Invitae Propionic Acidemia Panel


Test description

The Invitae Propionic Acidemia panel analyzes PCCA and PCCB, the two genes associated with propionic acidemia (PPA). PPA is caused by decreased activity of the enzyme propionyl-CoA carboxylase (PCC). PPA is a life-threatening organic acidemia. Any individual with a positive newborn screen for PPA (elevated C3, propionylcarnitine), biochemical studies consistent with PPA (elevated 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine levels in urine organic acids; plasma amino acids with elevated glycine), suspected diagnosis of PPA based on clinical presentation, or a positive family history should be tested for PPA. Rare cases of isolated cardiomyopathy of unknown etiology have also been found to be a mild presentation of PPA. Correct diagnosis and subsequent metabolic control is the greatest determinant of long-term cognitive outcome.

Order test

Primary panel (2 genes)


Add-on methylmalonic acidemia genes (5 genes)

Methylmalonic acidemia (MMA) is caused by an enzyme or cofactor-related defect in the propionate metabolic pathway, but downstream of propionyl-CoA carboxylase. Patients with severe MMA can get a backlog of propionate metabolism intermediates and can have similar findings on biochemical analyses as well as overlapping clinical features. Analyzing the genes associated with MMA may also be appropriate. These genes can be included at no additional charge.


Add-on multiple carboxylase deficiency genes (2 genes)

Propionyl-CoA carboxylase (PCC) is a biotin-dependent enzyme. Consequently, individuals with biotin metabolism disorders can develop impaired PCC activity, causing elevated PPA metabolites on biochemical analysis. Analyzing the genes associated with multiple carboxylase deficiency may also be appropriate. These genes can be included at no additional charge.


Alternative tests to consider

The Invitae Organic Acidemias Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.

Propionic acidemia (PPA)

  • Isolated cardiomyopathy due to mild PPA

Propionic acidemia (PPA) is an organic acidemia resulting in a deficiency in the enzyme propionyl-CoA carboxylase (PCC). PCC catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA during the catabolism of the amino acids valine, isoleucine, threonine, and methionine as well as odd-chain fatty acids, cholesterol side chains, thymine, and uracil. Impairment of PCC results in a metabolic block that leads to elevated concentrations of propionate precursors and their metabolic by-products.

Propionic acidemia is a fully penetrant disorder that displays broad clinical heterogeneity ranging from a severe neonatal onset encephalopathy to isolated cardiomyopathy presenting in late adolescence to early adulthood. The heterogeneity is due to the residual PCC enzymatic activity, with the least activity associated with the most severe presentation of the disease. The severe, neonatal-onset presentation is the classic and most-common form; patients present in the first days of life, after protein catabolism has taken place, and is characterized by poor feeding, vomiting, somnolence, and acute clinical deterioration. Affected individuals can become lethargic and encephalopathic, can develop seizures or cardiorespiratory failure, and may possibly experience coma or death. Biochemically, affected individuals have anion-gap metabolic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Patients who survive the first metabolic crisis often suffer from cognitive delay, seizures, basal ganglia lesions, growth impairment, pancreatitis, and cardiomyopathy.

Late-onset PPA (outside of the newborn period) can present during intercurrent illness, with symptoms that are similar to those in neonatal cases and ranging from mild to acute decompensation. Alternatively, there may be a chronic progressive course, with neurocognitive regression, failure to thrive, and other neurologic abnormalities. Individuals with neonatal and late-onset PPA are also susceptible to intermittent episodes of acute metabolic decompensation; such episodes are frequently precipitated by infection, injury, or physiologic stress.

Atypical presentations include adult-onset chorea and dementia without documented metabolic acidosis. Recently, PPA has been reported as a cause of isolated cardiomyopathy without metabolic acidosis or neurologic deficits. These cases have not experienced acute metabolic decompensation but have had biochemical abnormalities consistent with PPA.

Propionic acidemia is treatable by lifetime dietary restriction of the amino acids valine, methionine, isoleucine, and threonine, and by aggressive intervention during metabolic crises. Dietary therapy must be managed by a nutritionist to prevent malnutrition. Some affected individuals have been treated with a liver transplant.

Pathogenic variants in PCCA account for approximately 35%–50% of diagnosed cases of propionic acidemia. Approximately 20% of these pathogenic variants are due to exonic deletions. Pathogenic variants in PCCB account for approximately 50%–65% of diagnosed cases of propionic acidemia. Deletions in PCCB have not been described. Approximately 100% of patients with a clinical and biochemical diagnosis of PPA are expected to have biallelic pathogenic variants in either PCCA or PCCB.

Propionic acidemia is inherited in an autosomal recessive pattern.

The worldwide incidence of propionic acidemia is estimated at 1 in 50,000–100,000, but it has a much higher incidence in certain isolated populations. Incidence in the Inuit population of Greenland is reported at 1 in 1,000 due to the variant 1540insCCC in PCCB. In Saudi Arabia, incidence is estimated at 1 in 2,000–5,000.

This panel may be appropriate for:

  • any individual with elevated organic acids consistent with PPA (3-hydroxypropionate, methylcitrate, tiglylglycine, propionylglycine)
  • any individual with a biochemical or clinical picture consistent with PPA, even with a past history of a normal newborn screen (newborn screening can miss milder, later-onset forms of PPA because biochemical abnormalities are generally unmasked during times of physiologic stress)

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
BTD NM_000060.3
HLCS NM_000411.6
MMAA NM_172250.2
MMAB NM_052845.3
MMACHC NM_015506.2
MMADHC NM_015702.2
MUT NM_000255.3
PCCA NM_000282.3
PCCB NM_000532.4