Short communicationDopa-responsive infantile hypokinetic rigid syndrome due to dominant guanosine triphosphate cyclohydrolase 1 deficiency
Introduction
GTP cyclohydrolase 1 (GTPCH) is encoded by the GCH-1 gene, located on chromosome 14q22.1-q22.2. Patients heterozygous for GCH-1 mutations develop dopa-responsive dystonia (DRD) [1]. DRD may be classified into three groups: 1) autosomal dominant GTPCH deficiency (adGTPCH); 2) tyrosine hydroxylase (TH) deficiency; 3) other forms of BH4 deficiency (autosomal recessive GTPCH deficiency, 6-pyruvoyl-tetrahydropterin synthase, dihydropteridine reductase and sepiapterin reductase) [2]. DRD due to adGTPCH deficiency typically presents insidiously between the ages of 1 and 9 years with a diurnally fluctuating dystonia of one limb spreading to the other extremities after several years, together with subsequent parkinsonian signs in adult ages. Some atypical cases presenting with an isolated parkinsonian state with onset in middle age have been reported [3], [4], [5], [6], [7], [8]. Levodopa-responsive infantile hypokinetic rigid syndrome due to mutations in the TH gene has been described [9], [10]. Nevertheless, to our knowledge, infantile hypokinetic rigid syndrome due to adGTPCH deficiency has not been previously reported. We describe a case of adGTPCH deficiency who presented with an infantile hypokinetic rigid syndrome and delay in attainment of early motor milestones, thus expanding the clinical spectrum of Segawa disease.
Section snippets
Neurological examination
Dystonia and parkinsonism were classified according to Nygaard et al. and Uncini et al. [3], [7].
Samples from patients were obtained in accordance with the Helsinki Declaration of 1964, as revised in 2000. Informed consent for the study was obtained from the adult and adolescent patients themselves and from the parents of the children.
Biochemical studies
Biogenic amine metabolites (5-hydroxyindoleacetic and homovanilic acids) and pterines (neopterin and biopterin) in cerebrospinal fluid (CSF) were analysed by HPLC
Case report
The patient was born to healthy nonconsanguineous parents after an uneventful pregnancy at term and delivery (birth weight 3.130 g, length 49 cm, head circumference 34 cm). His mental and motor developments were considered normal until the age of 7 months, when a delay in attainment of early motor milestones became evident. At age 17 months he had generalized rigidity and had very little spontaneous movement. He could not sit, crawl, walk or stand by himself and was referred to our department
Discussion
We describe a case of DRD presenting with infantile hypokinetic rigid syndrome and delay in attainment of motor milestones. The patient was heterozygous for the mutation Q89X in exon 1 of GCH-1. This mutation was first described and confirmed with restriction-enzyme digestion by Hoenicka et al. in an unrelated Spanish family from the same region of southern Spain, affected with DRD and parkinsonism and studied in our center [13]. Q89X consists of a 265C to T transition that creates a premature
Acknowledgments
This study was partially supported by grants Redemeth (G03/054), Inergen (C03/05) and PI051318 from FIS (Ministerio de Sanidad, Spain). We extend our sincere thanks to Dr. Masaya Segawa and Dr. Emilio Fernández-Álvarez for their advice in the preparation of this manuscript.
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Cited by (16)
Genetic landscape of Segawa disease in Spain. Long-term treatment outcomes
2022, Parkinsonism and Related DisordersCitation Excerpt :Eighty subjects (49 female and 31 male) belonging to 24 pedigrees were included in the study (Fig. 1). Twenty-six cases have been updated since earlier reports [9,14–17]. Fifty-six AD-GTPCHD individuals (70%) were identified as symptomatic, with a higher penetrance observed in women (symptomatic female:male ratio 2:1).
Early-onset autosomal dominant GTP-cyclohydrolase I deficiency: Diagnostic delay and residual motor signs
2021, Brain and DevelopmentCitation Excerpt :For these 61 articles, each patient’s details were checked to identify patients with early-onset AD GCH1 deficiency (onset before the age of 15 years old) and description of RMS. A total of 137 DRD patients satisfied the inclusion criteria for analysis (Fig. 1, Table 2) [12–70]. The mean age of symptom onset was 6.7 years (range 0–15), and the mean age of treatment initiation was 21.5 (range 1.5–75) years.
Clinical Phenomenology and Genetics of Other Parkinsonian Syndromes Associated with Either Dystonia or Spasticity
2015, Movement Disorders: Genetics and Models: Second EditionHypokinetic-rigid syndrome in children and inborn errors of metabolism
2011, European Journal of Paediatric NeurologyCitation Excerpt :Dopa-responsive dystonia was initially used as a synonymous of Segawa disease, however this sign, whether isolated or not, can be also found in almost all inherited dopaminergic defects. On the other hand, childhood-onset parkinsonism has also been described in Segawa disease.6 The most important biochemical tests for the diagnosis of these neurological diseases are cerebrospinal fluid investigations of neurotransmitter metabolites and pterins.
Dopa-responsive dystonia
2011, Handbook of Clinical NeurologyCitation Excerpt :Since the discovery of the causative gene, phenotypical variation of AD GCH-1 deficiency has greatly expanded (Bandmann et al., 1996, 1998). Phenotypic variation is further expanded by studies of early-onset cases (Lopez-Laso et al., 2007; Nagata et al., 2007; Cheyette et al., 2008), families with psychiatric disorders (Van Hove et al., 2006), compound heterozygotes (Furukawa et al., 1998a), and a case with dopa-responsive myoclonus-dystonia syndrome (Leuzzi et al., 2002). Considerable attention has been paid to whether postural or action dystonia is present, and to patients with postural hypotonia and psychological disorders.
Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines
2021, Nature Communications