Elevated Levels of C6, C8 and C10 Acylcarnitine via the ACADM Gene

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006. PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is designed for individuals with NBS results showing elevated levels of C6, C8, C10 acylcarnitine which can indicate medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD). MCAD deficiency is a core condition on the RUSP.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive disease. Medium chain acyl-CoA dehydrogenase, encoded by the ACADM gene, catalyzes the first step in the breakdown of fatty acids with 4-12 carbon atoms. For patients with Northern European ancestry, one missense variant in exon 11 (c.985A>G, p.Lys329Glu; historically known as p.Lys304Glu) is predominant, comprising up to about 76% of alleles in individuals with MCAD deficiency. This variant tends to cause particularly severe disease. Many other causative missense, frameshift, splicing, and nonsense variants as well as gross deletions have been described throughout the length of the gene; most are private variants. Individuals who are compound heterozygous for the p.Lys329Glu (p.Lys304Glu) variant, or homozygous for other variants in the ACADM gene, tend to have less severe disease. It appears that diagnosis by tandem mass spectrometry is more sensitive than diagnosis by other clinical features and may identify subclinical cases (Andresen et al. 2001. PubMed ID: 11349232; Maier et al. 2005. PubMed ID: 15832312; Merritt and Change. 2019. PubMed ID: 20301597; Waddell et al. 2006. PubMed ID: 16291504).

Sensitivity of this test appears to be high. Approximately 50% of patients are homozygous for the p.Lys329Glu (p.Lys304Glu) variant, and 40% of affected individuals are heterozygous for this variant (Merritt and Change. 2019. PubMed ID: 20301597).

This test provides full coverage of all coding exons of the ACADM 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).