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Systematic literature review and meta-analysis on the epidemiology of propionic acidemia.

ABSTRACT: Propionic acidemia (PA, OMIM #606054) is a serious, life-threatening, inherited, metabolic disorder caused by the deficiency of the mitochondrial enzyme propionyl-coenzyme A (CoA) carboxylase (EC 6.4.1.3). The primary objective of this study was to conduct a systematic literature review and meta-analysis on the epidemiology of PA. The literature search was performed covering Medline, Embase, Cochrane Database of Systematic Reviews, CRD Database, Academic Search Complete, CINAHL and PROSPERO databases. Websites of rare disease organizations were also searched for eligible studies. Of the 2338 identified records, 188 articles were assessed for eligibility in full text, 43 articles reported on disease epidemiology, and 31 studies were included into the quantitative synthesis. Due to the rarity of PA, broadly targeted population-based prevalence studies are not available. Nonetheless, implementation of newborn screening programs has allowed the estimation of the birth prevalence data of PA across multiple geographic regions. The pooled point estimates indicated detection rates of 0.29; 0.33; 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. Our systematic literature review and meta-analysis confirm that PA is an ultra-rare disorder, with similar detection rates across all regions with the exception of the MENA region where the disease, similar to other inherited metabolic disorders, is more frequent.

SUBMITTER: Almasi T

PROVIDER: S-EPMC6375193 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Systematic literature review and meta-analysis on the epidemiology of propionic acidemia.

Almási Tímea T Guey Lin T LT Lukacs Christine C Csetneki Kata K Vokó Zoltán Z Zelei Tamás T

Orphanet journal of rare diseases 20190213 1

Propionic acidemia (PA, OMIM #606054) is a serious, life-threatening, inherited, metabolic disorder caused by the deficiency of the mitochondrial enzyme propionyl-coenzyme A (CoA) carboxylase (EC 6.4.1.3). The primary objective of this study was to conduct a systematic literature review and meta-analysis on the epidemiology of PA. The literature search was performed covering Medline, Embase, Cochrane Database of Systematic Reviews, CRD Database, Academic Search Complete, CINAHL and PROSPERO data ...[more]

PMID: 30760309

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Project description:BackgroundOrganic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data.Study design/methodsWe performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected.ResultsThe median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT.ConclusionIn a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.

Project description:Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates.The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine ?-ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia.Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension.The urinary excretion of the Krebs cycle intermediates, ?-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study.These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: ?-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

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Systematic literature review and meta-analysis on the epidemiology of propionic acidemia.

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Systematic literature review and meta-analysis on the epidemiology of propionic acidemia.

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