven additional children diagnosed with CA-VA deficiency (but not yet published) presented similarly.

Diagnosis/testing.

CA-VA deficiency is suspected in children with neonatal, infantile, or early-childhood metabolic hyperammonemic encephalopathy combined with hyperlactatemia and metabolites suggestive of multiple carboxylase deficiency. The diagnosis is established in a proband with these metabolic findings and biallelic pathogenic variants in CA5A.

Management.

Treatment of manifestations: Admit to the hospital children with insufficient oral intake or refusal to take anything by mouth and/or signs of metabolic decompensation such as encephalopathy. Always provide IV fluids including maintenance glucose plus extra calories via IV lipids, and always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters. If ammonia-lowering medication is needed, carglumic acid may be preferable as it has anecdotally shortened the period of hyperammonemia. Other medications such as sodium benzoate would also be reasonable.

Surveillance: Follow up with a metabolic disease specialist every 3-6 months for physical and neurologic examinations. Consider neurodevelopmental testing and measuring of plasma ammonia and amino acids; serum lactate and glucose; blood gases; liver parameters; and urine organic acids.

Agents/circumstances to avoid: Acetazolamide as it inhibits carbonic anhydrase activity.

Evaluation of relatives at risk: When both CA5A pathogenic variants have been identified in an affected family member, it is appropriate to evaluate all sibs in order to identify those who would benefit from prompt treatment when symptoms appear.

Pregnancy management: For an affected child: Delivery in hospital with monitoring for several days (physical examination and measurement of serum glucose, blood gases, plasma ammonia, serum lactate, plasma amino acids, and urine organic acids).

Genetic counseling.

CA-VA deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of inheriting two CA5A pathogenic variants and usually being affected (in some families, asymptomatic [older] sibs with biallelic CA5A pathogenic variants have been identified), a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither pathogenic variant and being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the CA5A pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Carbonic anhydrase VA (CA-VA) deficiency should be suspected in children with neonatal, infantile, or early childhood-onset metabolic hyperammonemic encephalopathy (like that observed in the urea cycle disorders) combined with hyperlactatemia and metabolites suggestive of multiple carboxylase deficiency.

Abnormal laboratory findings. Outside of acute events, clinical and biochemical parameters often remain normal in affected children except for mildly elevated blood lactate and/or the presence of ketonuria [van Karnebeek et al 2014b; J Häberle, unpublished data].

During acute decompensation, the laboratory findings are consistent with dysfunction of all four enzymes to which CA-VA provides bicarbonate as substrate in mitochondria (i.e., carbamoyl phosphate synthetase 1, propionyl CoA carboxylase, pyruvate carboxylase, and 3-methylcrotonyl CoA carboxylase), thereby differentiating CA-VA deficiency from other urea cycle disorders (see Pathophysiology). These laboratory findings include:

  • Significant elevation of plasma ammonia, lactate, and ketones (with concomitant increased urinary ketones); hypoglycemia can also be seen.
  • Complex acid-base status that includes respiratory alkalosis and metabolic acidosis (with decreased bicarbonate and base excess), reflecting the respiratory consequence of hyperammonemia and accumulation of titratable organic acids, respectively
  • Plasma amino acid analysis showing elevation of glutamine and alanine and low-to-normal citrulline
  • Urine organic acid analysis showing elevations of carboxylase substrates and related metabolites: 3-OH propionate, propionylglycine, methylcitrate and lactate, beta-hydroxybutyrate and acetoacetate

Normal laboratory findings. While newborn screening using tandem mass spectrometry (MS/MS) can theoretically detect carboxylase substrates (specifically C3 and C5OH levels as seen in multiple carboxylase deficiency), they were unremarkable in all four individuals reported to date [van Karnebeek et al 2014b]. This is likely due to the relatively mild biochemical profile for the carboxylase-related metabolites along with the low sensitivity of acylcarnitine analyses compared to urine organic acids. Note that because of this theoretic finding, individuals with elevated C3 and C5OH should be considered for this disorder in addition to multiple carboxylase deficiency.

