Maple Syrup Urine Disease Panel

Maple syrup urine disease (MSUD; OMIM 248600) is a heterogeneous organic aciduria disorder caused by the impairment of the branched-chain α-keto acid dehydrogenase complex (BCKD). BCKD is a mitochondrial complex, encoded by four nuclear genes (BCKDHA, BCKDHB, DBT, and DLD), which is involved in the metabolism of the branched-chain amino acids leucine, isoleucine, and valine (Morton et al. Pediatrics 109:999-1008, 2002; Nellis et al. Molec Genet Metab 80:189-195, 2003; Chuang et al. J Biol Chem 279:17792-17800, 2004). Defective BCKD complex activity leads to the accumulation of the branched-chain amino acids to toxic levels (Chuang et al. 2004). MSUD, in untreated neonates, is characterized by mental and physical retardation, maple syrup odor in cerumen and urine, poor feeding, ketonuria, irritability, lethargy, intermittent apnea, opisthotonus, stereotyped movements such as “fencing” and “bicycling,” coma, and respiratory failure. Biochemically, MSUD is characterized by elevated plasma concentrations of branched-chain amino acids (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios (Schadewaldt et al. Clin Chem 45:1734-1740, 1999; Morton et al. 2002; Nellis et al. 2003; Chuang et al. 2004).

MSUD is an autosomal recessive genetically heterogeneous disorder caused by variants in one of the four BCKD complex encoded genes (BCKDHA, BCKDHB, DBT, and DLD) (Zhang et al. Clin. Invest. 83:1425-1429, 1989; Zhang et al. Molec. Biol. Med. 8: 39-47, 1991). Of note, DLD gene sequencing is not included in this panel since variants in DLD gene result in a clinically distinguishable phenotype. DLD sequencing may be ordered separately (Test #529).

Sensitivity for MSUD testing is approximately 85% overall.

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).

In addition to the regions described above, this testing includes coverage of the following DBT variants that reside in deep intronic or untranslated regions: c.1018-550A>G and c.*358A>C.