Brief Communication
Growth Hormone Deficiency in a Dopa-Responsive Dystonia Patient With a Novel Mutation of Guanosine Triphosphate Cyclohydrolase 1 Gene
Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538498 jcn.sagepub.com
Yu Lin, MD, PHD1, Dan-Ni Wang, MD1, Wan-Jin Chen, MD, PhD1,2, Xiang Lin, MD1, Min-Ting Lin1, and Ning Wang, MD, PhD1,2
Abstract Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency. Keywords growth hormone deficiency, dopa-responsive dystonia, guanosine triphosphate cyclohydrolase 1 Received January 08, 2014. Received revised April 21, 2014. Accepted for publication May 07, 2014.
The autosomal dominant dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene.1 The GCH1 protein is involved in the biosynthesis of tetrahydrobiopterin (BH4), which is the primary cofactor for tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of dopamine.2 This condition is characterized by marked diurnal fluctuation and a dramatic response to levodopa,3 mainly involving dystonia of lower legs in childhood. Some patients also exhibit dystonic movement of upper extremities and neck.4 However, growth retardation in dopa-responsive dystonia has rarely been reported.5 In addition, there are only few studies on the etiology of short stature in dopa-responsive dystonia patients. In this study, we reported a short dopa-responsive dystonia patient with a novel mutation in GCH1 and demonstrated growth hormone deficiency.
experienced the same symptom in his left leg and right arm; these symptoms were mild in the morning but worsened toward the afternoon. Moreover, his parents noticed that the patient was shorter than his peers. His symptom was not diagnosed after consulting with several hospitals. The patient then consulted our neurology department. Clinical examination showed dystonia in both legs and exaggerated deep tendon reflexes without ankle clonus. Babinski reflexes were absent. His height was 146 cm (normal range between 3rd and 97th percentile in Chinese children is 152.3-179.4 cm) and weight was 35.5 kg (normal range between 3rd and 97th percentile in Chinese children is 37.36-77.2 kg).6 His body mass index was 16.65 kg/m2. He was pubertal: secondary sexual maturation had appeared and the testicular volume was 8 mL. 1
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China 2 Center of Neuroscience, Fujian Medical University, Fuzhou, China
Case Report The case was a 14-year-old boy born of a normal pregnancy and delivery. From the age of 12 years, he experienced a stiffness of the right leg and gait disturbance. After 2 years, he
Corresponding Author: Ning Wang, MD, PhD, Department of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, China 350005. Email: [email protected]
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
2
Journal of Child Neurology
Table 1. Endocrine Evaluation of the Patient.
T3 (pg/mL) T4 (pmol/L) TSH (mIU/mL) Plasma cortisol at 8:00 AM (nmol/L) ACTH (pg/mL) Peak LH in GnRH test (IU/L) Peak LH/FSH ratio in GnRH test Peak GH level responding to arginine 0.5 g/kg, iv (ng/mL) Peak GH level responding to levodopa 10 mg/kg, orally (ng/mL) Serum IGF-I (ng/mL)
Value
Normal range
3.2 23.6 0.928 328 12 17.9 4.1 9.77
1.5-4.1 8.3-29.6 0.4-5 138-690 0.00-46.00 5 0.6 >10
4.74
>10
334
350.89-850.45
Abbreviations: ACTH, adrenocorticotropin hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; iv, intravenously; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
Laboratory examinations, including routine blood examination, routine urine analysis, liver function test, renal function test and the levels of electrolytes, serum glucose, essential trace elements, bone alkaline phosphatase, and blood lead, were within normal limits. Endocrine evaluation shown in Table 1 revealed normal thyroid function, normal plasma cortisol, and adrenocorticotropin hormone (ACTH) level. Gonadotropin measured by the gonadotropin-releasing hormone simulation test (gonadorelin 2.5 mg/kg, intravenously) was at the pubertal level. Peak growth hormone levels responding to 2 provocative tests (arginine 0.5 g/kg, intravenously, and levodopa 10 mg/kg, orally) were lower than the normal value. The serum insulinlike growth factor I level was low (334 ng/mL; 2 SD) (Table1). Magnetic resonance