Malonyl-CoA Decarboxylase Deficiency via the MLYCD Gene

Malonyl-CoA decarboxylase deficiency is a rare inborn error of metabolism caused by defects in the MLYCD gene. Although the clinical presentation is variable, patients with this disorder may present with developmental delay, seizures, hypoglycemia, cardiomyopathy and structural brain abnormalities (FitzPatrick et al. 1999; Celato et al. 2013; Liu et al. 2016). Biochemically, this disorder is characterized by elevated malonylcarnitine on an acylcarnitine profile and the presence of malonic and methylmalonic acid in the urine (FitzPatrick et al. 1999; Celato et al. 2013; Baertling et al. 2014). Metabolic acidosis is also frequently observed (Celato et al. 2013; Liu et al. 2016). More severely affected patients may die in infancy (Polinati et al. 2015).

Treatment of MLYCD deficient patients is generally via dietary modification as well as medications to treat cardiomyopathy, if needed. While this treatment may not prevent or eliminate all symptoms, there does seem to be benefit to diagnosing affected patients early in life so that treatment can begin as soon as possible (Baertling et al. 2014).

Malonyl-CoA decarboxylase deficiency is an autosomal recessive disorder caused by defects in the MLYCD gene, which is located on chromosome 16 at 16q23.3. Over 35 pathogenic variants have been reported in the MLYCD gene, approximately one-third of which have been missense variants. Nearly half of the reported variants are splice site or protein truncating variants, and approximately one-fifth of reported variants are larger copy number variants (Human Gene Mutation Database). Most reported MLYCD variants seem to be private, familial variants.

The malonyl-CoA decarboxylase enzyme catalyzes the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide (Sacksteder et al. 1999). The malonyl-CoA metabolite has at least two functions in mammalian cells. First, it is used in the de novo synthesis and elongation of fatty acids in lipogenic tissues. Secondly, malonyl-CoA acts as an inhibitor of the carnitine palmitoyltransferase I (CPTI) enzyme, thereby regulating mitochondrial fatty acid β-oxidation in non-lipogenic tissues (Sacksteder et al. 1999; Polinati et al. 2015). For these reasons, MLYCD deficient patients often have some phenotypic overlap with patients who have a defect in fatty acid oxidation (Salomons et al. 2007).

Based on collective totals of many of the patients reported in the literature, the clinical sensitivity of MLYCD gene sequencing for patients with confirmed malonyl-CoA decarboxylase deficiency is estimated to be ~73% (22 pathogenic MLYCD alleles out of 30 alleles, with only one patient counted if multiple family members were affected) (FitzPatrick et al. 1999; Salomons et al. 2007; Celato et al. 2013; Baertling et al. 2014; Polinati et al. 2015; Liu et al. 2016). The remaining ~27% of alleles contained exonic or larger deletions that may not be detected by this test.

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