Carnitine Palmitoyltransferase 1A Deficiency via the CPT1A Gene

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Age of onset varies, but is typically in infancy or early childhood. Symptoms typically occur concurrently with febrile and/or gastrointestinal illness, and onset can be quite rapid. Patients present with hepatic encephalopathy which may lead to coma, hypoketotic hypoglycemia, liver failure indicated by elevated transaminases, fatty liver infiltration, transient hepatomegaly, elevated plasma carnitine and free fatty acids. In addition, some patients are hyperammonemic and have elevated urine organic acids. In between such episodes patients are typically normal (Brown et al. 2001; Gobin et al. 2002; Bonnefont et al. 2004; Bennett and Santani 2016).

Women who are pregnant with a fetus with CPT1A deficiency may present with HELLP-like syndrome, acute fatty liver of pregnancy (AFLP), hypoglycemia, abnormal liver enzymes, and/or hyperammonemia (Bonnefont et al. 2004; Bennett and Santani 2016).

Carnitine palmitoyltransferase 1A deficiency is an autosomal recessive disorder, and CPT1A is the only gene that is known to be involved. CPT1A deficiency is a relatively rare disorder, with ~40 pathogenic variants reported to date. The majority of pathogenic variants are missense, though one small in-frame deletion as well as nonsense and other premature termination variants (small insertions, deletions, and splice variants) have also been reported. One gross deletion has been reported (Human Gene Mutation Database). At least three variants have been reported at higher frequencies in specific populations. The p.G710E variant is common among Alaskan and American Hutterites, the p.P497L variant is common among Alaskan Native populations, and the p.K455T variant is common among Finnish patients (Greenberg et al. 2009; Gillingham et al. 2011; Roomets et al. 2012).

The carnitine palmitoyltransferase system is comprised of several proteins with enzyme and transporter functions. These proteins are involved in long-chain fatty acid (LCFA) metabolism, being specifically responsible for the net transport of LCFAs from the cytosol into the mitochondrial matrix. The CPT1 protein is the first component of this system. CPT1 activates LCFAs by catalyzing the transfer of an acyl group to carnitine, which is then transported into the mitochondrial matrix. Multiple isoforms of CPT1 exist. The CPT1A isoform is expressed predominantly in the liver and is the only isoform that has thus far been associated with human disease (Brown et al. 2001; Bonnefont et al. 2004).

Clinical sensitivity of this test is expected to be high for patients with confirmed carnitine palmitoyltransferase 1A deficiency as, to date, nearly all reported patients have had two pathogenic variants detectable via sequencing. Based on combined results from several studies, 55 pathogenic alleles were identified in 29 affected patients for an overall sensitivity of ~95% (Brown et al. 2001; Gobin et al. 2002; Bennett et al. 2004; Greenberg et al. 2009; Fontaine et al. 2012; Roomets et al. 2012).

Only one gross deletion has been reported in the CPT1A gene (Gobin et al. 2002). Therefore, the sensitivity of duplication/deletion testing for this rare disorder, although not precisely known, is expected to be low.

This test provides full coverage of all coding exons of the CPT1A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).