A Novel PCCA Mutation in a Patient With Late-Onset Propionic Acidemia Identified by Genetic Diagnosis Panel

Abstract

Background: Propionic acidemia (PA) is an extremely rare autosomal recessive disorder which is caused by the deficiency of propionyl-CoA carboxylase (PCC) and associated with pathogenic variants in PCCA or PCCB gene.Case Report: Detection of PA in neonates is possible using Propionyl carnitine (C3) analysis by tandem mass spectrometry (MS/MS) in dried blood spots (DBS). Here we report one patient with PA. C3 in this case was normal in the initial screening and recall check and only manifested as the slightly increase of C3/C2, 3-hydroxypropionate in urine was only slightly elevated. Then two pathogenic mutations (c.802C>T/c.827delG) were detected in the PCCA gene by Genetic diagnosis panel. Among them, the variation rs774738181 (c.802C>T) was present on the dbSNP database which appeared to be “Likely pathogenic” in GenBank dbSNP (100915068). c.827delG was a novel frameshift mutation, leading to p.Gly276ValfsX46 mutation of amino acid sequence in PCCA. The patient underwent 1 year of follow-up, had total of 7 times and remain asymptomatic whose blood ammonia and liver function were normal. When the child was 1 year of age (in May of 2017), C3 and 3-Hydroxypropionate sudden elevated significantly, that proved pathogenicity of c.802C>T and c.827delG.Conclusion: Two novel mutations (c. 802C>T and c.827delG) in PCCA gene may be associated with late-onset PA, expanding its mutational spectrum. Maybe there is relation between the severity of propionyl-CoA carboxylase (PCC) activity defects and different genotypes.

Whole‐exome sequencing of a Saudi epilepsy cohort reveals association signals in known and potentially novel loci

“…SEC24D was reported to play a role in in vesicle trafficking and mutations in this gene are associated with Cole-Carpenter syndrome, a disorder affecting bone formation [ 52 ]. PCCA codes for the alpha subunit of the mitochondrial enzyme Propionyl-CoA carboxylase, and mutations in this gene leads to enzyme deficiency and are associated with propionic acidemia [ 53 ]. MYO5A encodes myosin 5A, and mutations in this gene are associated with Griscelli syndrome, which is characterized by hypopigmentation and a primary neurological abnormality [ 54 ].…”

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

“…SECD24D was reported to play a role in in vesicle tra cking and mutations in this gene are associated with Cole-Carpenter syndrome, a disorder affecting bone formation [52]. PCCA codes for the alpha subunit of the mitochondrial enzyme Propionyl-CoA carboxylase, and mutations in this gene leads to enzyme de ciency and are associated with propionic acidemia [53]. MYO5A encodes myosin 5A and mutations in this genes are associated with Griscelli Syndrome, which is characterized by hypopigmentation and a primary neurological abnormality [54].…”

A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report

“…There are several clinical reports of PA in Chinese population in recent years [10][11][12][13][14]. Although mutations are mainly found on the PCCA gene, no predominant mutations exist in Chinese PA patients [10].…”

“…However, clinical manifestations of PA are often nonspecific, especially in the infant period. In some cases, the patient showed no typical abnormal biochemical result, especially for the late-onset patient [ 12 ]. The combination of genetic analysis and biochemical tests may offer a more precise diagnosis Next-generation sequencing (NGS) has demonstrated the efficiency for the wide variety of variant classes, such as SNVs, INDELs, and structural variation for hereditary disorders [ 16 , 17 ].…”