Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

Dı́ez-Fernández, Carmen; Rüfenacht, Véronique; Santra, Saikat; Lund, Allan M.; Santer, René; Tangeraas, Trine; Unsinn, Caroline; Lonlay, Pascale de; Burlina, Alberto; Häberle, Johannes

doi:10.1038/gim.2015.201

Cited by 39 publications

(64 citation statements)

References 30 publications

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“…The mutant enzyme was thermolabile with decreased activity at body temperature. Furthermore, the acute presentation of this IMD is amenable to carglumic acid, a synthetic N-acetyl glutamate analogue, and thus CA-VA deficiency expanded the differential diagnosis of treatable hyperammonemia in the neonate and young child (Diez-Fernandez et al 2016 ). In this case, elaborate pre-WES metabolic testing provided clues regarding the underlying etiology, facilitating a hypothesis driven prioritization of long variant lists generated by WES and subsequently validated by a functional analysis of the CA-VA enzyme.…”

Section: -Omics In Concert For Imd Discoverymentioning

confidence: 99%

The role of the clinician in the multi‐omics era: are you ready?

Karnebeek

Wortmann

Tarailo‐Graovac

et al. 2018

J of Inher Metab Disea

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Since Garrod’s first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team’s plan to his/her and the family’s wishes most certainly is the capstone. Are you ready?

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Section: -Omics In Concert For Imd Discoverymentioning

confidence: 99%

The role of the clinician in the multi‐omics era: are you ready?

Karnebeek

Wortmann

Tarailo‐Graovac

et al. 2018

J of Inher Metab Disea

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“…Finally, regarding the identified homozygous deletion of the first two exons of the CA5A gene, this variant clearly destroys the normal gene function. 2 Absence of metabolic decompensation in this patient after birth could be the result of the early anabolic treatment that he likely received when born preterm at 26 weeks.…”

Section: Response To Baertling Et Almentioning

confidence: 93%

“…The patient received early and adequate therapeutic measures, which led to rapid normalization of the biochemical abnormalities. 2 Despite this, the patient died after developing severe intracranial hypertension, brain edema, and herniation.…”

Section: Response To Baertling Et Almentioning

confidence: 99%

Response to Baertling et al.

Häberle

Rüfenacht

2020

Genetics in Medicine

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“…A recent study conducted by Carmen, et al [14], found that defective hepatic bicarbonate production leads to hypoglycemia, elevated lactate level, metabolic acidosis and hyperammonemia, further confirming bicarbonate as a necessary requirement for hepatic glucose synthesis. Thus carbonic anhydrase must keep the [HCO3 -]/ [CO2] ratio constant.…”

Section: Introductionmentioning

confidence: 89%

Carbon Dioxide: A Pre - Requisite for Increased Hepatic Glucose Production in Type 2 Diabetes

Ismail¹

2018

DOIJ

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Type 2 diabetic patient have an increased rate of production of hepatic glucose which leads to persistent hyperglycemia. The increase in hepatic glucose production was found to be due to availability and uptake of gluconeogenic substrates, but that alone cannot drive glucose synthesis. Carbon dioxide produced at the end of metabolic combustion of fuel is then used as a substrate for the first step in hepatic glucose production i.e the pyruvate carboxylase reaction. Decrease in carbon dioxide is associated with decrease in hepatic glucose production. Furthermore, inhibition of carbonic anhydrase which interconverts carbon dioxide and bicarbonate has been found to decrease hepatic glucose synthesis. Therefore, it can be concluded that increased substrate delivery to the liver and increased efficiency of hepatic substrate uptake alone cannot drive glucose synthesis that continues supply of carbon dioxide is necessary for hepatic glucose production.

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Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis

Cited by 39 publications

References 30 publications

The role of the clinician in the multi‐omics era: are you ready?

The role of the clinician in the multi‐omics era: are you ready?

Response to Baertling et al.

Carbon Dioxide: A Pre - Requisite for Increased Hepatic Glucose Production in Type 2 Diabetes

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