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Useful second-tier tests in expanded newborn screening of isovaleric acidemia and methylmalonic aciduria

Yosuke Shigematsu1, Ikue Hata, Go Tajima

  • 1Department of Health Science, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui, Japan. yosuke@u-fukui.ac.jp

Journal of Inherited Metabolic Disease
|May 5, 2010
PubMed

Insights

Newborn screening for isovaleric acidemia (IVA) using acylcarnitine (C5) generated many false positives. A new test measuring isovalerylglycine (IVG) in dried blood spots accurately identified severe IVA cases and assessed disease severity.

Area of Science:

  • Biochemistry
  • Metabolic Disorders
  • Newborn Screening

Background:

  • Pivalate-generating antibiotics and low C5-acylcarnitine cutoff values in Japan led to numerous false positives in newborn screening for isovaleric acidemia (IVA).
  • Existing screening methods require refinement for accurate diagnosis and severity assessment of IVA and related metabolic disorders.

Purpose of the Study:

  • To develop and validate second-tier tests for accurate IVA diagnosis and severity assessment using dried blood spots (DBS).
  • To establish a reliable method for detecting methylmalonic aciduria (MMAU) and propionic acidemia.

Main Methods:

  • Developed a second-tier test measuring isovalerylglycine (IVG) levels in DBS with a cutoff of 0.5 nmol/ml.
  • Developed a gas chromatography/mass spectrometry (GC/MS) method to measure methylmalonic acid (MMA) levels in DBS.

Main Results:

  • The IVG test identified one severe IVA patient among 1,065 initial positive screens, avoiding unnecessary recalls.
  • Retrospective analysis showed decreased free carnitine and higher IVG than C5 levels in moderate to severe IVA patients.
  • MMAU patients exhibited significantly higher DBS MMA concentrations (24.2-321.9 nmol/ml) compared to controls (0.34 ± 0.11 nmol/ml).
  • High MMA levels in MMAU patients correlated with decreased free carnitine and mildly increased propionylcarnitine.

Conclusions:

  • Measuring IVG in DBS is an effective second-tier test for confirming IVA and evaluating its severity.
  • GC/MS measurement of DBS MMA provides valuable information for diagnosing MMAU and assessing its severity.
  • These refined methods improve the accuracy and efficiency of newborn screening for inherited metabolic disorders.

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