High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots
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High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots. / Brennenstuhl, Heiko; Kohlmüller, Dirk; Gramer, Gwendolyn; Garbade, Sven F; Syrbe, Steffen; Feyh, Patrik; Kölker, Stefan; Okun, Jürgen G; Hoffmann, Georg F; Opladen, Thomas.
In: J INHERIT METAB DIS, Vol. 43, No. 3, 05.2020, p. 602-610.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots
AU - Brennenstuhl, Heiko
AU - Kohlmüller, Dirk
AU - Gramer, Gwendolyn
AU - Garbade, Sven F
AU - Syrbe, Steffen
AU - Feyh, Patrik
AU - Kölker, Stefan
AU - Okun, Jürgen G
AU - Hoffmann, Georg F
AU - Opladen, Thomas
N1 - © 2019 SSIEM.
PY - 2020/5
Y1 - 2020/5
N2 - Aromatic l-amino-acid decarboxylase (AADC) deficiency is an inherited disorder of biogenic amine metabolism with a broad neurological phenotype. The clinical symptoms overlap with other diseases resulting in an often delayed diagnosis. Innovative disease-changing treatment options, particularly gene therapy, have emphasised the need for an early diagnosis. We describe the first method for 3-O-methyldopa (3-OMD) analysis in dried blood spots (DBS) suitable for high throughput newborn screening (NBS). We established a novel tandem mass spectrometry method to quantify 3-OMD in DBS and successfully tested it in 38 888 unaffected newborns, 14 heterozygous DDC variant carriers, seven known AADC deficient patients, and 1079 healthy control subjects. 3-OMD concentrations in 38 888 healthy newborns revealed a mean of 1.16 μmol/L (SD = 0.31, range 0.31-4.6 μmol/L). 1079 non-AADC control subjects (0-18 years) showed a mean 3-OMD concentration of 0.78 μmol/L (SD = 1.75, range 0.24-2.36 μmol/L) with a negative correlation with age. Inter- and intra-assay variability was low, and 3-OMD was stable over 32 days under different storage conditions. We identified seven confirmed AADC deficient patients (mean 3-OMD 9.88 μmol/L [SD = 13.42, range 1.82-36.93 μmol/L]). The highest concentration of 3-OMD was found in a NBS filter card of a confirmed AADC deficient patient with a mean 3-OMD of 35.95 μmol/L. 14 DDC variant carriers showed normal 3-OMD concentrations. We demonstrate a novel high-throughput method to measure 3-OMD in DBS, which allows integration in existing NBS programs enabling early diagnosis of AADC deficiency.
AB - Aromatic l-amino-acid decarboxylase (AADC) deficiency is an inherited disorder of biogenic amine metabolism with a broad neurological phenotype. The clinical symptoms overlap with other diseases resulting in an often delayed diagnosis. Innovative disease-changing treatment options, particularly gene therapy, have emphasised the need for an early diagnosis. We describe the first method for 3-O-methyldopa (3-OMD) analysis in dried blood spots (DBS) suitable for high throughput newborn screening (NBS). We established a novel tandem mass spectrometry method to quantify 3-OMD in DBS and successfully tested it in 38 888 unaffected newborns, 14 heterozygous DDC variant carriers, seven known AADC deficient patients, and 1079 healthy control subjects. 3-OMD concentrations in 38 888 healthy newborns revealed a mean of 1.16 μmol/L (SD = 0.31, range 0.31-4.6 μmol/L). 1079 non-AADC control subjects (0-18 years) showed a mean 3-OMD concentration of 0.78 μmol/L (SD = 1.75, range 0.24-2.36 μmol/L) with a negative correlation with age. Inter- and intra-assay variability was low, and 3-OMD was stable over 32 days under different storage conditions. We identified seven confirmed AADC deficient patients (mean 3-OMD 9.88 μmol/L [SD = 13.42, range 1.82-36.93 μmol/L]). The highest concentration of 3-OMD was found in a NBS filter card of a confirmed AADC deficient patient with a mean 3-OMD of 35.95 μmol/L. 14 DDC variant carriers showed normal 3-OMD concentrations. We demonstrate a novel high-throughput method to measure 3-OMD in DBS, which allows integration in existing NBS programs enabling early diagnosis of AADC deficiency.
KW - Amino Acid Metabolism, Inborn Errors/blood
KW - Amino Acids
KW - Aromatic-L-Amino-Acid Decarboxylases/blood
KW - Case-Control Studies
KW - Dried Blood Spot Testing/methods
KW - Female
KW - High-Throughput Screening Assays
KW - Humans
KW - Infant, Newborn
KW - Male
KW - Neonatal Screening
KW - Tandem Mass Spectrometry
KW - Tyrosine/analogs & derivatives
U2 - 10.1002/jimd.12208
DO - 10.1002/jimd.12208
M3 - SCORING: Journal article
C2 - 31849064
VL - 43
SP - 602
EP - 610
JO - J INHERIT METAB DIS
JF - J INHERIT METAB DIS
SN - 0141-8955
IS - 3
ER -
