Brain & Development 37 (2015) 359–361 www.elsevier.com/locate/braindev

Case report

A novel missense mutation in GCH1 gene in a Korean family with Segawa disease Ji-In Kim a, Jin Kyo Choi a, Jin-Woo Lee a, Juwon Kim b, Chang-Seok Ki c, Jin Yong Hong a,⇑ a Department of Neurology, Yonsei University Wonju College of Medicine, Wonju, South Korea Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea c Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea b

Received 16 April 2014; received in revised form 27 May 2014; accepted 27 May 2014

Abstract Segawa disease is a rare disorder presenting gait disturbance and dystonia with marked fluctuation, and caused by GTP cyclohydrolase 1 (GCH1) deficiency. Our 15-year-old patient was admitted for fluctuating gait disturbance lasted for 4 years. Administration of levodopa resulted in a dramatic improvement, and positron emission tomography using 18F-FP-CIT showed normal striatal dopamine transporter activity. Genetic study revealed a novel missense mutation in the exon 5 of GCH1 gene at c.623C>A in the proband and his father, and in silico analysis predicted that the protein function was probably damaged. Mutation analysis and searching with genetic databases might help diagnosing Segawa disease and predicting protein function. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Segawa disease; Dopa-responsive dystonia; GTP cyclohydrolase 1; Missense mutation; GCH1

1. Introduction Segawa disease (dopa-responsive dystonia) is a movement disorder characterized by childhood-onset dystonia and gait disturbance, diurnal symptom fluctuation, and a sustained response to low-dose levodopa [1]. The most common cause of Segawa disease is a mutation of the GTP cyclohydrolase 1 (GCH1) gene on chromosome 14q22.1-22.2 [2]. GTP cyclohydrolase 1 is the ratelimiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), which is an essential co-factor for tyrosine hydroxylase. ⇑ Corresponding author. Address: Department of Neurology, Yonsei

University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 220-701, South Korea. Tel.: +82 33 741 1253; fax: +82 33 748 1752. E-mail address: [email protected] (J.Y. Hong).

Early studies detected mutations in the GCH1 gene in 50–60% of Segawa disease cases, while a recent study found mutations in up to 87% [3]. Therefore, detecting mutations is becoming more important for confirming the diagnosis of Segawa disease. To date, more than 130 mutations associated with Segawa disease have been reported; and additional mutations continue to be found [4]. Here, we report a novel missense mutation in the GCH1 gene in a Korean Segawa disease family. 2. Case report A 15-year-old male was admitted our hospital for gait disturbance. He had developed normally and had no remarkable past medical history. His parent and elder brother had no medical history including neuromuscular

http://dx.doi.org/10.1016/j.braindev.2014.05.008 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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Fig. 1. Positron emission tomography using 18F-FP-CIT shows normal dopamine transporter activity in the striatum bilaterally (A).

and congenital metabolic disorders. He had two uncles, one aunt, and three cousins on his father’s side, and one uncle, three aunts, and six cousins on his mother’s side. The patient and his parents reported that none of the relatives had remarkable history. His walking difficulty developed at the age of 10 years and progressed gradually. The difficulty was absent after nocturnal sleep, but appeared toward afternoon. Physical exercise worsened the gait disturbance, whereas some rest relieved the symptom. He had visited other hospitals in the first 2 years after symptom onset. There were no

abnormal findings in brain magnetic resonance imaging (MRI), spinal MRI, nerve conduction studies, or electromyography. Hence, he remained undiagnosed and untreated before admission to our department. The neurological examination showed dystonia of both feet and bradykinesia of all four extremities. His dystonia was more prominent in the left foot, where it caused pes equinovarus. A pharmacological test with 100 mg of levodopa plus 25 mg of carbidopa (SinemetÒ 25 mg/100 mg) improved the foot dystonia and gait disturbance dramatically. Positron emission tomography (PET) using 18F-FPCIT revealed normal dopamine transporter activity in the striatum bilaterally (Fig. 1). A genetic study revealed a novel missense variation in the GCH1 gene at c.623C>A in exon 5 (Fig. 2), which resulted in an amino acid change from alanine to glutamate (Ala208Glu). After giving informed consent, his parents and brother underwent genetic studies. An identical variation was found in the proband’s father. To assess the functional effect of the novel variation, we performed multiple sequence alignment of GCH1 proteins using ClustalW [5] and in silico analysis using the SIFT and Polyphen software based on the information obtained from UniProtKB [6]. Multiple sequence alignment revealed that Ala-208 is a highly conserved residue, indicating that it might be important for the function of GCH1 (Fig. 3), and the mutation was predicted to be “Damaging” by SIFT and “Probably damaging” by Polyphen. We prescribed 100 mg of levodopa plus 25 mg of carbidopa three times per day. His symptoms and signs disappeared within 1 week of starting the medication, and the improvement has been maintained without any adverse events for 1 year.

