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Recurrent hyperammonaemia in a patient with carbonic anhydrase VA deficiency.

ABSTRACT: Carbonic anhydrase VA deficiency is a recently described inherited cause of paediatric hyperammonaemia. Most published cases describe patients with only one episode of hyperammonaemia whilst others report patients who had up to three metabolic crises with the first invariably being the most severe. We describe a patient with carbonic anhydrase VA deficiency who experienced 7 hyperammonemic episodes over a 3-year period, up to age 5 years 9 months. These episodes did not clearly decrease in severity over time. This report expands the clinical phenotype and the age window for metabolic crises associated with this condition.

SUBMITTER: Stockdale C

PROVIDER: S-EPMC9626664 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Recurrent hyperammonaemia in a patient with carbonic anhydrase VA deficiency.

Stockdale Christopher C Bowron Ann A Appleton Marie M Richardson Ruth R Anderson Mark M

JIMD reports 20220810 6

Carbonic anhydrase VA deficiency is a recently described inherited cause of paediatric hyperammonaemia. Most published cases describe patients with only one episode of hyperammonaemia whilst others report patients who had up to three metabolic crises with the first invariably being the most severe. We describe a patient with carbonic anhydrase VA deficiency who experienced 7 hyperammonemic episodes over a 3-year period, up to age 5 years 9 months. These episodes did not clearly decrease in sever ...[more]

PMID: 36341166

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Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.

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A case of carbonic anhydrase type VA deficiency presenting as West syndrome in an infant with a novel mutation in the CA-VA gene.

Project description:Carbonic anhydrase VA (CA-VA) deficiency is a rare autosomal-recessive inborn error of metabolism. It is imperative to consider CA-VA deficiency as a differential diagnosis in neonates with hyperammonemia not attributed to defects in urea cycle enzymes, organic acid disorders, hypoglycemia, and primary hyperlactatemia. The case described in this report had a metabolic crisis on day three of life with biochemical abnormalities demonstrating hypoglycemia, elevated ammonia, and lactate. At eight months, he presented with developmental delay and infantile spasms. Considering the history of consanguinity and infantile spasms, clinical exome sequencing was done, which revealed a pathogenic novel mutation suggestive of CA-VA deficiency. On review of the literature, we found that about 21 affected individuals have been reported to date. Unprovoked seizures or epilepsy have not yet been described in CA-VA deficiency. This report expands the phenotypic spectrum of neurological manifestations of CA-VA deficiency and adds to the existing number of cases in the reported literature.

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Mitochondrial carbonic anhydrase VA and VB: properties and roles in health and disease.

Project description:Carbonic anhydrase V (CA V), a mitochondrial enzyme, was first isolated from guinea-pig liver and subsequently identified in mice and humans. Later, studies revealed that the mouse genome contains two mitochondrial CA sequences, named Car5A and Car5B. The CA VA enzyme is most highly expressed in the liver, whereas CA VB shows a broad tissue distribution. Car5A knockout mice demonstrated a predominant role for CA VA in ammonia detoxification, whereas the roles of CA VB in ureagenesis and gluconeogenesis were evident only in the absence of CA VA. Previous studies have suggested that CA VA is mainly involved in the provision of HCO3 - for biosynthetic processes. In children, mutations in the CA5A gene led to reduced CA activity, and the enzyme was sensitive to increased temperature. The metabolic profiles of these children showed a reduced supply of HCO3 - to the enzymes that take part in intermediary metabolism: carbamoylphosphate synthetase, pyruvate carboxylase, propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase. Although the role of CA VB is still poorly understood, a recent study reported that it plays an essential role in human Sertoli cells, which sustain spermatogenesis. Metabolic disease associated with CA VA appears to be more common than other inborn errors of metabolism and responds well to treatment with N-carbamyl-l-glutamate. Therefore, early identification of hyperammonaemia will allow specific treatment with N-carbamyl-l-glutamate and prevent neurological sequelae. Carbonic anhydrase VA deficiency should therefore be considered a treatable condition in the differential diagnosis of hyperammonaemia in neonates and young children.

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Two cases of carbonic anhydrase VA deficiency-An ultrarare metabolic decompensation syndrome presenting with hyperammonemia, lactic acidosis, ketonuria, and good clinical outcome.