Liver transaminases, albumin, and clotting factors have been normal in the patients reported.

Establishing the Diagnosis

The diagnosis of CA-VA deficiency is established in a proband with the metabolic findings described above and identification of biallelic pathogenic variants in CA5A on molecular genetic testing (see Table 1).

One molecular genetic testing strategy is sequence analysis of CA5A from leukocyte DNA, followed by deletion/duplication analysis if only one or no pathogenic variant is found.

Table 1.

Molecular Genetic Testing Used in Carbonic Anhydrase VA Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2
CA5ASequence analysis 310/15 probands
Deletion/duplication analysis 45/15 probands 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

From a total of 15 probands identified with pathogenic variants out of 98 individuals with suggestive phenotypes who were tested [van Karnebeek et al 2014b; Authors, unpublished data]

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Clinical Characteristics

Clinical Description

The four children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented during the newborn period (day 2 of life) or in early childhood (up to age 20 months) with hyperammonemic encephalopathy, i.e. lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma [van Karnebeek et al 2014b]. The clinical presentation – often triggered by a catabolic state – is thus similar to a combination of mild carbamoyl phosphate synthetase 1 deficiency and mild multiple carboxylase deficiency. However, the range of severity on presentation is probably not yet completely understood given the small number of reported cases to date.

Data on long-term follow up are limited as the oldest known patient is age seven years. Two of the four children reported show normal psychomotor development and two showed mild learning difficulties and delay in motor skills.

Seven other children who have been diagnosed but not yet published presented similarly.

Pathophysiology

CA-VA deficiency results in dysfunction of all four enzymes to which CA-VA provides bicarbonate as substrate in mitochondria:

The authors propose several explanations for the relatively benign clinical course observed in children with carbonic anhydrase VA deficiency: (1) the overlapping function of CA-VB may help prevent deleterious sequelae of reduced CA-VA activity [Shah et al 2013]; (2) some bicarbonate is produced via the non-enzymatic reaction, even in the absence of carbonic anhydrases; thus, during stable periods, this may be sufficient for the four different bicarbonate-requiring intra-mitochondrial enzymes.

Genotype-Phenotype Correlations

Genotype-phenotype correlations remain to be determined. Of note, because of the high rate of consanguinity most affected individuals are homozygous for a pathogenic variant.

Interestingly, for family 3 reported by van Karnebeek et al [2014b] with a homozygous CA5A4kb deletion of exon 6 in whom carbonic anhydrase VA was absent in liver, the phenotype was not more severe than in the other two families with splice-site and missense variants and residual (albeit reduced) carbonic anhydrase VA enzymatic activity.

Prevalence

Prevalence is currently unknown. Of note, a high proportion of affected individuals in the UK were born to consanguineous Pakistani parents.

Differential Diagnosis

The biochemical profiles of the disorders to be considered in the differential diagnosis of carbonic anhydrase VA (CA-VA) deficiency are summarized in Table 2.

Table 2.

Biochemical Findings in CA-VA Deficiency and Other Inborn Errors of Metabolism in the Differential Diagnosis

CA-VA DeficiencyDifferential Diagnosis
PC DeficiencyMultiple Carboxylase DeficiencyCPS1 or NAGS Deficiency
Plasma ammoniaNl
Serum lactateNl
Serum glucoseNl to↓NlNl
Plasma citrullineNl to↓Nl
Plasma glutamineNl
Plasma lysineNlNlNl
HCO3, base excessNl to ↓ 1Nl
Urine 3-OH butyrateNl
Urine alpha-ketoglutarateNl
Urine 3-OH propionic acid, propionylglycine, methylcitrateNlNl
Urine 3-methyl-crotonylglycine, 3-OH isovaleric acidNlNl
Fatty acids, total & free carnitine, acylcarnitine profilesNlNlAbnormal 2Nl

↑= elevated

↓ = decreased

Nl = normal

CA-VA = carbonic anhydrase VA

PC = pyruvate carboxylase

CPS1 = carbamoyl phosphate synthetase 1

NAGS = N-acetyl-glutamate synthase

1.

