Carglumic acid for the treatment of<i>N</i>-acetylglutamate synthase deficiency and acute hyperammonemia

Häberle, Johannes

doi:10.1586/eem.12.17

Cited by 13 publications

(9 citation statements)

References 66 publications

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“…The metabolites identified in the urine organic acid analysis of our cases are like those described in the 15 published CA‐VA deficient patients 1,2 . The main treatment is carglumic acid (Carbaglu), which is an analogue of N‐acetylglutamate (NAG) approved for treating acute hyperammonemia in NAGS deficiency 4,5 . Propionyl CoA carboxylase cannot function efficiently because of the HCO 3 − deficiency caused by CA‐VA deficiency and propionyl CoA is a potent inhibitor of NAGS.…”

Section: Discussionsupporting

confidence: 56%

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

et al. 2020

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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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Section: Discussionsupporting

confidence: 56%

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

et al. 2020

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“…At present, the treatment of CPS1D is to strictly follow the recommendations of UCDs, which focuses on reduction of ammonia production by a restricted protein diet and management of ammonia scavengers, such as sodium benzoate, sodium phenylbutyrate, and sodium phenylacetate, as well as drugs of l-arginine and l-citrulline to improve the residual urea cycle function and the renal excretion of ammonia (Diez-Fernandez and Häberle, 2017). In case of severe hyperammonemia, hemodialysis or peritoneal dialysis can be administered (Häberle, 2012; Diez-Fernandez and Häberle, 2017). However, these approaches cannot cure CPS1D, and the only available cure currently is liver transplantation, which has demonstrated excellent results with approximately 90% survival rate in UCD children, though it is limited by donor sources (Diez-Fernandez and Häberle, 2017; Zhang and Li, 2017).…”

Section: Discussionmentioning

confidence: 99%

Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature

et al. 2019

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Carbamoyl phosphate synthetase I (CPS1) deficiency (CPS1D), is a rare autosomal recessive disorder, characterized by life-threatening hyperammonemia. In this study, we presented the detailed clinical features and genetic analysis of two patients with neonatal-onset CPS1D carrying two compound heterozygous variants of c.1631C > T (p.T544M)/c.1981G > T (p.G661C), and c.2896G > T (p.E966X)/c622-3C > G in CPS1 gene, individually. Out of them, three variants are novel, unreported including a missense (c.1981G > T, p.G661C), a nonsense (c.2896G > T, p.E966X), and a splicing change of c.622-3C > G. We reviewed all available publications regarding CPS1 mutations, and in total 264 different variants have been reported, with majority of 157 (59.5%) missense, followed by 35 (13.2%) small deletions. This study expanded the mutational spectrum of CPS1 . Moreover, our cases and review further support the idea that most (≥90%) of the mutations were “private” and only ∼10% recurred in unrelated families.

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“…In contrast to all other UCDs, prenatal testing for NAGS deficiency is controversial, since an effective treatment leading to good outcome in affected patients is available by carbamylglutamate which is a licensed drug in many countries (but maybe not in the developing part of the world) [32][33][34].…”

Section: Prenatal Testingmentioning

confidence: 99%

Mutation analysis of urea cycle disorders

Häberle

Rüfenacht

2016

J Pediatr Biochem

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Urea cycle disorders (UCDs) are a group of autosomal or X-linked, recessively inherited errors of metabolism that lead to severe neurological disease due to insufficient detoxification of excess nitrogen. The resulting hyperammonemia is the key feature of UCDs, but at the same time only a surrogate marker. In the majority of cases, a sole biochemical analysis is indicative but not diagnostic. Therefore, additional means are required and mutation analysis is the method of choice for confirmation in most cases of UCD. In addition to confirming the diagnosis, mutation analysis enables genetic counseling and prenatal testing and contributes to new research approaches. All genes involved in any of the enzymatic (namely the genes for N-acetylglutamate synthase, NAGS; carbamoylphosphate synthetase, CPS1; ornithine transcarbamylase, OTC; argininosuccinate synthetase, ASS1; argininosuccinate lyase, ASL; arginase, ARG1) or transporter steps (namely the genes for the ornithine/citrulline antiporter ORNT1, SLC25A15; glutamate/aspartate antiporter citrin, SLC25A13) of the urea cycle are known and thus accessible for genetic testing. In most situations, direct Sanger sequencing using DNA from peripheral blood cells can be done but there are exceptions to this such as in the case of the relatively large CPS1 gene which renders RNA based mutation analysis an attractive alternative. With this review, we provide an overview on the current methods used for mutation analysis of each UCD gene, we mention possible pitfalls and their solutions, and discuss alternative methods which may become standard in the future.

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Carglumic acid for the treatment ofN-acetylglutamate synthase deficiency and acute hyperammonemia

Cited by 13 publications

References 66 publications

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

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

Novel Neonatal Variants of the Carbamoyl Phosphate Synthetase 1 Deficiency: Two Case Reports and Review of Literature

Mutation analysis of urea cycle disorders

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