OBJECTIVE: To detect pathogenic variants in a pedigree affected with propionic acidemia (PA). METHODS: The proband was subjected to high-throughput next-generation sequencing. Suspected variants were validated by Sanger sequencing of his family members. mRNA was extracted from peripheral blood lymphocytes from the proband's father in order to verify the impact of the splicing variant by RT-PCR combined with Sanger sequencing. The pathogenicity of the missense variant was predicted by using PolyPhen-2, Mutation Taster, SIFT, COBALT and HOPE software. RESULTS: The proband was found to harbor compound heterozygous variants of the PCCB gene, namely c.184-2A>G and c.733G>A (p.G245S), which were respectively inherited from his father and mother. RT-PCR combined with Sanger sequencing confirmed skipping of exon 2 during transcription. Bioinformatic analysis indicated the c.733G>A (p.G245S) variant to be damaging. CONCLUSION The two variants of the PCCB gene probably underlay the disease in this patient. Above findings have enriched the spectrum of PCCB gene variants.
Exons ; Humans ; Mutation ; Mutation, Missense ; Pedigree ; Propionic Acidemia/genetics*

OBJECTIVETo analyze PCCA and PCCB gene mutations in 10 Chinese patients with propionic acidemia(PA).

METHODSGenomic DNA was extracted from peripheral blood leukocytes. The 39 exons and flanking sequences of the PCCA and PCCB genes were amplified with polymerase chain reaction and subjected to direct DNA sequencing.

RESULTSDNA sequencing has revealed that 7 patients have carried a PCCA gene mutation, 2 patients carried PCCB gene mutation and 1 patient carried mutations in both PCCA and PCCB genes. Ten PA mutations were confirmed, including 8 affecting the PCCA gene and 2 affecting the PCCB gene. Three PCCA mutations c.245G>A, IVS15+5del5, c.1288C>T and 2 PCCB mutations c.838insC, c.1087T>C were found for the first time.

CONCLUSIONAmong Chinese patients with propionic acidemia patients, their genetic mutations are mainly found on the PCCA gene.

Child, Preschool ; Female ; Humans ; Infant ; Male ; Methylmalonyl-CoA Decarboxylase ; genetics ; Mutation ; Propionic Acidemia ; genetics

Objective: Propionic acidemia is a rare inherited metabolic disorder caused by propionyl CoA carboxylase (PCC) deficiency. This study aims to analyze the clinical characteristics and gene variations of Chinese patients with propionic acidemia, and to explore the correlation between clinical phenotypes and genotypes. Methods: Single-center, retrospective and observational study. Seventy-eight patients of propionic acidemia (46 males and 32 females) from 20 provinces and autonomous regions were admitted from January 2007 to April 2022. Their age of initial diagnosis ranged from 7 days to 15 years. The clinical manifestations, biochemical and metabolic abnormalities, genetic variations, diagnosis, treatment and outcome were studied. Chi-Square test or Mann-Whitney U test were used for statistical analysis. Results: Among 78 cases, 6 (7.7%) were identified by newborn screening; 72 (92.3%) were clinically diagnosed after onset, and the age of onset was 2 hours after birth to 15 years old; 32 cases had early-onset disease and 40 cases had late-onset disease. The initial manifestations included lethargy, hypotonia, vomiting, feeding difficulties, developmental delay, epilepsy, and coma. Among the 74 cases who accepted gene analysis, 35 (47.3%) had PCCA variants and 39 (52.7%) had PCCB variants. A total of 39 PCCA variants and 32 PCCB variants were detected, among which c.2002G>A and c.229C>T in PCCA and c.838dupC and c.1087T>C in PCCB were the most common variants in this cohort. The variants c.1228C>T and c.1283C>T in PCCB may be related to early-onset type. The variants c.838dupC, c.1127G>T and c.1316A>G in PCCB, and c.2002G>A in PCCA may be related to late-onset disease. Six patients detected by newborn screening and treated at asymptomatic stage developed normal. The clinically diagnosed 72 cases had varied complications. 10 (12.8%) cases of them died. 62 patients improved after metabolic therapy by L-carnitine and diet. Six patients received liver transplantation because of recurrent metabolic crisis. Their clinical symptoms were markedly improved. Conclusion: The clinical manifestations of propionic acidemia are complex and lack of specificity. Newborn screening and high-risk screening are keys for early treatment and better outcome. The correlation between the genotype and phenotype of propionic acidemia is unclear, but certain variants may be associated with early-onset or late-onset propionic acidemia.
Carnitine ; Female ; Genotype ; Humans ; Male ; Methylmalonyl-CoA Decarboxylase/metabolism* ; Mutation ; Phenotype ; Propionic Acidemia/genetics* ; Retrospective Studies

OBJECTIVEPropionic acidemia is a common organic acidemia, caused by deficiency of propionyl-CoA carboxylase (PCC), which catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a dodecameric enzyme of alpha-PCC and beta-PCC subunits, nuclearly encoded by genes PCCA and PCCB, respectively. Mutation in either gene cause propionic acidemia, the PCCA gene is located on chromosome 13q32 with 24 exons and the PCCB gene is located on chromosome 3q13.2-q22 with 15 exons. In this study, we analyzed gene mutations of 11 PCCA and PCCB deficient patients from China and to explore the possible mutation spectrum.

METHODSAll 39 exons of PCCA and PCCB genes in 11 unrelated Chinese PA patients were analyzed by polymerase chain reaction (PCR) and direct sequencing. Genomic DNA was extracted using phenol-chloroform method from the peripheral blood leukocytes of each patient. PCR amplification products were checked by 1.8% agarose gel electrophoresis and were subsequently sequenced with ABI 3700 Automated DNA Sequencer.

RESULTSThe authors identified 13 PA mutations, 8 affecting the PCCA gene, 5 affecting the PCCB gene, including 10 novel mutations and 3 previously reported mutations. Three missense mutations (1079T > G, 1102G > C and 1850T > C), one splicing mutation (716-2A > G) and one short deletion (1863delA) were found in alpha-PCC subunit while three missense mutations (484G > A, 601G > A and 1253C > T) and two short insertion-deletions (167-179del13ins1, 560-561delCCinsT) were found in beta-PCC subunit. The 167-179del13ins1 change was identified in two homozygous PA patients, with allelic frequency of 40% in beta-PCC subunit deficiencies.

CONCLUSIONThirteen mutations were found in 11 Chinese PA patients including ten novel mutations. No mutation is predominant in Chinese PCCA and PCCB deficient patients.

Base Sequence ; DNA Mutational Analysis ; Exons ; Humans ; Infant ; Infant, Newborn ; Methylmalonyl-CoA Decarboxylase ; genetics ; Molecular Sequence Data ; Mutation ; Propionic Acidemia ; genetics ; Sequence Deletion