Propionic acidemia (PA) is an autosomal recessive disorder of organic acid metabolism caused by a defect of propionyl-CoA carboxylase (PCC) . PCC catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA in the catabolic pathway of odd-numbered carbon fatty acids and amino acids, i.e. isoleucine, valine, threonine, and methionine. The major biochemical features of PA include:
- mild to severe ketoacidosis
- diagnostic urine organic acid profile (3-hydroxypropionate, methylcitrate, propionylglycine, and tiglylglycine)
The common clinical presentation includes:
- frequent vomiting
- refusal to feed
In most patients there is a neonatal clinical onset associated with development delay and neurological impairment, but late-onset patients are also described with a milder course .
Conventional treatment of PA consists of dietary restriction of protein, increase of caloric intake, avoidance of long-fasting periods and carnitine supplementation, and may include oral antibiotic therapy.
PCC is a biotin-dependent mitochondrial enzyme which consists of two non-identical alpha and beta-subunits, encoded by the PCCA (13q32) and PCCB (3q13) genes, respectively . Mutations in either the PCCA or PCCB genes can cause reduced or deficient enzyme activity. In both genes, missense mutations are the most frequent defects (39 and 46%, for PCCA and PCCB, respectively), followed by small insertions/deletions and splicing mutations (24-29% each in either gene), with most resulting in a truncated protein. Gene sequencing is available to test for mutations in the PCCA and PCCB genes. For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array.
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This test is indicated for:
- Confirmation of a clinical/biochemical diagnosis of PA.
- Carrier testing in adults with a family history of PA.
DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations.
Results of molecular analysis must be interpreted in the context of the patient\'s clinical and/or biochemical phenotype.
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
- Amino Acid Analysis - Plasma (AA), Urine Organic Acids (OA), and Acylcarnitine Profile - Plasma (AR) are used in the diagnoses of a patient with PA.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.