imaging (MRI) scans of the brain, pituitary, and hypothalamus showed normal results. Abdominal ultrasonography demonstrated normal results. Bone age was retarded and compatible with that of a 13-year-old boy. The patient’s symptoms disappeared completely after levodopa treatment with a low dose of 125 mg/d for 3 days. He was followed up in our outpatient clinic and had grown 4 cm within 6 months. Moreover, his repeat insulin-like growth factor I had increased (487 ng/mL; –1 SD). In the family pedigree (Figure 1A), a different symptom was found in the boy’s father (aged 40 years). He developed posture tremor in his upper extremities and torticollis during adulthood. At the age of 40, the father’s symptom showed partial remission after the administration of levodopa/benserazide (200 mg/d levodopa and 50 mg/d benserazide) for 10 days. The boy’s mother was healthy. Both the parents had no growth arrest before adolescence, and their heights were within the standard range. Having the written informed consent, we extracted DNA from the peripheral blood of all family members and performed GCH1 gene analysis including 6 exons and the intron-exon boundaries by direct sequencing of PCR product as described in a previous study.7 In 2 subjects, a heterozygous mutation
Figure 1. Sequencing data for the GCH1 gene in the Chinese family with dopa-responsive dystonia. (A) Pedigrees of families with GCH1 mutation. (B) Sequencing chromatograms showing the wild-type and heterozygous G232V mutant in GCH1 sequence. In the mutant sequence, the position of the G-to-T transition at nucleotide position 695 (c.695G>T) results in the replacement of glycine (Gly) by valine (Val) at codon 232. (C) Sequence alignment of GCH1 in different species. The numbers at the top are related to the human amino acid sequence. Amino acid 232, the site of the G232V mutation, is indicated by the rectangle.
c.695G>T p.G232V in exon 6 of GCH1 was identified (Figure 1B), leading to a transition at codon 232 from glycine to valine (Gly232Val). This mutation was not found in the Human Gene Mutation Database (http://www.hgmd.org), indicating that it is a novel missense mutation. Neither the boy’s mother nor 100 Chinese healthy controls carried this novel mutation. The mutation site was found to be conserved among species after analyzing the phylogenetic conservation using Clustal W (http:// www.genome.jp/tools/clustalw/) (Figure 1C). The variant c.695G>T is probably pathogenetic, as predicted by SIFT (http://sitf.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/ pph/), and mutation taster (http://www.mutationtaster.org).
Discussion This study describes a novel mutation in GCH1 in a Chinese family, thus expanding the spectrum of mutations associated with dopa-responsive dystonia. Glycine 232 is highly conserved in evolution; it is involved in the formation of C-terminal b-strand of GTPCH1 monomer.8 The Gly232Val substitution may interfere with polymerization of decamer structure of the GCH1 protein.9 Consequently, the mutation may impair enzymatic activity. The evaluation for growth hormone deficiency in a short child should first exclude other causes of growth failure,10 such as organic disease or metabolic or chromosomal disorders. According to the laboratory and imaging results of the patient, hypothyroidism, liver and renal disorders, Cushing syndrome or disorders of calcium and phosphorus metabolism were
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
Lin et al
3 responsive dystonia as well as a dopa-responsive dystonia patient with growth failure resulting from growth hormone deficiency. Although the pathogenetic relationship between growth hormone deficiency and dopa-responsive dystonia is unknown, our case revealed a rare feature for doparesponsive dystonia. We recommend treatment with levodopa as the first choice in dopa-responsive dystonia children with growth hormone deficiency. Acknowledgments
Figure 2. Possible pathways of dopamine and arginine action that modulate growth hormone secretion. Dopamine and arginine may cause somatostatin reduction. Declined somatostatin may facilitate growth hormone–releasing hormone action. Increased growth hormone–releasing hormone levels further evoke secretion of growth hormone.
