Carglumic acid

Mitochondrial carbonic anhydrase VA (CA‐VA) deficiency is a rare inherited metabolic disorder caused by biallelic variants of the CA5A gene. It presents with hyperammonemia, lactic acidosis, and ketonuria, with or without hypoglycemia. We report the long‐term follow‐up of the first two reported cases of CA‐VA deficiency: a 16‐year‐old female (case 1) and her 14‐year‐old brother (case 2), both of whom presented with neonatal hyperammonemic encephalopathy, hypoglycemia, elevated lactate, ketonuria, and compensated metabolic acidosis. The diagnosis was made in both cases through the TIDEX study, which identified a homozygous pathogenic variant in the CA5A gene (c.697T>C, (p.Ser233Pro)). The clinical course of the index patient revealed three additional metabolic decompensation episodes (MDEs) triggered by intercurrent illnesses, with the last episode occurring at 8 years of age, highlighting the unusual timing of her MDEs compared to previously reported cases. Case 2 remained metabolically stable without any additional MDEs. These episodes were successfully treated with parenteral dextrose, a single dose of enteral carglumic acid, and occasionally parenteral lipids. Management of intercurrent illness included a sick‐day formula high in carbohydrates and fats. Currently, both cases show normal growth, development, and neurological outcomes, suggesting a favorable prognosis, and in keeping with previously reported cases. Early diagnosis of CA‐VA deficiency allows prompt treatment and prevents severe complications. With proper management, long‐term outcomes are favorable, although severe and fatal outcomes have been reported. The impact on longevity needs to be assessed over longer durations. The development of consensus management for CA‐VA deficiency is warranted.

Enteric methane (CH₄) emissions from dairy cows are an inevitable by-product of rumen fermentation and represent both an environmental concern and a loss of dietary energy, highlighting the need for nutritional strategies that mitigate CH₄ emissions while maintaining or improving productivity. To this aim, this study evaluated the effects of dietary N-carbamylglutamate (NCG) supplementation on lactation performance, rumen fermentation, enteric CH₄ emissions, and rumen microbiota in dairy cows. Following a 1-week adaptation period, 32 multiparous Holstein cows were assigned to either a control diet or the same diet supplemented with NCG (20 g/d per cow) for 60 days in a completely randomised design; milk yield, DM intake (DMI), rumen fermentation parameters, enteric CH₄ and hydrogen (H₂) emissions measured using the GreenFeed system, and rumen microbial composition were assessed. Compared with the control group, NCG supplementation significantly increased milk yield while reducing DMI, resulting in improved feed efficiency expressed as milk yield per unit of DMI. However, apparent total-tract digestibility, milk composition, and feed efficiency calculated based on energy-corrected milk (ECM), fat-corrected milk (FCM), or fat- and protein-corrected milk (FPCM) were not significantly affected. NCG supplementation significantly reduced ruminal ammonia nitrogen concentration and increased the concentrations of acetate, propionate, butyrate, and total volatile fatty acid. Enteric CH₄ emissions (g/d), yield (g/kg DMI), and emission intensities (g/kg ECM, FCM, and FPCM) were significantly reduced in cows receiving NCG. Rumen microbial analysis revealed increased abundances of NK4A214_group, Acetobacter, Anaeroplasma, Providencia, Saccharopolyspora, Bacillus, Paenibacillus, and unclassified_f__Trichostomatia in the NCG group. Correlation analysis showed that total volatile fatty acid was positively associated with Saccharopolyspora and unclassified_f__Trichostomatia, whereas CH₄ emissions were negatively associated with Acetobacter, Anaeroplasma, and Providencia. In conclusion, dietary NCG supplementation improved milk production efficiency and rumen fermentation while reducing enteric CH₄ emissions, suggesting that NCG may represent a practical nutritional strategy to enhance productivity and mitigate CH₄ emissions in dairy production systems.