BH 4 -Sensitive Hyperphenylalaninemia: New Case and Review of Literature Thomas Lu ¨ cke, MD*, Sabine Illsinger, MD*, Christa Aulehla-Scholz, PhD † , Johannes Sander, MD, PhD ‡ , and Anibh M. Das, MD, PhD ‡ We report a patient with BH 4 -sensitive phenylketonu- ria. In neonatal screening, phenylalanine levels above 10 mg/dl were detected. In the tetrahydrobiopterin- (BH 4 ) loading test, phenylalanine concentrations in serum fell significantly. Dihydropteridine reductase activity in blood, pterines, and neurotransmitters in cerebrospinal fluid, as well as pterines in urine were all normal. Mutation analysis revealed compound-het- erozygosity for the mutations R408W and K320N. Under BH 4 -supplementation without a specific pheny- lalanine-reduced diet, phenylalanine-concentrations are in the therapeutic range and our patient developed normally. © 2003 by Elsevier Inc. All rights reserved. Lu ¨cke T, Illsinger S, Aulehla-Scholz C, Sander J, Das AM. BH4-sensitive hyperphenylalaninaemia: new case and review of literature. Pediatr Neurol 2003;28:228-230. Introduction Hyperphenylalaninemias (HPAs) belong to the group of inborn metabolic disorders with multifactorial, multilocus, and complex traits. In Western countries the incidence of HPAs is about 1 in every 5000 newborns. Diagnosis can be made in neonatal screening programs on dry blood spot by measuring phenylalanine levels. The underlying biochemical defect of HPA is a dys- function of the phenylalanine-hydroxylase (PAH)-reac- tion. This reaction requires tetrahydrobiopterin (BH 4 ) as a co-factor. Not only the PAH-reaction is BH 4 -dependent: tyrosine-3-hydroxylase and tryptophan-5-hydroxylase (two key enzymes in the biosynthesis of catecholamines and serotonin) need BH 4 as co-factor too [1]. The following diseases are collected under the umbrella of hyperphenylalaninaemia (HPA): (1) Classical phenyl- ketonuria (PKU) with reduced activity of the apoenzyme PAH, which does not respond to BH 4 and requires a low-phenylalanine diet; (2) Defects of BH 4 -metabolism (sometimes called atypical PKU), responding to BH 4 substitution; and (3) A mild variant of HPA (with phenyl- alanine levels  10 mg/dl) that does not respond to BH 4 and does not require a diet (also known as benign PKU). To differentiate between these forms of HPA a BH 4 - loading test is performed [2]. Although patients with classical PKU usually do not demonstrate a significant reduction of blood phenylalanine concentration in the BH 4 -loading test, patients with defects in BH 4 -metabolism exhibit a decrease of phenylalanine levels after BH 4 application. Because of co-factor deficiency in patients with the latter form of PKU, reduced concentrations of neurotransmitters in cerebrospinal fluid (CSF) are found. Therapy of these patients consists of BH 4 -supplementation and application of neurotransmitter precursors [3]. Recently, there have been a few reports on patients with classical PKU who respond to BH 4 [4-9]. In this subgroup, BH 4 metabolism is normal (as demonstrated by normal neurotransmitter concentrations, pterine levels, and dihy- dropteridine reductase activity in blood). It has been speculated that the underlying mutations cause a K m - variant of PAH in which residual activity can be enhanced by supplementation of BH 4 [10]. A review of the pub- lished cases and the mutations found is given. Further- more, a new patient with BH 4 -sensitive PKU is presented. Case Report We report on a 2-month-old male infant with an unremarkable peripartum period and a normal neurologic status. He was the first child of an unrelated caucasian couple and had been delivered at 40 weeks of gestation with a birth weight of 3600 g. In the neonatal screening performed at day 4 an elevated phenylalanine concentration was found. Before BH 4 -loading, the blood phenylalanine concentration was 11.6 mg/dl (705 mol/l). Eight hours after BH 4 application (20 mg/kg b.w.), phenylalanine concentration decreased to From the *Department of Paediatrics, Hanover Medical School, Hanover, Germany; the † Institute of Clinical Genetics, Department of Paediatrics, General Hospital, Stuttgart, Germany; and the ‡ Screening Lab Prof. Sander, Hanover, Germany. Communications should be addressed to: Dr. Lu ¨cke; Carl-Neuberg Str. 1; 30623 Hannover, Germany. Received June 4, 2002; accepted September 5, 2002. 228 PEDIATRIC NEUROLOGY Vol. 28 No. 3 © 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(02)00516-7 ● 0887-8994/03/$—see front matter