Fig. 2. The sequencing chromatograms of proband revealed c.623C>A in exon 5 of the GCH1 gene.

Fig. 3. Comparison of the amino acid sequences of GCH1 in different species indicates high level of conservation of A208 residue.

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3. Discussion

References

Our patient showed a characteristic symptom of Segawa disease, dramatic response to levodopa. The PET scan revealed normal dopamine transporter activity, which suggested that patient’s clinical symptoms did not caused by juvenile Parkinson disease [7]. A genetic study demonstrated a novel missense variation in exon 5 of GCH1 gene, and the in silico analysis also predicted that protein function was probably damaged. A previous biochemical study revealed that amino acids Cys-141, His-144, and Cys-212 are the active sites of GTP cyclohydrolase 1, and that Ala-208 is in the b-sheet structure extending to Cys-212 [8]. Moreover, reports have shown loss of enzymatic function in mutations of Val205Gly and His210Gln located in the same b-sheet [9,10]. Therefore, the amino acid change Ala208Glu in our patient might result in malfunction of GTP cyclohydrolase 1 via structural deformation. For detection rate of genetic mutation is growing, genetic study is becoming more important in diagnosing Segawa disease. Furthermore, CSF pterin analysis is not available in many clinical settings and sometimes patients refuse spinal tapping. However, detecting genetic variation does not convince the dysfunction of relevant protein or enzyme. Recently, several programs help predicting the functional effect of genetic variations. In this case, programs for multiple sequence alignment and in silico analysis revealed predicted dysfunction of GTP cyclohydrolase and highly conserved Ala-208 residue. Although the genetic study revealed an identical mutation in the proband’s father, there was no family history on father’s side. Several studies of large families with Segawa disease have found a reduced penetrance of 27–53% [11,12], and the penetrance is markedly lower in males [12]. In this study, the genetic study examined in only the proband’s parents and brother. However it is possible that other relatives carry the mutation.

[1] Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 1976;14:215–33. [2] Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994;8:236–42. [3] Hagenah J, Saunders-Pullman R, Hedrich K, Kabakci K, Habermann K, Wiegers K, et al. High mutation rate in doparesponsive dystonia: detection with comprehensive GCHI screening. Neurology 2005;64:908–11. [4] Blau N, Thony B. BIOMDBdb. http://www.biopku.org/biomdb/ search-results.asp. [5] Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 2003;31:3497–500. [6] UniProt Consortium. http://www.ebi.uniprot.org/; Swiss-Prot code/ UniProtKB number: P30793. [7] Jeon BS, Jeong JM, Park SS, Kim JM, Chang YS, Song HC, et al. Dopamine transporter density measured by [123I]beta-CIT single-photon emission computed tomography is normal in dopa-responsive dystonia. Ann Neurol 1998;43:792–800. [8] Auerbach G, Herrmann A, Bracher A, Bader G, Gutlich M, Fischer M, et al. Zinc plays a key role in human and bacterial GTP cyclohydrolase I. Proc Natl Acad Sci USA 2000;97: 13567–72. [9] De Rosa A, Carducci C, Antonozzi I, Giovanniello T, Xhoxhi E, Criscuolo C, et al. A novel mutation in GCH-1 gene in a case of dopa-responsive dystonia. J Neurol 2007;254:1133–4. [10] Garavaglia B, Invernizzi F, Carbone ML, Viscardi V, Saracino F, Ghezzi D, et al. GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations. J Inherit Metab Dis 2004;27:455–63. [11] Nygaard TG, Trugman JM, de Yebenes JG, Fahn S. Doparesponsive dystonia: the spectrum of clinical manifestations in a large North American family. Neurology 1990;40:66–9. [12] Souza CP, Valadares ER, Trindade AL, Rocha VL, Oliveira LR, Godard AL. Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family. Genet Mol Res 2008;7:687–94.

A novel missense mutation in GCH1 gene in a Korean family with Segawa disease.

Segawa disease is a rare disorder presenting gait disturbance and dystonia with marked fluctuation, and caused by GTP cyclohydrolase 1 (GCH1) deficien...
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