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.
1. Fenton, Gravel, Rosenberg. Disorders of propionate and methylmalonate metabolism., in: C.R. Scriver, A.L. Beaudet, W. Sly, D. Valle (Eds.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 2165-2190.
2. Lehnert et al. Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 1994, 153:S68-80.
3. Lucke et al. Propionic acidemia: unusual course with late onset and fatal outcome, Metabolism 2004, 53:809-810.
4. Desviat et al. Propionic acidemia: mutation update and functional and structural effects of the variant alleles. Mol Genet Metab 2004, 83:28-37.
5. Perez-Cerda et al. Potential relationship between genotype and clinical outcome in propionic acidaemia patients. Eur J Hum Genet 2000, 8:187-194.
6. Ravn et al. High incidence of propionic acidemia in Greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet 2000, 67:203-206.
7. Yorifuji et al. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet 2002, 111:161-165.
8. Rashed. Clinical applications of tandem mass spectrometry: ten years of diagnosis and screening for inherited metabolic diseases. J Chromatogr B Biomed Sci Appl 2001, 758:27-48.
9. Chace et al. Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem 2001, 47:2040-2044.
10. Schulze et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003, 111:1399-1406.
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.
Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.
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.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
Please submit copies of diagnostic biochemical test results along with the sample. Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of Emory Genetics Laboratory, please submit a copy of the sequencing report with the test requisition.
- 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.