Phenylalanine Loading in Pediatric Patients with Dopa-responsive Dystonia: Revised Test Protocol and Pediatric Cutoff Values

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2010 Jul 30

PMID 20668943

Citations 5

Authors

Thomas Opladen

Jurgen G Okun

Peter Burgard

Nenad Blau

Georg F Hoffmann

Affiliations

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Abstract

Objectives: The objectives of this study were to determine the value of phenylalanine (Phe) loading for diagnosing dopa-responsive dystonia (DRD) in children.

Methods: We investigated orally administered Phe loading tests (100 mg/kg) in seven patients with confirmed DRD and 17 pediatric patients with clinically suspected but excluded DRD. Results of Phe, tyrosine (Tyr), and biopterin from plasma and dried blood spot (DBS) analyses were correlated, and pediatric cutoff values established.

Results: The peak Phe concentration following a Phe load in the pediatric DRD population is lower than reported in adults. By using adult cutoff values and either Phe/Try ratios or biopterin concentrations only, false positive and false negative results are frequent. Only the combined analysis of the Phe/Tyr ratio and biopterin concentration is reliable in children. In children with DRD, dried blood Phe/Tyr ratio exceeded 4.6 (plasma Phe/Tyr ratio >5.4) after 2 h and biopterin concentration in dried blood remained below 16.2 nmol/L (plasma biopterin <14 nmol/L) 1 h after Phe challenge.

Conclusions: Phe loading is a useful tool for diagnosing DRD in children. Test duration can be reduced to only 2 h, and specific pediatric cutoff values need to be applied. Simultaneous measurements of the Phe/Tyr ratio and biopterin in plasma or DBS are essential in pediatric patients.

Citing Articles

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Berger S, Miller I, Tochen L Pediatrics. 2022; 149(2).

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Recognizing Atypical Dopa-Responsive Dystonia and Its Mimics.

Salles P, Teran-Jimenez M, Vidal-Santoro A, Chana-Cuevas P, Kauffman M, Espay A Neurol Clin Pract. 2022; 11(6):e876-e884.

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Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH) deficiencies.

Opladen T, Lopez-Laso E, Cortes-Saladelafont E, Pearson T, Sivri H, Yildiz Y Orphanet J Rare Dis. 2020; 15(1):126.

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Dopa-responsive dystonia in a ten-year-old girl.

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Urinary neopterin and phenylalanine loading test as tools for the biochemical diagnosis of segawa disease.

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References

Nygaard T . Dopa-responsive dystonia. Delineation of the clinical syndrome and clues to pathogenesis. Adv Neurol. 1993; 60:577-85. View

Segawa M, Nomura Y, Nishiyama N . Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol. 2003; 54 Suppl 6:S32-45. DOI: 10.1002/ana.10630. View

Zurfluh M, Giovannini M, Fiori L, Fiege B, Gokdemir Y, Baykal T . Screening for tetrahydrobiopterin deficiencies using dried blood spots on filter paper. Mol Genet Metab. 2005; 86 Suppl 1:S96-103. DOI: 10.1016/j.ymgme.2005.09.011. View

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann G . Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics. 2003; 111(6 Pt 1):1399-406. DOI: 10.1542/peds.111.6.1399. View

Lopez-Laso E, Ormazabal A, Camino R, Gascon F, Ochoa J, Mateos M . Oral phenylalanine loading test for the diagnosis of dominant guanosine triphosphate cyclohydrolase 1 deficiency. Clin Biochem. 2006; 39(9):893-7. DOI: 10.1016/j.clinbiochem.2006.03.002. View

Grimes D, Barclay C, Duff J, Furukawa Y, Lang A . Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture?. J Neurol Neurosurg Psychiatry. 2002; 72(6):801-4. PMC: 1737930. DOI: 10.1136/jnnp.72.6.801. View

Blau N, Bonafe L, Thony B . Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab. 2001; 74(1-2):172-85. DOI: 10.1006/mgme.2001.3213. View

Bonafe L, Thony B, Leimbacher W, Kierat L, Blau N . Diagnosis of dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem. 2001; 47(3):477-85. View

Hyland K, Fryburg J, Wilson W, Bebin E, Arnold L, Gunasekera R . Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test. Neurology. 1997; 48(5):1290-7. DOI: 10.1212/wnl.48.5.1290. View

10.

Thony B, Auerbach G, Blau N . Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000; 347 Pt 1:1-16. PMC: 1220924. View

11.

Bandmann O, Goertz M, Zschocke J, Deuschl G, Jost W, Hefter H . The phenylalanine loading test in the differential diagnosis of dystonia. Neurology. 2003; 60(4):700-2. DOI: 10.1212/01.wnl.0000048205.18445.98. View

12.

Bandmann O, Valente E, Holmans P, Surtees R, Walters J, Wevers R . Dopa-responsive dystonia: a clinical and molecular genetic study. Ann Neurol. 1998; 44(4):649-56. DOI: 10.1002/ana.410440411. View

13.

Saunders-Pullman R, Blau N, Hyland K, Zschocke J, Nygaard T, Raymond D . Phenylalanine loading as a diagnostic test for DRD: interpreting the utility of the test. Mol Genet Metab. 2004; 83(3):207-12. DOI: 10.1016/j.ymgme.2004.07.010. View