A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F20%3A73605275" target="_blank" >RIV/61989592:15110/20:73605275 - isvavai.cz</a>

Result on the web

<a href="https://onlinelibrary.wiley.com/doi/full/10.1002/jmd2.12118" target="_blank" >https://onlinelibrary.wiley.com/doi/full/10.1002/jmd2.12118</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/jmd2.12118" target="_blank" >10.1002/jmd2.12118</a>

Result language

angličtina

Original language name

A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

Original language description

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as the most discriminating metabolites between the groups. In order to evaluate the NBS potential of these metabolites we quantified the most discriminating metabolites from untargeted metabolomics in 23 blood spots from 4 HMGCLD patients and 55 controls by UHPLC tandem mass spectrometry. The results provide a tool for expanded NBS of HMGCLD using tandem mass spectrometry. Selected reaction monitoring transition 262/85 could be used in a first-tier NBS analysis to screen for elevated 3-hydroxyisovalerylcarnitine. In a positive case, a second-tier analysis of 3-hydroxy-3-methylglutaric acid and 3-methylglutaconic acid in a dry blood spot using UHPLC tandem mass spectrometry instruments confirms the diagnosis. In conclusion, we describe the identification of new diagnostic biomarkers for HMGCLD and their application in NBS in dry blood spots. By using second-tier testing, all patients with HMGCLD were unequivocally and correctly diagnosed.

Czech name

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Czech description

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Type

J_ost - Miscellaneous article in a specialist periodical

CEP classification

—

OECD FORD branch

30209 - Paediatrics

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

JIMD Reports

ISSN

2192-8312

e-ISSN

—

Volume of the periodical

54

Issue of the periodical within the volume

1

Country of publishing house

DE - GERMANY

Number of pages

8

Pages from-to

79-86

UT code for WoS article

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EID of the result in the Scopus database

2-s2.0-85094870029