excluded. The boy exhibited deficits in body length, delayed bone age, decreased insulin-like growth factor I, and reduced peak serum levels of growth hormone following 2 provocative tests. These clinical findings confirmed the diagnosis of growth hormone deficiency. Although short stature has been described in dopa-responsive dystonia subjects,5 our patient is the first case with documented growth hormone deficiency. However, a possible linkage between the pathogenesis of the 2 conditions might be hypothesized. It is generally accepted that growth hormone release is regulated by many neurotransmitters, including dopamine. Dopaminergic stimulation of growth hormone secretion may increase the levels of growth hormone–releasing hormone probably via somatostatin withdrawal in hypothalamus (Figure 2).11 Consequently, the growth retardation that results from inadequate growth hormone secretion seems to be initiated by dopamine deficiency in dopa-responsive dystonia patients. Interestingly, the boy’s father who carried the same mutation in GCH1 gene had no growth arrest. The cause of the absence of growth retardation in the father is still unknown. However, growth hormone deficiency as in our patient with doparesponsive dystonia may be an incidental finding. Further studies with more cases are required to confirm the existence of a pathogenetic link between dopa-responsive dystonia and growth hormone deficiency. Growth hormone supplementation is recommended for children with growth hormone deficiency.10 Interestingly, after treatment with levodopa for 6 months, our patient’s height increased by 4 cm and his serum insulin-like growth factor I levels also increased. These observations indicate that levodopa is beneficial for the physical growth of dopa-responsive dystonia patients before disappearance of the epiphyseal line; this is in concordance with the reports of a previous study.12 Thus, for dopa-responsive dystonia patients with growth hormone deficiency, we suggest levodopa as the first choice of treatment, with the alternative of a growth hormone injection. In conclusion, we reported a novel mutation responsible for impairing GCH1 activity in a Chinese family with dopa-
The authors sincerely thank the patients for their participation in this study.
Author Contributions NW conceived and designed the study. YL, D-NW, and XL are responsible for data acquisition. YL and D-NW drafted the manuscript. W-JC and NW critically reviewed the manuscript for important intellectual content. YL and NW obtained funding. W-JC, XL, and MTL were responsible for administrative, technical, or material support. NW supervised the study. YL and D-NW contributed equally to this work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the National Natural Science Foundation of China (grant no. 81100838), the Natural Science Foundation of Fujian Province of China (grant no. 2011J05063), and the National key clinical specialty discipline construction program of China.
Ethical Approval This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University(IRB number: FYYY2013-02-20-09).
References 1. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994;8:236-242. 2. Nagatsu T, Levitt M, Udenfriend S. Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem. 1964; 239:2910-2917. 3. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol. 1988;50:377-384. 4. Segawa M.Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5). Chang Gung Med J. 2009;32:1-11. 5. Segawa M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 2000;22(suppl 1):S65-S80. 6. Li H, Ji CY, Zong XN, Zhang YQ. Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Chinese J Pediatr. 2009;47:487-492.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
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Journal of Child Neurology
7. Xie H, Wu ZY, Wang N, Li ZW, Lin MT, Murong SX. Clinical analysis of dopa-responsive dystonia and mutation analysis of the GCH I gene. Chinese J Pediatr. 2006;44:492-495. 8. Swick L, Kapatos G. A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions. J Neurochem. 2006;97: 1447-1455. 9. Nar H, Huber R, Meining W, Schmid C, Weinkauf S, Bacher A. Atomic structure of GTP cyclohydrolase I. Structure. 1995;3: 459-466.
