Elevated Levels of C5-hydroxyacylcarnitine (C5-OH) Panel

Elevated levels of C5-hydroxyacylcarnitine (C5-OH), detected through the newborn screening program or plasma acylcarnitine analysis, are associated with a group of amino acid disorders with enzymatic defects leading to abnormal catabolism of branched chain amino acids. 

Multiple carboxylase deficiency encompasses two disorders caused by enzymatic defect affecting biotin metabolism: holocarboxylase synthase deficiency (HCS) and biotinidase deficiency (BTD). Both disorders overlap in their clinical presentation, but may be differentiated by their age of onset. Clinical signs of BTD typically appear after 3 months of age while HCS is typically evident earlier (Wolf et al. 1985. PubMed ID: 4073853, Wolf. 2000. PubMed ID: 20301497). Overlapping clinical features include seizures, hypotonia, respiratory symptoms, developmental delay, and ataxia. Eczema, alopecia, dermatitis, and skin infections are also common findings (Wolf. 2000. PubMed ID: 20301497; Suzuki et al. 2005. PubMed ID: 16134170).

Three disorders can be linked to enzymatic defects leading to abnormal leucine catabolism: 3-methylglutaconic aciduria type I (MGA1), 3-hydroxy-3-methylglutaryl (HMG)-CoA lyase deficiency (HMGCL), and 3-methylcrotonyl-CoA carboxylase deficiency (MCC). HMGCL and MCC are both associated with episodes of vomiting, lethargy, diarrhea, and hypotonia. In contrast to MCC, children with HMGCL can develop hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis during these episodes (Al-Sayed et al. 2006. PubMed ID: 17173698). In MGA1, the accumulation of toxic leucine metabolites results mainly in a neurologic condition with variable severity. Two main presentations have been described: children with various types of delays (mostly speech and motor) and adults with progressive neurodegenerative disorders (Wortmann et al. 2010 PubMed ID: 20855850).

β-ketothiolase deficiency is a disorder of isoleucine catabolism leading to intermittent ketoacidotic episodes associated with vomiting, lethargy, and fever with onset early in life (median age is 15 months old). In about half of affected patients, a severe attack is associated with unconsciousness/coma, which can result in subsequent intellectual disability or death. Affected individuals are typically asymptomatic between episodes, but the extent of the clinical features varies based on the patient and the severity of the attack (Nakamura et al. 2001. PubMed ID: 11161837, Fukao et al. 2001. PubMed ID: 11161836). 

MCC, BTD, and HCS are the most prevalent disorders included on this panel affecting approximately 1 in 50,000, 1 in 60,000, and 1 in 87,000 live births, respectively (Wolf et al. 2000. PubMed: 20301497, Baumgartner et al. 2001. PubMed ID: 11181649). HMGCL, MGA1, and β-ketothiolase deficiency are much rarer with less than ~250 individuals reported in the medical literature.

Molecular testing can be useful for confirmation of a genetic cause associated with elevated C5-hydroxyacylcarnitine on newborn screening or plasma acylcarnitine. Since this can be associated with multiple conditions, molecular diagnosis may help with determining appropriate treatment measures and allow for appropriate screening for potential future symptoms. 

This sequencing panel includes genes associated with inborn errors of metabolism that may result in elevated C5-hydroxyacylcarnitine on newborn screening or plasma acylcarnitine analysis. All conditions covered by this test are inherited in an autosomal recessive mode of inheritance. Pathogenic defects in the genes in this panel include missense, nonsense, splice site variants, small deletions, small insertions/duplications, small indels, and exon-level large deletions (Human Gene Mutation Database). See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with elevated 5-hydroxyacylcarnitine as the primary indication for testing. The clinical sensitivity of sequencing the relevant gene(s) in patients with biochemical or enzymatic diagnoses of the relevant disorders is expected to be high; details are available on the individual gene test description pages.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).