title: Newborn screening for dihydrolipoamide dehydrogenase deficiency: Citrulline as a useful analyte.
abstract: Dihydrolipoamide dehydrogenase deficiency, also known as maple syrup urine disease (MSUD) type III, is caused by the deficiency of the E3 subunit of branched chain alpha-ketoacid dehydrogenase (BCKDH), α-ketoglutarate dehydrogenase (αKGDH), and pyruvate dehydrogenase (PDH). DLD deficiency variably presents with either a severe neonatal encephalopathic phenotype or a primarily hepatic phenotype. As a variant form of MSUD, it is considered a core condition recommended for newborn screening. The detection of variant MSUD forms has proven difficult in the past with no asymptomatic DLD deficiency patients identified by current newborn screening strategies. Citrulline has recently been identified as an elevated dried blood spot (DBS) metabolite in symptomatic patients affected with DLD deficiency. Here we report the retrospective DBS analysis and second-tier allo-isoleucine testing of 2 DLD deficiency patients. We show that an elevated citrulline and an elevated allo-isoleucine on second-tier testing can be used to successfully detect DLD deficiency. We additionally recommend that DLD deficiency be included in the "citrullinemia/elevated citrulline" ACMG Act Sheet and Algorithm.
authors.affiliation: University of Michigan, Department of Pediatrics, Division of Pediatric Genetics, 1500 East Medical Center Drive, D5240 MPB/Box 5718, Ann Arbor, MI 48109-5718, USA.
authors.forename: Shane C
authors.initials: SC
authors.lastname: Quinonez
authors.affiliation: University of Michigan, Department of Pediatrics, Division of Pediatric Genetics, 1500 East Medical Center Drive, D5240 MPB/Box 5718, Ann Arbor, MI 48109-5718, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Seeley
authors.affiliation: Newborn Screening Section, Michigan Department of Community Health, Bureau of Laboratories, Chemistry and Toxicology, 3350 N. MLK Jr. Blvd., Lansing, MI 48906, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Seeterlin
authors.affiliation: Newborn Screening Section, Michigan Department of Community Health, Bureau of Laboratories, Chemistry and Toxicology, 3350 N. MLK Jr. Blvd., Lansing, MI 48906, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Stanley
authors.affiliation: University of Michigan, Department of Pediatrics, Division of Pediatric Genetics, 1500 East Medical Center Drive, D5240 MPB/Box 5718, Ann Arbor, MI 48109-5718, USA.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Ahmad
keywords: Citrulline; DLD deficiency; Maple syrup urine disease; Newborn screening; Second-tier testing