Dopa-responsive infantile hypokinetic rigid syndrome due to dominant guanosine triphosphate cyclohydrolase 1 deficiency

doi:10.1016/j.jns.2007.02.007

Journal of the Neurological Sciences

Volume 256, Issues 1–2, 15 May 2007, Pages 90-93

https://doi.org/10.1016/j.jns.2007.02.007 Get rights and content

Abstract

We report on a GTP cyclohydrolase 1 mutation-confirmed heterozygous case presenting with an infantile hypokinetic rigid syndrome and delay in attainment of motor milestones starting from the first year of life. He had a family history of dopa-responsive dystonia-parkinsonism. CSF neopterin, biopterin and HVA values were decreased. Molecular study of GCH-1 gene showed the Q89X mutation in exon 1. Treatment with l-dopa resulted in a complete remission of symptoms.

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 Disorders
Citation 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).
In 2009, we described a possible founder effect of autosomal dominant Segawa disease in Córdoba (Spain) due to mutation c.265C>T (p. Q89*) in the GCH1 gene. We present a retrospective multicentre study aimed at improving our knowledge of Segawa disease in Spain and providing a detailed phenotypic-genotypic description of patients.
Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals.
Eighty subjects belonging to 24 pedigrees had heterozygous mutations in GCH1. Seven genetic variants have been described only in our cohort of patients, 5 of which are novel mutations. Five families not previously described with p. Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0–16). The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in the phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with a levodopa/decarboxylase inhibitor for (mean ± SD) 12.4 ± 8.12 years, with 81% at doses lower than 350 mg/day (≤5 mg/kg/d in children). Eleven of 53 (20%) patients had nonresponsive symptoms that affected daily life activities. Dyskinesias (4 subjects) were the most prominent adverse effects.
This study identifies 5 novel mutations and supports the hypothesis of a founder effect of p. Q89* in Andalusia. New insights are provided for the phenotypes and long-term treatment responses, which may improve early recognition and therapeutic management.
Early-onset autosomal dominant GTP-cyclohydrolase I deficiency: Diagnostic delay and residual motor signs
2021, Brain and Development
Citation 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.
Autosomal dominant (AD) guanosine triphosphate cyclohydrolase 1 (GCH1) deficiency is the most common cause of dopa-responsive dystonia (DRD). Patients with GCH1 deficiency are likely to experience diagnostic delay, but its consequences have not been described thoroughly in patients with early-onset disease. We describe the diagnostic delay and residual motor signs (RMS) observed in patients with early-onset (before 15 years of age) disease.
Twelve patients with early-onset AD GCH1 deficiency from a single center were included in the case series analysis. For the meta-analysis, the PubMed database was searched for articles on early-onset AD GCH1 deficiency published from 1995 to 2019.
In the case series, the mean duration of diagnostic delay was 5.6 years. Two patients exhibited RMS, and four patients underwent orthopedic surgery. The literature search yielded 137 AD GCH1 deficiency cases for review; gait disturbance was reported in 92.7% of patients, diurnal fluctuation of symptoms in 91.9%, and RMS in 39%. The mean duration of diagnostic delay was 14.6 years overall: 12.0 years in RMS-negative patients and 21.2 years in RMS-positive patients.
Diagnostic delay in early-onset AD GCH1 deficiency is more closely associated with later RMS. Early clinical suspicion, timely diagnosis, and levodopa treatment may reduce the occurrence of RMS in patients with early-onset AD GCH1 deficiency.
Clinical Phenomenology and Genetics of Other Parkinsonian Syndromes Associated with Either Dystonia or Spasticity
2015, Movement Disorders: Genetics and Models: Second Edition
Parkinsonism is a hypokinetic movement disorder. In its classic presentation, it is characterized by rest tremor, rigidity, bradykinesia, and postural instability. However, the phenotypic range of parkinsonism is broad. It includes idiopathic Parkinson disease (PD), which may present as akinetic rigid, tremor-dominant, or intermediate type; with more or less nonmotor involvement and individual rates of progression. Atypical forms of primary parkinsonism have been recognized, including multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, which will be briefly introduced with regard to their typical clinical presentation and the contribution of genetic factors. Furthermore, other less common conditions with a focus on inherited disorders that may mimic idiopathic PD or present with signs of parkinsonism, sometimes as part of complex syndromes, will be reviewed.
Hypokinetic-rigid syndrome in children and inborn errors of metabolism
2011, European Journal of Paediatric Neurology
Citation 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.
Hypokinetic-rigid syndrome (HRS) or “parkinsonism” is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits.
Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age.
Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases.
In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism.
Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided.
Dopa-responsive dystonia
2011, Handbook of Clinical Neurology
Citation 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.
Clinical characteristics and pahophysiologies of dopa-responsive dystonia are discussed by reviewing autosomal-dominant GTP cyclohydrolase-I deficiency (AD GCHI D), recessive deficiencies of enzymes of pteridine metabolism, and recessive tyrosine hydroxylase (TH).
Pteridine and TH metabolism involve TH activities in the terminals of the nigrostriatal dopamine neuron which show high in early childhood and decrease exponentially with age, attaining stational low levels by the early 20s.
In these disorders, TH in the terminals follows this course with low levels and develops particular symptoms with functional maturation of the downstream structures of the basal ganglia; postural dystonia through the direct pathway and descending output matured earlier in early childhood and parkinsonism in TH deficiency in teens through the D2 indirect pathway ascending output matured later.
In action-type AD GCHI D, deficiency of TH in the terminal on the subthalamic nucleus develops action dystonia through the descending output in childhood, focal and segmental dystonia and parkinsonism in adolescence and adulthood through the ascending pathway maturing later.
Dysfunction of dopamine in the terminals does not cause degenerative changes or higher cortical dysfunction. In recessive disorders, hypofunction of serotonin and noradrenaline induces hypofunction of the dopamine in the perikaryon and shows cortical dysfunction.
Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines
2021, Nature Communications

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Short communicationDopa-responsive infantile hypokinetic rigid syndrome due to dominant guanosine triphosphate cyclohydrolase 1 deficiency

Abstract

Introduction

Section snippets

Neurological examination

Biochemical studies

Case report

Discussion

Acknowledgments

J Neurosci Methods

Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene

Nat Genet

Tetrahydrobiopterin deficiencies and movement disorders

Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family

Neurology

Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia

Ann Neurol

Lessons from a remarkable family with dopa-responsive dystonia

J Neurol Neurosurg Psychiatry

Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture?

J Neurol Neurosurg Psychiatry

Short communication
Dopa-responsive infantile hypokinetic rigid syndrome due to dominant guanosine triphosphate cyclohydrolase 1 deficiency