# Six Chinese patients with propionic acidemia: from asymptomatic to death in the neonatal period

## TL;DR

This study reports six Chinese patients with propionic acidemia, a rare metabolic disorder, and identifies new genetic mutations linked to different disease severities.

## Contribution

The study expands the genetic mutation spectrum of propionic acidemia and provides insights into genotype-phenotype correlations in Chinese patients.

## Key findings

- The incidence of propionic acidemia was 1 in 114,820 in Beijing and 1 in 189,671 in Ningxia.
- Five novel mutations in PCCA and PCCB genes were identified, including one in PCCA and four in PCCB.
- Certain mutations were associated with late-onset or early-onset disease progression.

## Abstract

Propionic acidemia (PA) is a severe organic acidemia that can result in multi-organ damage and is potentially fatal. The rarity of this disease and the limited number of reported cases contribute to a lack of comprehensive knowledge, particularly concerning the genotype-phenotype correlation. This study aims to report on PA cases in Beijing and Ningxia, China, identify the pathogenic genetic factors involved, and explore the relationship between genotype and phenotype.

We calculated the positive screening rates of PA in Beijing and Ningxia and summarized data from six Chinese patients with PA identified at the Beijing Newborn Screening Center and Ningxia Newborn Screening Center. Clinical examinations included blood tandem mass spectrometry, urine gas chromatography-mass spectrometry, and the next-generation sequencing (NGS) technology. Candidate mutations were validated using polymerase chain reaction and Sanger sequencing technology. Bioinformatics software was used to analyze the pathogenicity of the variants, and Swiss PDB Viewer software was employed to predict the effect of mutations on PCCA and PCCB proteins.

The updated incidence of PA was 1 in 114,820 in Beijing and 1 in 189,671 in Ningxia. We reported five patients diagnosed with PA through newborn screening (NBS) and one additional patient diagnosed clinically. Among the five patients diagnosed by NBS, the two late-onset patients exhibited normal neurodevelopment, while all three early-onset patients succumbed between 4 days and 18 months of age. The patient diagnosed clinically passed away at 20 days of age. NGS showed one patient carries compound mutations in the PCCA gene and three patients carry compound heterozygous or homozygous mutations in the PCCB gene. A total of two mutations in PCCA (c.985T > A and c.1195 C > T) and five mutations in PCCB (c.1076 C > T, c.1087T > C, c.224 A > C, c.1339 C> T, and c.1033G > C)were identified, including one novel PCCA mutation (c.985T > A) and four novel PCCB mutations (c.1076 C > T, c.224 A > C, c.1339 C> T, and c.1033G > C). Bioinformatics analysis indicated these mutations are pathogenic, and Swiss PDB Viewer predictions suggest that these variations affect protein conformation.

The updated incidence rates of PA in Beijing and Ningxia provide new epidemiological insights. We reported six patients with PA, and identified one novel mutation (c.985T > A) in PCCA and four novel mutations (c.1076 C > T, c.224 A > C, c.1339 C> T, and c.1033G > C) in PCCB, which expands the spectrum of clinical features and genetic mutations associated with PA. The c.985T > A mutation in PCCA and the c.1076 C > T mutation in PCCB may be associated with late-onset PA, while the c.224 A > C, c.1339 C > T, and c.1033G > C mutations in PCCB are related to early-onset PA.