Long-term effectiveness of carglumic acid in patients with propionic acidemia (PA) and methylmalonic acidemia (MMA): a randomized clinical trial

(2021) 16:422 Alfadhel et al. Orphanet J Rare Dis https://doi.org/10.1186/s13023-021-02032-8 Open Access RESEARCH Long‑term effectiveness of carglumic acid in patients with propionic acidemia (PA) and methylmalonic acidemia (MMA): a randomized clinical trial Majid Alfadhel1* , Marwan Nashabat1, Mohammed Saleh2, Mohammed Elamin2, Ahmed Alfares3, Ali Al Othaim4, Muhammad Umair5, Hind Ahmed1, Faroug Ababneh1, Fuad Al Mutairi1, Wafaa Eyaid1, Abdulrahman Alswaid1, Lina Alohali1, Eissa Faqeih2, Mohammed Almannai2, Majed Aljeraisy6, Bayan Albdah7, Mohamed A. Hussein7, Zuhair Rahbeeni8 and Ali Alasmari2 Abstract Background: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare, autosomal recessive inborn errors of metabolism that require life-long medical treatment. The trial aimed to evaluate the effectiveness of the administration of carglumic acid with the standard treatment compared to the standard treatment alone in the management of these organic acidemias. Methods: The study was a prospective, multicenter, randomized, parallel-group, open-label, controlled clinical trial. Patients aged ≤ 15 years with confirmed PA and MMA were included in the study. Patients were followed up for two years. The primary outcome was the number of emergency room (ER) admissions because of hyperammonemia. Secondary outcomes included plasma ammonia levels over time, time to the first episode of hyperammonemia, biomarkers, and differences in the duration of hospital stay. Results: Thirty-eight patients were included in the study. On the primary efficacy endpoint, a mean of 6.31 ER admissions was observed for the carglumic acid arm, compared with 12.76 for standard treatment, with a significant difference between the groups (p = 0.0095). Of the secondary outcomes, the only significant differences were in glycine and free carnitine levels. Conclusion: Using carglumic acid in addition to standard treatment over the long term significantly reduces the number of ER admissions because of hyperammonemia in patients with PA and MMA. Keywords: Carglumic acid, Hyperammonemia, Methylmalonic academia, Organic academia, Propionic acidemia *Correspondence: 1 Genetics and Precision Medicine department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences (KSAUHS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia Full list of author information is available at the end of the article Background Organic acidemias, such as propionic acidemia (PA, OMIM #606054) and methylmalonic acidemia (MMA, OMIM #251000), are rare, autosomal recessive inborn errors of metabolism. Patients usually present symptoms such as acidosis, recurrent vomiting, and poor feeding in the neonatal period. If left untreated, they progress to encephalopathy, coma, or even death. Patients tend to © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alfadhel et al. Orphanet J Rare Dis (2021) 16:422 exhibit developmental delay, secondary hyperammonemia, cardiomyopathy, bone marrow suppression, and metabolic stroke. The prevalence of MMA ranges from 1:50,000 to 1:100,000 newborns [1], while that of PA may range from 1:2000 in the Middle East to 1:250,000 in Europe [2]. PA is caused by pathogenic variants of the PCCA (OMIM #232050) or PCCB (OMIM #232000) genes encoding the enzyme propionyl-CoA carboxylase. MMA is caused by pathogenic variants of the MUT gene (OMIM #609058) encoding methylmalonyl-CoA mutase. These enzymes participate in the catabolism of branchedchain amino acids, synthesis of propionyl-CoA by normal gut flora, and breakdown of odd chain fatty acids [3]. A defect in their function will result in the accumulation of toxic levels of propionyl-CoA and methylmalonyl-CoA, which can cause metabolic decompensation, a common characteristic of both MMA and PA. Various mechanisms have been proposed for hyperammonemia in patients with PA and MMA. The accumulation of propionyl-CoA or methylmalonyl-CoA results in the competitive inhibition of N-acetyl glutamate synthase (NAGS) and carbamoylphosphate synthase, causing a disruption in the urea cycle and consequently inducing hyperammonemia [4]. High concentrations of 2-methylcitric acid inhibit the function of glutamine synthase essential for ammonia detoxification, which results in an increase in ammonia levels and a decrease in glutamine concentrations [5]. Elevated levels of ammonia can damage the developing brain, induce astrocyte swelling, increase nitric oxide levels, suppress ATP synthesis, and increase free radicals leading to vasogenic edema and cell death [6]. The management of PA and MMA focuses mainly on decreasing the accumulation of toxic substances, which can be achieved in two ways; first, by restricting dietary protein, thereby preventing protein catabolism and decreasing their production, or by decreasing the production of propionyl-CoA by the gut flora using antibiotics [7]. Second, by increasing the excretion of toxic metabolites through the administration of l-carnitine, which converts propionyl-CoA and methylmalonyl-CoA to non-toxic propionylcarnitine and methylmalonylcarnitine, respectively [8]. l-Carnitine also replenishes intracellular carnitine stores [9]. An alternative approach is to increase enzyme levels through liver transplantation. During acute decompensation, hyperammonemia can be managed using carglumic acid (N-carbamylglutamate), a structural analog of NAG, which stimulates carbamoyl phosphate synthase and promotes the removal of ammonia via the urea cycle [10, 11]. The effects of carglumic acid on reducing ammonia levels and decompensation episodes in PA and MMA have Page 2 of 10 been well established [12]. However, this approach usually starts after the onset of hyperammonemia, with longterm detrimental consequences on the nervous system. There is currentl (...truncated)