Propionic acidemia (PROP) OMIM ID #606054 is an inherited metabolic disorder caused by a deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). PCC converts propionyl-CoA to methylmalonyl-CoA, in the catabolism of the amino acids, isoleucine (ILE), valine (VAL), methionine (MET) and threonine (THR), as well as cholesterol, odd-chain fatty acids, thymine, and uracil.  In PROP, the accumulated propionic acid inhibits enzymes of the urea cycle, Krebs cycle and other pathways.

Similar to other IMD, PROP manifests as a spectrum of phenotypes. Clinical symptoms may present in neonates prior to the availability of newborn screening results. Early onset untreated neonates, on a normal intake of protein, develop feeding difficulties, emesis, and sleepiness that may progress to lethargy, seizures, coma and death.  Older children and adults with a milder phenotype may first present with clinical symptoms due to the catabolic stress of illness and/or excessive dietary protein intake. Individuals with later-onset PROP may exhibit developmental regression, chronic vomiting, protein intolerance, hypotonia, cardiomyopathy, and have a risk for basal ganglia infarction resulting in dystonic movements. Metabolically unstable individuals with PROP can present with acute onset of: metabolic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenia.

Natural history studies note poor long-term outcomes for individuals with PROP including: impaired growth, intellectual disability and neurological deficits such as seizures, basal ganglia lesions, pancreatitis and cardiomyopathy. Additional complications in rare cases include optic atrophy, hearing loss, and chronic renal failure.

Newborn screening for PROP is included on the Recommended Uniform Screening Panel resulting in some individuals with PROP being identified and diagnosed prior to onset of clinical symptoms and neurological damage, or with milder phenotypes.

Elevated propionylcarnitine (C3) is the analyte used as a marker for PROP in mass spectrometry (MS/MS) newborn screening. Since elevated C3 is also seen in samples from individuals with methylmalonic acidemia and disorders of vitamin B₁₂ (cobalamin) transport and biosynthesis, confirmatory testing is required.

Newborn screening is not diagnostic. Those with an elevated propionylcarnitine (C3) on the newborn screen require follow-up biochemical testing and clinical evaluation for confirmation

Common laboratory findings are listed below and in Table TABLE #1, Clinical Symptoms and Laboratory Findings in PROP.

• Elevated propionylcarnitne (C3)
• Urine organic acids: elevated 3-hydroxypropionate and abnormal presence of methylcitrate, tiglyglycine, propionylglycine
• Decreased plasma free carnitine
• Elevated ammonia
• Plasma amino acid analysis: elevated glycine and possibly elevated alanine

Molecular genetic testing is often performed; however, phenotype-genotype correlations have not been well elucidated.

Propionic acidemia is an autosomal recessive disorder with an incidence of 1:105,000-1:130,000 in the U.S  and higher in the Middle East (1:2,000 to 1:40,000).  PCC deficiency results from defects in either of two genes (PCCA and PCCB) that code for the alpha and beta subunits of the enzyme mapped to chromosome loci: 13q32.3 and 3q22.3 respectively  More than 50 mutations in the PCCB gene and more than 30 mutations in the PCCA gene have been identified in different populations (Y.16).

The most common mutation is c.1218_1231del14ins12 reported in 32% of mutations in the PCCB gene in mixed Caucasian populations. This mutation was reported in 7 homozygotes all of whom had early onset symptoms of developmental delay and hypotonia. The newborn screening program in Japan found milder disease in infants with the c.1304T>C (p.Y435C) mutation in the PCCB gene. Y435C was identified in 25% of Japanese PCCB gene mutations but long-term outcomes for these infants is not yet known  (F.3118) Mutations in the PCCA gene are associated with variable age of onset of the disease and severity of symptoms . The majority of patients are compound heterozygotes (F.3118).