Case report Early replacement therapy in a first Japanese case with autosomal recessive guanosine triphosphate cyclohydrolase I deficiency with a novel point mutation Hiroki Sato a , Mitsugu Uematsu a,⇑ , Wakaba Endo a , Tojo Nakayama a , Tomoko Kobayashi a , Naomi Hino-Fukuyo a , Osamu Sakamoto a , Haruo Shintaku b , Shigeo Kure a a Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan b Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan Received 30 December 2012; received in revised form 9 April 2013; accepted 10 April 2013 Abstract Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatment, a patient with GTPCH deficiency develops complex neurological dysfunctions, including dystonia and developmental delays. The first Japanese patient with GTPCH deficiency was discovered by HPA during asymptomatic newborn screening. The phenylalanine level at the age of 5 days was 1273 lmol/L (cutoff value, 180.0 lmol/L). The high serum phenylalanine level was decreased to normal after adequate BH4 oral supplementation. Serum and urinary pteridine examination revealed very low levels of neopterin and biopterin. Sequence analysis of GCH1 revealed compound heterozygous point mutations, including a novel point mutation (p.R235W). Replacement therapy with BH4 and L-dopa/carbidopa were started at the age of 1 month, and 5-hydroxytryptophan (5-HTP) was started at the age of 5 months. At 10 months of age, the patient showed slight dystonia but no obvious developmental delay. Cerebrospinal fluid should be examined to determine the appropriate dosage of supplement drugs. In conclusion, it is important to control the serum phenylalanine level and perform early replacement of neurotransmitters to prevent neurological dysfunction. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH); Tetrahydrobiopterin (BH4); Hyperphenylalaninemia; Early replacement therapy 1. Introduction Tetrahydrobiopterin (BH4) is an essential cofactor in the enzymatic hydroxylation of phenylalanine, tyrosine, and tryptophan. The BH4 loading test is performed to distinguish BH4 deficiency from hyperphenylalaninemia (HPA) during newborn screening. BH4 deficiency causes HPA and decreased production of the neurotransmitters dopamine and serotonin. Five types of enzyme deficien- cies have been reported in BH4 deficiency: guanosine triphosphate cyclohydrolase I (GTPCH), 6-pyruvoyl- tetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), and pterin- 4a-carbinolamine dehydratase (PCD) [1]. GTPCH deficiency is an error of BH4 synthesis. GCH1, the gene 0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.04.003 ⇑ Corresponding author. Address: Department of Pediatrics, Toho- ku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan. Fax: +81 22 717 7287. E-mail address: uematsu@bk9.so-net.ne.jp (M. Uematsu). www.elsevier.com/locate/braindev Brain & Development 36 (2014) 268–271