Abstract
BackgroundHyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment.MethodsA post-hoc analysis of two retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH3) scavengers compared with scavengers alone for reducing plasma NH3 levels in patients with OAs and hyperammonaemia (plasma NH3 > 60 μmol/L) during decompensation episodes. NH3 was analysed in 12-h periods at 0–48 h and 24-h periods at 48–120 h. Treatment-emergent adverse events (TEAEs) were recorded.ResultsOf 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH3 scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH3 scavenger group. Median baseline NH3 level was: 199 μmol/L, carglumic acid; 122 μmol/L, NH3 scavengers; and 271 μmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3 scavengers’ group; reductions were greatest in the combination group.Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was − 13, + 12% and − 27% at 0–12 h (p < 0.05 NH3 scavengers vs combination); − 47, − 22% and − 52% at 12–24 h (not significant); − 44, − 5% and − 61% at 24–48 h; and − 66, − 16% and − 76% at 48–72 h (p < 0.05 carglumic acid/combination groups vs NH3 scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition.ConclusionsCarglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH3 scavengers, the reduction in NH3 was greater than with NH3 scavengers alone in the first 72 h.
Highlights
Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, requiring rapid treatment
Episodes and treatments In total, 98 episodes in 83 patients were included in the full analysis set: 38 episodes were treated with carglumic acid (n = 34 patients), 33 with NH3 scavengers (n = 22 patients) and 27 with a combination of both (n = 27 patients)
More than 80% of episodes lasted fewer than 15 days, with a median episode duration of 6.0 days in the carglumic acid alone and combination groups, and 8.5 days in the NH3 scavengers’ group
Summary
Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, requiring rapid treatment. MMA occurs due to a deficiency of methylmalonyl CoA mutase or due to defects of vitamin B12 metabolism. PA occurs as a result of propionyl CoA carboxylase deficiency These disorders affect the metabolism of isoleucine, valine, methionine and threonine [1]. Secondary inhibition of the enzyme N-acetylglutamate synthase (NAGS) through accumulation of isovaleryl CoA, methylmalonyl CoA and propionyl CoA in OAs is thought to be one of the pathogenic mechanisms impeding elimination of ammonia (NH3) through the urea cycle, resulting in hyperammonaemia [2, 3]. The inability to maintain adequate levels of glutamine precursors secondary to a dysfunctional Krebs’ (tricarboxylic acid) cycle due to lack of succinyl CoA synthesis, impaired in both MMA and PA, is proposed as a mechanism of hyperammonaemia in the OAs [4]
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