Newborn Screening for Vitamin B6Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy.
BACKGROUND
In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.


METHODS
We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy.


RESULTS
Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly.


CONCLUSIONS
The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany. juergen.okun@med.uni-heidelberg.de.
Jürgen G
JG
Okun
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Hongying
H
Gan-Schreier
Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Tawfeq
T
Ben-Omran
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Kathrin V
KV
Schmidt
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Junmin
J
Fang-Hoffmann
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Gwendolyn
G
Gramer
Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Ghassan
G
Abdoh
Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Noora
N
Shahbeck
Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Hilal
H
Al Rifai
Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
Abdul Latif
AL
Al Khal
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Gisela
G
Haege
Chinese Foundation of Health, Taipei City, Taiwan.
Chuan-Chi
CC
Chiang
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
David C
DC
Kasper
NSW Newborn Screening Programme, The Children's Hospital at Westmead, Westmead, NSW, Australia.
Bridget
B
Wilcken
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Peter
P
Burgard
Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Georg F
GF
Hoffmann
Classical homocystinuria; Cystathionine β-synthase; Dried blood spots; Homocysteine; Newborn screening; Two-tier strategy