10. Growth Hormone Research S. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85:3990-3993. 11. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev. 1998;19:717-797. 12. Segawa M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 2011;33:195-201.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
Growth Hormone Deficiency in a Dopa-Responsive Dystonia Patient With a Novel Mutation of Guanosine Triphosphate Cyclohydrolase 1 Gene
Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538498 jcn.sagepub.com
Yu Lin, MD, PHD1, Dan-Ni Wang, MD1, Wan-Jin Chen, MD, PhD1,2, Xiang Lin, MD1, Min-Ting Lin1, and Ning Wang, MD, PhD1,2
Abstract Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency. Keywords growth hormone deficiency, dopa-responsive dystonia, guanosine triphosphate cyclohydrolase 1 Received January 08, 2014. Received revised April 21, 2014. Accepted for publication May 07, 2014.
The autosomal dominant dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene.1 The GCH1 protein is involved in the biosynthesis of tetrahydrobiopterin (BH4), which is the primary cofactor for tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of dopamine.2 This condition is characterized by marked diurnal fluctuation and a dramatic response to levodopa,3 mainly involving dystonia of lower legs in childhood. Some patients also exhibit dystonic movement of upper extremities and neck.4 However, growth retardation in dopa-responsive dystonia has rarely been reported.5 In addition, there are only few studies on the etiology of short stature in dopa-responsive dystonia patients. In this study, we reported a short dopa-responsive dystonia patient with a novel mutation in GCH1 and demonstrated growth hormone deficiency.
experienced the same symptom in his left leg and right arm; these symptoms were mild in the morning but worsened toward the afternoon. Moreover, his parents noticed that the patient was shorter than his peers. His symptom was not diagnosed after consulting with several hospitals. The patient then consulted our neurology department. Clinical examination showed dystonia in both legs and exaggerated deep tendon reflexes without ankle clonus. Babinski reflexes were absent. His height was 146 cm (normal range between 3rd and 97th percentile in Chinese children is 152.3-179.4 cm) and weight was 35.5 kg (normal range between 3rd and 97th percentile in Chinese children is 37.36-77.2 kg).6 His body mass index was 16.65 kg/m2. He was pubertal: secondary sexual maturation had appeared and the testicular volume was 8 mL. 1
Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China 2 Center of Neuroscience, Fujian Medical University, Fuzhou, China
Case Report The case was a 14-year-old boy born of a normal pregnancy and delivery. From the age of 12 years, he experienced a stiffness of the right leg and gait disturbance. After 2 years, he
Corresponding Author: Ning Wang, MD, PhD, Department of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, China 350005. Email: [email protected]
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
2
Journal of Child Neurology
Table 1. Endocrine Evaluation of the Patient.
T3 (pg/mL) T4 (pmol/L) TSH (mIU/mL) Plasma cortisol at 8:00 AM (nmol/L) ACTH (pg/mL) Peak LH in GnRH test (IU/L) Peak LH/FSH ratio in GnRH test Peak GH level responding to arginine 0.5 g/kg, iv (ng/mL) Peak GH level responding to levodopa 10 mg/kg, orally (ng/mL) Serum IGF-I (ng/mL)
Value
Normal range
3.2 23.6 0.928 328 12 17.9 4.1 9.77
1.5-4.1 8.3-29.6 0.4-5 138-690 0.00-46.00 5 0.6 >10
4.74
>10
334
350.89-850.45
Abbreviations: ACTH, adrenocorticotropin hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; iv, intravenously; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
Laboratory examinations, including routine blood examination, routine urine analysis, liver function test, renal function test and the levels of electrolytes, serum glucose, essential trace elements, bone alkaline phosphatase, and blood lead, were within normal limits. Endocrine evaluation shown in Table 1 revealed normal thyroid function, normal plasma cortisol, and adrenocorticotropin hormone (ACTH) level. Gonadotropin measured by the gonadotropin-releasing hormone simulation test (gonadorelin 2.5 mg/kg, intravenously) was at the pubertal level. Peak growth hormone levels responding to 2 provocative tests (arginine 0.5 g/kg, intravenously, and levodopa 10 