Yap Sufin, Gasperini Serena, Matsumoto Shirou, Feillet François
Department of Inherited Metabolic Diseases, Sheffield Children's Hospital, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, S10 2TH, UK.
Metabolic Rare Disease Unit "Fondazione Mariani", Pediatric Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Orphanet J Rare Dis. 2024 Dec 18;19(1):464. doi: 10.1186/s13023-024-03468-4.
Propionic aciduria (PA) and methylmalonic aciduria (MMA) are rare inherited disorders caused by defects in the propionate metabolic pathway. PA due to propionyl coenzyme A carboxylase deficiency results in accumulation of propionic acid, while in MMA, deficiency in methylmalonyl coenzyme A mutase leads to accumulation of methylmalonic acid. Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle. Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA. CGA is well tolerated and its use in normalizing ammonia levels during acute hyperammonemic episodes in patients with PA and MMA is well established. This expert opinion analyzed clinical evidence for CGA and discussed its place, along with other management strategies, in the long-term management of PA or MMA. A literature search of PubMed was undertaken to identify publications related to the chronic use of CGA, transplantation, dietary management, ammonia scavengers, and gene therapy for treatment of patients with PA or MMA. The authors selected the most relevant studies for inclusion. Four clinical studies, one single center case series, and three case reports show that CGA is safe and effective in the chronic treatment of PA and MMA. In particular, the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone. Current treatment guidelines and recommendations include the use of CGA mainly in acute decompensation, however, lag in considering the benefits of long-term CGA treatment on clinical and biochemical outcomes in patients with PA or MMA. CGA is safe and effective in the chronic treatment of PA and MMA and may help to resolve some of the issues associated with other strategies used to treat these disorders. Thus, CGA appears to have potential for the chronic management of patients with PA and MMA and should be recommended for inclusion in the chronic treatment of these disorders.
丙酸血症（PA）和甲基丙二酸血症（MMA）是由丙酸代谢途径缺陷引起的罕见遗传性疾病。由于丙酰辅酶A羧化酶缺乏导致的PA会致使丙酸蓄积，而在MMA中，甲基丙二酰辅酶A变位酶缺乏会导致甲基丙二酸蓄积。高氨血症与N - 乙酰谷氨酸（NAG）继发性缺乏有关，NAG是氨甲酰磷酸合成酶1的激活剂，而氨甲酰磷酸合成酶1是尿素循环中一种不可逆的限速酶。卡谷氨酸（CGA）是人类NAG的合成结构类似物，已被批准用于治疗由PA或MMA引起的高氨血症患者。CGA耐受性良好，其在PA和MMA患者急性高氨血症发作期间使氨水平正常化方面的应用已得到充分证实。本专家意见分析了CGA的临床证据，并讨论了其在PA或MMA长期管理中的地位以及与其他管理策略的比较。对PubMed进行文献检索，以确定与CGA的长期使用、移植、饮食管理、氨清除剂以及用于治疗PA或MMA患者的基因治疗相关的出版物。作者选择了最相关的研究纳入其中。四项临床研究、一项单中心病例系列研究和三项病例报告表明，CGA在PA和MMA的长期治疗中是安全有效的。特别是，与单纯传统饮食治疗相比，添加CGA与高氨血症失代偿发作次数减少和住院次数减少相关。目前的治疗指南和建议主要将CGA用于急性失代偿情况，然而，在考虑CGA长期治疗对PA或MMA患者临床和生化结果的益处方面存在滞后。CGA在PA和MMA的长期治疗中是安全有效的，并且可能有助于解决与用于治疗这些疾病的其他策略相关的一些问题。因此，CGA似乎在PA和MMA患者的长期管理中具有潜力，应推荐将其纳入这些疾病的长期治疗。