HCO3 as low as 5 mmol/L and base excess as low as -21 were found in some affected individuals.

2.

Low C0 (free carnitine) and elevated C2, C3, and C5OH

Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized:

  • Type A (infantile form), in which most affected children die in infancy or early childhood;
  • Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and
  • Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.

As in patients with PC deficiency, patients with CA-VA have hyperammonemia and hyperlactatemia (+/- hypoglycemia) in common. The differences, however, include the following:

  • Glutamine levels are elevated in CA-VA deficiency whereas they are normal to decreased in PC deficiency.
  • Citrulline levels are decreased to normal in CA-VA deficiency whereas they are often elevated in PC deficiency.
  • Lysine levels are normal, and 2-α-ketoglutaric acid and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.

The biochemical profiles in the four reported children with CA-VA deficiency support a predominant effect of (secondary) CPS1 deficiency versus PC deficiency.

Multiple carboxylase deficiency (holocarboxylase synthetase and biotinidase deficiency). If untreated, children with profound deficiency of either of these two enzymes usually exhibit neurologic abnormalities including seizures, lethargy, and hypotonia which can resemble CA-VA deficiency. The cutaneous abnormalities, ataxia, developmental delay, vision problems, and hearing loss observed in multiple carboxylase deficiency differentiate it clinically from CA-VA deficiency.

Although biotinidase deficiency and holocarboxylase synthetase (HCS) deficiency share the metabolite profiles of secondary deficiencies of PC, PCC, and 3MCC, the three major differences relative to primary CA-VA deficiency are:

  • 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 presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
  • The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO3-.

Urea cycle defects. Severe deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life [Häberle 2013]. Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, poor feeding, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. In milder (or partial) deficiencies the elevations of plasma ammonia concentration and symptoms are often subtle and the first recognized clinical episode may not occur for months or decades. In particular, the proximal urea cycle defects (NAGS deficiency and CPS1 deficiency) show the following similarities with CA-VA deficiency:

  • Hyperammonemia, low plasma citrulline and high plasma glutamine, and no orotic aciduria; and
  • Good response to carglumic acid.

Differences include:

  • Absence of hyperlactatemia; and
  • Presence of multiple carboxylase deficiency metabolites.

Ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2) deficiency (OMIM 191329) can present with a similar combination of lactic acidosis and episodes of hyperammonemia and hypoglycemia. The pathogenesis of the biochemical phenotype is currently unclear. Inheritance is autosomal recessive. Diagnosis is by identification of either decreased activity of complex III of the respiratory chain in a skeletal biopsy sample or biallelic pathogenic variants in UQCRC2.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with carbonic anhydrase VA (CA-VA) deficiency, the following evaluations are recommended:

  • Measurement of serum lactate, plasma ammonia, serum glucose, blood gases, plasma amino acids, urine ketone bodies, and urine organic acid profiles (during periods of illness; when stable for monitoring, preferably fasting)
  • Liver function parameters (coagulation, albumin, AST, ALT) as acute liver failure can occur in the urea cycle disorders which are metabolically similar
  • Consideration of:
    • Brain MRI to define extent of or to exclude brain edema
    • Neurodevelopmental testing
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

During acute episodes. Admit to the hospital children with insufficient intake or refusal to take anything orally and/or signs of metabolic decompensation such as encephalopathy. The following are recommended:

  • Always provide IV fluids (with glucose at maintenance doses) and extra calories via IV lipids; restrict protein intake if plasma ammonia is elevated.
  • Always monitor plasma ammonia, serum lactate, serum glucose, blood gases, electrolytes, and liver parameters.
  • Consider administration of carglumic acid (which – though not approved yet for this indication – enhances CPS1 activity and thus partially compensates for reduced HCO3- resulting from CA-VA deficiency). In the three children who were given carglumic acid during the acute phase, hyperammonemia and clinical symptoms resolved within 12 hours. Without carglumic acid, hyperammonemia persisted longer (i.e., an additional 1-2 days).
  • Other ammonia-lowering medications such as sodium benzoate would also be reasonable.

