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.

Investigating the Metabolic Model in Preterm Neonates by Tandem Mass Spectrometry: A Cohort Study

“…Decreased Alanine in preterm neonates was supported by the OR = 0.208 of Alanine, and increased free carnitine was supported by the OR = 3.777 of free carnitine. The decreased Alanine was observed in patients with dihydrolipoamide dehydrogenase (DLD) deficiency, one type of maple syrup urine disease (MSUD), the clinical presentations of which included developmental delay, failure to thrive, microcephaly, and so on [62]. Clinically, avoiding fasting, protein/BCAA-restriction, and ketogenic/high-fat diet are always used for DLD deficiency treatment [63].…”

First Reported Lebanese Patient with Dihydrolipoamide Dehydrogenase Deficiency

“…DLD, encoded by the DLD gene, is vital for catalysis. Thus, genetically induced deficiency of the enzyme, although very rare, is associated with failure to thrive, hypotonia, and metabolic acidosis [1,2].In this report, we present the case of a 12-year-old Lebanese boy with a homozygous mutation in the DLD gene: c.685G>T p. Gly229Cys, who presented with liver failure, hyperammonemia, and encephalopathy. Genetic testing of his sibling revealed homozygosity for the same pathogenic variant.…”

“…DLD, encoded by the DLD gene, is vital for catalysis. Thus, genetically induced deficiency of the enzyme, although very rare, is associated with failure to thrive, hypotonia, and metabolic acidosis [1,2].…”

Translational Detection of Nonproteinogenic Amino Acids Using an Engineered Complementary Cell-Free Protein Synthesis Assay

“…Ornithine and citrulline are nonproteinogenic amino acids with potential clinical applications as biomarkers of various diseases . Reduction in the blood level of citrulline is related to intestinal failure, whereas abnormally high levels of citrulline during newborn screening may indicate dihydrolipoamide dehydrogenase deficiency (DLD), a variant form of maple syrup urine disease (MSUD) . High concentrations of citrulline are also related to type I citrullinemia (CIT) .…”

“…16 Reduction in the blood level of citrulline is related to intestinal failure, 17 whereas abnormally high levels of citrulline during newborn screening may indicate dihydrolipoamide dehydrogenase deficiency (DLD), a variant form of maple syrup urine disease (MSUD). 18 High concentrations of citrulline are also related to type I citrullinemia (CIT). 19 On the other hand, ornithine has been investigated as a biomarker for hyperornithinemia−hyperammonemia−homocitrullinuria (HHH) syndrome.…”