mg/kg, orally) were lower than the normal value. The serum insulinlike growth factor I level was low (334 ng/mL; 2 SD) (Table1). Magnetic resonance imaging (MRI) scans of the brain, pituitary, and hypothalamus showed normal results. Abdominal ultrasonography demonstrated normal results. Bone age was retarded and compatible with that of a 13-year-old boy. The patient’s symptoms disappeared completely after levodopa treatment with a low dose of 125 mg/d for 3 days. He was followed up in our outpatient clinic and had grown 4 cm within 6 months. Moreover, his repeat insulin-like growth factor I had increased (487 ng/mL; –1 SD). In the family pedigree (Figure 1A), a different symptom was found in the boy’s father (aged 40 years). He developed posture tremor in his upper extremities and torticollis during adulthood. At the age of 40, the father’s symptom showed partial remission after the administration of levodopa/benserazide (200 mg/d levodopa and 50 mg/d benserazide) for 10 days. The boy’s mother was healthy. Both the parents had no growth arrest before adolescence, and their heights were within the standard range. Having the written informed consent, we extracted DNA from the peripheral blood of all family members and performed GCH1 gene analysis including 6 exons and the intron-exon boundaries by direct sequencing of PCR product as described in a previous study.7 In 2 subjects, a heterozygous mutation
Figure 1. Sequencing data for the GCH1 gene in the Chinese family with dopa-responsive dystonia. (A) Pedigrees of families with GCH1 mutation. (B) Sequencing chromatograms showing the wild-type and heterozygous G232V mutant in GCH1 sequence. In the mutant sequence, the position of the G-to-T transition at nucleotide position 695 (c.695G>T) results in the replacement of glycine (Gly) by valine (Val) at codon 232. (C) Sequence alignment of GCH1 in different species. The numbers at the top are related to the human amino acid sequence. Amino acid 232, the site of the G232V mutation, is indicated by the rectangle.
c.695G>T p.G232V in exon 6 of GCH1 was identified (Figure 1B), leading to a transition at codon 232 from glycine to valine (Gly232Val). This mutation was not found in the Human Gene Mutation Database (http://www.hgmd.org), indicating that it is a novel missense mutation. Neither the boy’s mother nor 100 Chinese healthy controls carried this novel mutation. The mutation site was found to be conserved among species after analyzing the phylogenetic conservation using Clustal W (http:// www.genome.jp/tools/clustalw/) (Figure 1C). The variant c.695G>T is probably pathogenetic, as predicted by SIFT (http://sitf.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/ pph/), and mutation taster (http://www.mutationtaster.org).
Discussion This study describes a novel mutation in GCH1 in a Chinese family, thus expanding the spectrum of mutations associated with dopa-responsive dystonia. Glycine 232 is highly conserved in evolution; it is involved in the formation of C-terminal b-strand of GTPCH1 monomer.8 The Gly232Val substitution may interfere with polymerization of decamer structure of the GCH1 protein.9 Consequently, the mutation may impair enzymatic activity. The evaluation for growth hormone deficiency in a short child should first exclude other causes of growth failure,10 such as organic disease or metabolic or chromosomal disorders. According to the laboratory and imaging results of the patient, hypothyroidism, liver and renal disorders, Cushing syndrome or disorders of calcium and phosphorus metabolism were
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
Lin et al
3 responsive dystonia as well as a dopa-responsive dystonia patient with growth failure resulting from growth hormone deficiency. Although the pathogenetic relationship between growth hormone deficiency and dopa-responsive dystonia is unknown, our case revealed a rare feature for doparesponsive dystonia. We recommend treatment with levodopa as the first choice in dopa-responsive dystonia children with growth hormone deficiency. Acknowledgments
Figure 2. Possible pathways of dopamine and arginine action that modulate growth hormone secretion. Dopamine and arginine may cause somatostatin reduction. Declined somatostatin may facilitate growth hormone–releasing hormone action. Increased growth hormone–releasing hormone levels further evoke secretion of growth hormone.