To prevent metabolic decompensation during any catabolic state (viral illness or fasting conditions)

  • Use a sick day formula (extra calories, with limited proteins and extra lipids).
  • Monitor plasma ammonia, serum glucose, blood gases, serum lactate, and plasma amino acids (frequency according to patient’s clinical state and physician’s expertise).

Prevention of Primary Manifestations

There is no evidence to date that use of a special diet and/or cofactor (zinc) treatment during periods of wellness prevents metabolic decompensations.

Surveillance

Follow up with a metabolic disease specialist every three to six months for physical and neurologic examinations. Consider neurodevelopmental testing and measurement of: plasma ammonia and amino acids (to check for chronic hyperammonemia and citrulline deficiency as well as general nutritional state); serum lactate and glucose; blood gases; liver parameters; and urine organic acids.

Agents/Circumstances to Avoid

Acetazolamide should be avoided, as it inhibits carbonic anhydrase activity.

Evaluation of Relatives at Risk

When both CA5A pathogenic variants have been identified in an affected family member, it is appropriate to evaluate all sibs in order to identify those who would benefit from prompt treatment when symptoms appear.

Of note, in some families, asymptomatic (older) sibs were found to have biallelic CA5A pathogenic variants through family screening [van Karnebeek et al 2014b]. This finding suggests a possible "susceptibility period" during childhood after which individuals with biallelic CA5A pathogenic variants may no longer be at risk of developing signs of CA-VA deficiency.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For an affected mother. No pregnancy manaagement issues are known.

For an affected child

  • No special management is required during pregnancy.
  • Delivery in hospital is indicated with monitoring for several days (including physical examination and measurement of plasma ammonia, serum lactate, serum glucose, blood gases, plasma amino acids, and urine organic acids).

Therapies Under Investigation

Zinc treatment to enhance residual CA-VA activity is under investigation.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Carbonic anhydrase VA (CA-VA) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one CA5A pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has:
    • A 25% chance of inheriting two CA5A pathogenic variants and usually being affected. Note: In some families, asymptomatic (older) sibs with biallelic CA5A pathogenic variants have been identified [unpublished];
    • A 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier;
    • A 25% chance of inheriting neither pathogenic variant being unaffected and not a carrier.
  • Clinical status of sibs cannot be used to refine their carrier risk as asymptomatic (older) sibs with biallelic CA5A pathogenic variants have been identified.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CA-VA deficiency are obligate heterozygotes (carriers) for a pathogenic variant in CA5A.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CA5A pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CA5A pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have or are at risk of having one or two CA5A pathogenic variants.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CA5A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantatino genetic diagnosis for CA-VA deficiency are possible. Note: The results of prenatal testing cannot be used to predict with certainty whether or not an individual will be affected as asymptomatic individuals with biallelic CA5A pathogenic variants have been identified.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing for conditions amenable to treatment, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Carbonic Anhydrase VA Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CA5A16q24​.2Carbonic anhydrase 5A, mitochondrialCA5A homepageCA5ACA5A

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Carbonic Anhydrase VA Deficiency (View All in OMIM)

114761CARBONIC ANHYDRASE VA; CA5A
615751CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO; CA5AD

Gene structure. There is one full-length coding transcript (Ensembl identifier ENST00000309893) with a length of 7567 bp, comprising seven exons. Two other transcripts do not encode any protein product. A pseudogene, CA5AP1, has sequences homologous to exons 3-7 and introns 3-6 [Nagao et al 1995]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Variants in Table 3 are reported in van Karnebeek et al [2014a].