Project description:The combination of neonatal hyperammonemia, lactic acidosis, ketonuria, and hypoglycemia is pathognomonic for carbonic anhydrase VA (CA-VA) deficiency. We present two cases of this rare inborn error of metabolism. Both newborns with South Asian ancestry presented with a metabolic decompensation characterized by hyperammonemia, lactic acidosis and ketonuria; one also had hypoglycemia. Standard metabolic investigations (plasma amino acids, acylcarnitine profile, and urine organic acids) were not indicative of a specific organic aciduria or fatty acid oxidation defect but had some overlapping features with a urea cycle disorder (elevated glutamine, orotic acid, and low arginine). Hyperammonemia was treated initially with nitrogen scavenger therapy and carglumic acid. One patient required hemodialysis. Both have had a favorable long-term prognosis after their initial metabolic decompensation. Genetic testing confirmed the diagnosis of carbonic anhydrase VA (CA-VA) deficiency due to biallelic pathogenic variants in CA5A. These cases are in line with 15 cases previously described in the literature, making the phenotypic presentation pathognomonic for this ultrarare (potentially underdiagnosed) inborn error of metabolism with a good prognosis.

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Hyperammonemia in Russia Due to Carbonic Anhydrase VA Deficiency Caused by Homozygous Mutation p.Lys185Lys (c.555G>A) of the CA5A Gene.

Project description:Hyperammonemia due to carbonic anhydrase VA deficiency (OMIM# 615751) is a rare, life-threatening hereditary disease caused by biallelic mutations in the CA5A gene, presenting as encephalopathic hyperammonemia of unexplained origin during the neonatal period and infancy. Here, we present a detailed description of a 5-year-old patient with the homozygous mutation p.Lys185Lys (c.555G>A) in the CA5A gene. This variant was previously described by van Karnebeek et al. in 2014 in a boy of Russian origin. We found a high frequency of carriers of this mutation in Russia; 1:213, which is 7 times higher than the expected frequency calculated based on data on Western European populations. Thus, targeted testing for the mutation p.Lys185Lys (c.555G>A) in the CA5A gene should be useful for early detection by selective screening in neonatal intensive care units.

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Global transcriptional response to carbonic anhydrase IX deficiency in the mouse stomach

Project description:Background Carbonic anhydrases (CAs) are a family of enzymes that regulate pH homeostasis in various tissues. CA IX is an exceptional member of this family because in addition to the basic CA function, it has been implicated in several other physiological and pathological processes. Functions suggested for CA IX include roles in cell adhesion and malignant cell invasion. In addition, CA IX likely regulates cell proliferation and differentiation, which was demonstrated in Car9‾/‾ mice. These mice had gastric pit cell hyperplasia and depletion of chief cells; however, the specific molecular mechanisms behind the observed phenotypes remain unknown. Therefore, we wanted to study the effect of CA IX deficiency on whole-genome gene expression in gastric mucosa. This was done using Illumina Sentrix Mouse-6 Expression BeadChip arrays. The expression of several genes with notable fold-change values was confirmed by QRT-PCR. Results CA IX deficiency caused the induction of 86 genes and repression of 46 genes in the gastric mucosa. There was 92.9% concordance between the results obtained by microarray analysis and QRT-PCR. The differentially expressed genes included those involved in developmental processes and cell differentiation. In addition, CA IX deficiency altered the expression of genes responsible for immune responses and downregulated the expression of several digestive enzymes. Conclusions Microarray analysis identified several potential genes whose altered expression could explain the disturbed cell lineage phenotype in the Car9‾/‾ gastric mucosa. The results also indicated a novel role for CA IX in the regulation of immunologic processes and digestion. These findings reinforce the concept that the main role of CA IX is not the regulation of pH in the stomach mucosa. Instead, it is needed for proper function of several physiological processes.

2010-07-01 | GSE20981 | GEO

Report of Another Mutation Proven Case of Carbonic Anhydrase II Deficiency.

Project description:Carbonic anhydrase (CA) II deficiency results in an uncommon type of autosomal recessive sclerosing bone dysplasia with renal tubular acidosis and intracerebral calcification. We report a classic case of CA II-associated osteopetrosis with a previously reported homozygous frameshift mutation. Child was evaluated for short stature and failure to thrive. He was diagnosed as osteopetrosis in view of the presence of hepatosplenomegaly and increased bone density though hematological parameters were normal. Further evaluation showed presence of associated distal renal tubular acidosis raising a possibility of CA II deficiency. Mutation analysis revealed a previously reported homozygous frameshift mutation c.143-146delCTGT (p.Ser48Phefs*9) in CA2. Child has normal growth after initiation of alkali therapy.

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Deficiency of Carbonic Anhydrase II Results in a Urinary Concentrating Defect.

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Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid-sulphonamide conjugates.

Project description:A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.

| S-EPMC6968503 | biostudies-literature

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