excluded. The boy exhibited deficits in body length, delayed bone age, decreased insulin-like growth factor I, and reduced peak serum levels of growth hormone following 2 provocative tests. These clinical findings confirmed the diagnosis of growth hormone deficiency. Although short stature has been described in dopa-responsive dystonia subjects,5 our patient is the first case with documented growth hormone deficiency. However, a possible linkage between the pathogenesis of the 2 conditions might be hypothesized. It is generally accepted that growth hormone release is regulated by many neurotransmitters, including dopamine. Dopaminergic stimulation of growth hormone secretion may increase the levels of growth hormone–releasing hormone probably via somatostatin withdrawal in hypothalamus (Figure 2).11 Consequently, the growth retardation that results from inadequate growth hormone secretion seems to be initiated by dopamine deficiency in dopa-responsive dystonia patients. Interestingly, the boy’s father who carried the same mutation in GCH1 gene had no growth arrest. The cause of the absence of growth retardation in the father is still unknown. However, growth hormone deficiency as in our patient with doparesponsive dystonia may be an incidental finding. Further studies with more cases are required to confirm the existence of a pathogenetic link between dopa-responsive dystonia and growth hormone deficiency. Growth hormone supplementation is recommended for children with growth hormone deficiency.10 Interestingly, after treatment with levodopa for 6 months, our patient’s height increased by 4 cm and his serum insulin-like growth factor I levels also increased. These observations indicate that levodopa is beneficial for the physical growth of dopa-responsive dystonia patients before disappearance of the epiphyseal line; this is in concordance with the reports of a previous study.12 Thus, for dopa-responsive dystonia patients with growth hormone deficiency, we suggest levodopa as the first choice of treatment, with the alternative of a growth hormone injection. In conclusion, we reported a novel mutation responsible for impairing GCH1 activity in a Chinese family with dopa-
The authors sincerely thank the patients for their participation in this study.
Author Contributions NW conceived and designed the study. YL, D-NW, and XL are responsible for data acquisition. YL and D-NW drafted the manuscript. W-JC and NW critically reviewed the manuscript for important intellectual content. YL and NW obtained funding. W-JC, XL, and MTL were responsible for administrative, technical, or material support. NW supervised the study. YL and D-NW contributed equally to this work.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the National Natural Science Foundation of China (grant no. 81100838), the Natural Science Foundation of Fujian Province of China (grant no. 2011J05063), and the National key clinical specialty discipline construction program of China.
Ethical Approval This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University(IRB number: FYYY2013-02-20-09).
References 1. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994;8:236-242. 2. Nagatsu T, Levitt M, Udenfriend S. Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem. 1964; 239:2910-2917. 3. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol. 1988;50:377-384. 4. Segawa M.Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5). Chang Gung Med J. 2009;32:1-11. 5. Segawa M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 2000;22(suppl 1):S65-S80. 6. Li H, Ji CY, Zong XN, Zhang YQ. Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Chinese J Pediatr. 2009;47:487-492.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
4
Journal of Child Neurology
7. Xie H, Wu ZY, Wang N, Li ZW, Lin MT, Murong SX. Clinical analysis of dopa-responsive dystonia and mutation analysis of the GCH I gene. Chinese J Pediatr. 2006;44:492-495. 8. Swick L, Kapatos G. A yeast 2-hybrid analysis of human GTP cyclohydrolase I protein interactions. J Neurochem. 2006;97: 1447-1455. 9. Nar H, Huber R, Meining W, Schmid C, Weinkauf S, Bacher A. Atomic structure of GTP cyclohydrolase I. Structure. 1995;3: 459-466.
10. Growth Hormone Research S. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85:3990-3993. 11. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev. 1998;19:717-797. 12. Segawa M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 2011;33:195-201.
Downloaded from jcn.sagepub.com at Bobst Library, New York University on April 16, 2015