Table 3.

CA5A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.697T>Cp.Ser233ProNM_001739​.1
NP_001730​.1
c.555G>A 1p.Lys185= 2, 3
c.619-3421_774+502del 4p.Asp207_Gln258del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Final nucleotide of exon 4 results in splicing defect.

2.

p.= designates that protein has not been analyzed but no change is expected.

3.

mRNA analysis documented an in-frame deletion of exon 4, p.Leu154_Lys185del [van Karnebeek et al 2014a].

4.

Deletion of exon 6 (4078 bp)

Normal gene product. Carbonic anhydrase VA (CA-VA) comprises 305 amino acids. The two annotated CA5A domains are: (1) the alpha carbonic anhydrase domain which spans from amino acid position 33 to 296; (2) the carbonic anhydrase, alpha-class, conserved site (within the aforementioned domain) which spans from amino acid position 141 to 157. Both domains are important for catalyzing the reversible hydration of carbon dioxide to bicarbonate.

Abnormal gene product. The consequences of the pathogenic variants described by van Karnebeek et al [2014a] and Table 3 above are:

  • Homozygous p.Ser233Pro pathogenic variants cause reduced protein stability and reduced enzymatic activity (20% of wildtype) with thermal sensitivity;
  • Homozygous deletion of exon 6 causes absence of protein in the liver;
  • Homozygous c.555G>A pathogenic variants disrupt the normal splicing process, leading to skipping of exon 4. Homozygosity for this pathogenic variant was observed in one patient with hyperammonemia in the neonatal period (based on Family 2) [van Karnebeek et al 2014a].

References

Literature Cited

  • Häberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013;536:101–8. [PubMed: 23628343]
  • Nagao Y, Batanian JR, Clemente MF, Sly WS. Genomic organization of the human gene (CA5) and pseudogene for mitochondrial carbonic anhydrase V and their localization to chromosomes 16q and 16p. Genomics. 1995;28:477–84. [PubMed: 7490083]
  • Shah GN, Rubbelke TS, Hendin J, Nguyen H, Waheed A, Shoemaker JD, Sly WS. Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both in ammonia detoxification and glucose metabolism. Proc Natl Acad Sci USA. 2013;110:7423–8. [PMC free article: PMC3645511] [PubMed: 23589845]
  • van Karnebeek CDM, Shevell MI, Zschocke J, Moeschler J, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab. 2014a;111:428–38. [PubMed: 24518794]
  • van Karnebeek CDM, Sly WS, Ross CJ, Salvarinova R, Yaplito-Lee J, Santra S, Shyr C, Horvath GA, Eydoux P, Lehman AM, Bernard V, Newlove T, Ukpeh H, Chakrapani A, Preece MA, Ball S, Pitt J, Vallance HD, Coulter-Mackie M, Nguyen H, Zhang L-H, Bhavsar AP, Sinclair G, Waheed A, Wasserman WW, Stockler-Ipsiroglu S. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet. 2014b;94:453–61. [PMC free article: PMC3951944] [PubMed: 24530203]

Chapter Notes

Author Notes

TIDE (www.tidebc.org) and Omics2TreatID (www.treatable-id.org)

Clara van Karnebeek, MD, PhD, is a pediatrician-biochemical geneticist who dedicates her research to enhancing early diagnosis and treatment of inborn errors of metabolism to prevent intellectual developmental disabilities.

Johannes Häberle, MD, is a neonatologist and metabolic pediatrician who specializes in the diagnosis and treatment of urea cycle defects and related disorders with hyperammonemia.

Acknowledgments

We gratefully acknowledge Casper Shyr, PhD student (University of British Columbia, Vancouver, Canada) for his contributions to the molecular genetics section of this paper.

Revision History

  • 2 April 2015 (me) Review posted live
  • 8 September 2014 (cvk) Original submission
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