Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients

TLDR: The study describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specificlevodopa-resistant symptoms.

Abstract: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower limb dystonia, diurnal fluctuations, and excellent response to levodopa has been well recognized in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow up of genetically proven cases. We present a detailed clinical evaluation of 34 patients (19 women, 15 men) with confirmed mutations in the GCH1 gene. We found that the classic phenotype was most frequent (n=23), with female predominance (F:M=16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n=4), or with an adult-onset (mean 37 years) Parkinson's disease-like phenotype (n=4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. We also describe a number of supplementary features including restless legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder, and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). We report that levodopa was used effectively and safely in 20 pregnancies, and did not cause any foetal abnormalities.

Figures

Table 2: Summary of the clinical characteristics of our 34 patients with DRD due to a GTPCH1 mutation (1 male patient could not state age of onset and initial symptoms)

Table 3: Four main groups of phenotypes according to age at onset, initial symptoms, natural course of disease prior to treatment, and response to levodopa (n=33; 1 patient could not state age at onset or initial symptoms)

Table 1: Mutations in the GCH1 gene found in the 34 DRD cases included in this study.

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Autosomal-dominant GTPCH1-decient DRD: clinical
characteristics and long-term outcome of 34 patients
Iris Trender-Gerhard, Mary G Sweeney, Petra Schwingenschuh, Pablo Mir,
Mark J Edwards, Alexander Gerhard, James M Polke, Mike G Hanna, Mary
B Davis, Nick W Wood, et al.
To cite this version:
Iris Trender-Gerhard, Mary G Sweeney, Petra Schwingenschuh, Pablo Mir, Mark J Edwards, et al..
Autosomal-dominant GTPCH1-decient DRD: clinical characteristics and long-term outcome of 34
patients. Journal of Neurology, Neurosurgery and Psychiatry, BMJ Publishing Group, 2009, 80 (8),
pp.839. �10.1136/jnnp.2008.155861�. �hal-00552711�

1
Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term
outcome of 34 patients
Iris Trender-Gerhard
1
, MD, Mary G. Sweeney
2
, PhD, Petra Schwingenschuh
1,3
, MD, Pablo
Mir
1, 4
, PhD, Mark J. Edwards
1
, PhD, Alexander Gerhard
5
, PhD, James M. Polke
2
, PhD, Mike
G. Hanna
6
, MD, Mary B. Davis
2
, PhD, Nick W. Wood
2
, PhD, and Kailash P. Bhatia
1
, MD
1
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology,
Queen Square, London, UK;
2
Department of Molecular Neuroscience, Institute of Neurology,
Queen Square, London, UK;
3
Department of Neurology, Medical University Graz, Austria;
4
Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospitales Universitarios
Virgen del Rocío, CIBERNED, Seville, Spain;
5
Wolfson Molecular Imaging Centre, The
University of Manchester, UK;
6
MRC Centre for Neuromuscular Disease, Institute of
Neurology, Queen Square, London, UK
Address for correspondence:
Address for Correspondence: Prof. KP Bhatia
Sobell Department
Institute of Neurology, UCL
Queen Square
London
WC1N 3BG
Tel: +44 207 837 3611 ext 4253
Fax: +44 207 676 2175
Email: k.bhatia@ion.ucl.ac.uk

2
The Corresponding Author has the right to grant on behalf of all authors and does grant on
behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group
Ltd and its Licensees to permit this article (if accepted) to be published in the Journal of
Neurology, Neurosurgery & Psychiatry editions and any other BMJPGL products to exploit
all subsidiary rights, as set in the licence (http://jnnp bmjjournals.com/ifora/licence.pdf).
Key words: Dopa-responsive dystonia, DRD, GTPCH1, treatment, pregnancy
Word Count:
Abstract: 267
Manuscript (excluding references, tables and figure legends): 3671
References: 36
Number of tables: 3

3
ABSTRACT
An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine
triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive
dystonia (DRD). A classic phenotype of young-onset lower limb dystonia, diurnal
fluctuations, and excellent response to levodopa has been well recognized in association with
GCH1 mutations, and rare atypical presentations have been reported. However, a number of
clinical issues remain unresolved including phenotypic variability, long-term response to
levodopa and associated non-motor symptoms, and there are limited data on long-term follow
up of genetically proven cases. We present a detailed clinical evaluation of 34 patients (19
women, 15 men) with confirmed mutations in the GCH1 gene. We found that the classic
phenotype was most frequent (n=23), with female predominance (F:M=16:7), and early onset
(mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients
developed craniocervical dystonia, with spasmodic dysphonia being the predominant
symptom in two subjects. A subset of patients, mainly men, presented with either a young-
onset (mean 6.8 years) mild DRD variant not requiring treatment (n=4), or with an adult-onset
(mean 37 years) Parkinson’s disease-like phenotype (n=4). Two siblings were severely
affected with early hypotonia and delay in motor development, associated with compound
heterozygous GCH1 gene mutations. We also describe a number of supplementary features
including restless legs-like symptoms, influence of female sex hormones, predominance of
tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent
episodes of depressive disorder, and specific levodopa-resistant symptoms (writer’s cramp,
dysphonia, truncal dystonia). We report that levodopa was used effectively and safely in 20
pregnancies, and did not cause any foetal abnormalities.

