Quantitation of gamma-hydroxybutyric acid in dried blood spots: Feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency

Sabrina Forni, Phillip L. Pearl, K. Michael Gibson, Yuezhou Yu, Lawrence Sweetman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Objective: SSADHdeficiency, themost prevalent autosomal recessive disorder of GABA degradation, is characterized by elevated gamma-hydroxybutyric acid (GHB). Neurological outcomes may be improved with early intervention and anticipatory guidance. Morbidity has been compounded by complications, e.g. hypotonia, in undiagnosed infants with otherwise routine childhood illnesses. We report pilot methodology on the feasibility of newborn screening for SSADH deficiency. Method: Dried blood spot (DBS) cards from patients affected with SSADH deficiency were compared with 2831 archival DBS cards for gamma-hydroxybutyric acid content. Following extraction with methanol, GHB in DBS was separated and analyzed using ultra high-performance liquid chromatography tandem mass spectrometry. Results: Methodology was validated to meet satisfactory accuracy and reproducibility criteria, including intra-day and inter-day validation. Archival refrigerated dried blood spot samples of babies, infants and children (N = 2831) were screened for GHB, yielding a mean +/- S.D. of 8 ± 5 nM (99.9%-tile 63 nM) (Min 0.0 Max 78 nM). The measured mean and median concentrations in blood spots derived from seven SSADH deficient patients were 1182 nM and 699 nM respectively (Min 124, Max 4851 nM). Conclusions: GHB concentration in all 2831 dried blood spot cards was well below the lowest concentration of affected children. These data provide proof-of-principle for screening methodology to detect SSADH deficiency with applicability to newborn screening and earlier diagnosis.

Original languageEnglish (US)
Pages (from-to)255-259
Number of pages5
JournalMolecular genetics and metabolism
Volume109
Issue number3
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Gamma-aminobutyric acid (GABA)
  • Gamma-hydroxybutyric acid (GHB)
  • Newborn screening
  • Rapid neonatal detection
  • Succinic semialdehyde dehydrogenase deficiency
  • UPLC-MS/MS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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