OBJECTIVES: Hyperammonemic Crisis (HAC) is a serious acute condition that may lead to coma or death in patients with Urea Cycle Disorders (UCD) or Organic Aciduria Disorders (OAD). This review provides an overview on incidence of HAC in UCD and OAD, beyond individual disease prevalence.

METHODS: A literature review conducted in Pubmed, Scopus, Embase, Medline, and GoogleScholar. Conference/research papers, medical/consortium guideline, information published by health technology assessment agencies, and manufacturer reports included. Only publications in English included. A mathematic multi-compartmental model used to calculate overall HAC in the US and 5 countries in Europe (UK, Germany, France, Italy, and Spain).

RESULTS: 21publications in UCD, and 12 publications in OAD identified. The prevalence of UCD in the US is 1:35’000 and ranged from 1:34’622 to 1:63’095 in Europe. HAC in OAD only occurred in Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), and Isovaleric Acidemia (IVA) with prevalence of 1:242’741 (PA), 1:69’354 (MMA), and 1:159’150 (IVA) in the US, and ranging from 1:105’082 to 1:202’617 (PA), 1:105’082 to 1:159’199 (MMA), and 1:155’000 (IVA) in Europe, respectively. HAC in UCD only occurred up to the age of 18 years, with an incidence of 0.58/ patient/ year for untreated patients, and an incidence of 0.28/patient/year for chronically treated patients (with glycerol phenylbutyrate and sodium phenylbutyrate). HAC in OAD occurred only up to the age of 4 years, with an incidence of 1.05/patient/year in an in-patient setting. The annual incidence of HAC within UCD and OAD patients estimated approximately 1’898 per year in 2021.

CONCLUSIONS: To author’s knowledge, this study provides the first calculation on incidence of HAC in patients with UCD and OAD. Estimated 1’898 HAC (around 1:368’000) in 2021, thus classified as ultra-orphan disease (<1:50’000). This estimate can be used to calculate burden of diseases and economic evaluation for acute HAC in Inborn Errors of Metabolism.