4
INTRODUCTION
Dopa-responsive dystonia (DRD) is an uncommon but treatable movement disorder caused in
about 50% of cases by an autosomal dominantly inherited defect in the gene GCH1 (14q22.1-
q22.2) that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1).[1, 2] So far more
than 112 different mutations have been identified in GCH1.[3, 4] GTPCH1 catalyzes the rate-
limiting step in tetrahydrobiopterin (BH4) biosynthesis, which itself is the essential cofactor
for production of tyrosine hydroxylase (TH), tryptophan hydroxylase, and phenylalanine
hydroxylase.[5] TH is the initial and rate-limiting enzyme in dopamine synthesis.[6] Patients
with autosomal-dominant GTPCH1-deficient DRD are usually heterozygote for a mutation in
GCH1 and therefore they have some residual GTPCH1 activity.[7]
A “classic” phenotype of DRD is recognised – onset in childhood with walking difficulties
due to lower limb dystonia progressing to generalised dystonia, diurnal fluctuation of
symptoms, concurrent or subsequent development of parkinsonism (mainly rigidity and
bradykinesia), and an excellent and sustained response to levodopa.[8]
The classic phenotype described above seems to account for the majority of patients, but a
number of cases have been reported with either an entirely different presentation or additional
clinical features, such as benign adult-onset parkinsonism, DRD simulating cerebral palsy or
spastic paraplegia and various types of focal dystonia.[2, 9-15] This is an important issue for
the clinician as DRD is both a rare disorder and also a very treatable one. Here we describe
the detailed clinical findings of 34 DRD patients (2 isolated cases, 32 familial cases from 16
different families) with mutations in the GCH1 gene. In each patient, we conducted a clinical
reassessment after genetic analysis with special emphasis on 4 aspects; 1) to report the
frequency of “classic” versus “atypical” phenotypes in our cohort; 2) to assess the long-term

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Autosomal-dominant gtpch1-deficient drd: clinical characteristics and long-term outcome of 34 patients" ?

The authors present a detailed clinical evaluation of 34 patients ( 19 women, 15 men ) with confirmed mutations in the GCH1 gene. The authors also describe a number of supplementary features including restless legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder, and specific levodopa-resistant symptoms ( writer ’ s cramp, dysphonia, truncal dystonia ). The authors report that levodopa was used effectively and safely in 20 pregnancies, and did not cause any foetal abnormalities. 

Q2. What future works have the authors mentioned in the paper "Autosomal-dominant gtpch1-deficient drd: clinical characteristics and long-term outcome of 34 patients" ?

However, the clinician should be aware of the possibility of both young presentation with very minor motor symptoms, or adult presentation ( particularly in males ) with symptoms and signs resembling young-onset Parkinson ’ s disease which led to misdiagnosis in their cohort. Based on the twenty pregnancies reported here, their data suggest that levodopa retains efficacy during pregnancy and was not associated with any foetal abnormalities. The authors have also found that controlled release levodopa or dopamine agonists can be useful in rare cases either in isolation or as adjuvant therapy. Further structured assessment of the nature of these symptoms and how they add to the clinical burden of DRD is needed so that appropriate assessment and treatment guidelines can be developed. 

Q3. What was the reason for the withdrawal of levodopa?

Cabergoline was added to levodopa in 4 subjects, but was withdrawn in 3 of them because of side effects or insufficient response. 

Q4. What was the initial dopaminergic drug used in all the patients?

In all the 27 patients requiring treatment, levodopa in combination with a decarboxylase inhibitor (DCI) was the initial dopaminergic drug. 

Q5. What was the predominant feature of the levodopa treatment?

Progression of symptoms prior to levodopa therapy Dystonia affected the legs in 94%, with upper limbs also involved in 88% (in the majority the dominant upper limb feature was focal hand dystonia). 

Q6. What did the patients experience before initiation of dopaminergic therapy?

Before initiation of dopaminergic therapy one third of their female patients experienced premenstrual or menstrual aggravation of symptoms. 

Q7. What is the phenotype of the second group of patients?

A second group of patients (n=4) have a young-onset “mild” phenotype with symptoms that start in childhood, but in contrast to the “classic” phenotype, remain very mild and often do not require treatment. 

Q8. What is the effect of BH4 on the phenotype of young-onset disease?

The female predominance in young-onset disease may reflect a higher vulnerability of the dopaminergic system to BH4 deficiency in females, particularly in early development. 

Q9. What are the clinical issues that remain unresolved?

a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow up of genetically proven cases. 

Q10. What did the patient report after taking levodopa?

One patient continued to have mild chorea and agitation half an hour after intake of 25 mg levodopa in the morning, and another patient reported severe levodopa induced mood swings. 

Q11. What type of DRD was found in the same compound heterozygote?

Lys224Arg had been found in one compound heterozygote (additional Gly108Asp mutation) reported by Furukawa presenting with the same disabling type of DRD with markeddevelopmental delay.[14] 

Q12. How many patients had excellent response to levodopa?

All but one patient required less than 600mg/d, with some patients having excellent response at less than 100mg/d. Immediateresponse was noted in all, even in longstanding severely disabled cases. 

Q13. What is the phenotype of a compound heterozygote?

This phenotype in compound heterozygotes for significant GCH1 mutations is clinically and biochemically intermediate between autosomal-dominant GTPCH1-deficient DRD (heterozygotes) and autosomal-recessive GTPCH1-deficiency (usually homozygotes) who develop BH4-dependent hyperphenylalaninemia in the first 6 months of life.[27] 

Q14. What is the common cause of dopa-responsive dystonia?

Key words: Dopa-responsive dystonia, DRD, GTPCH1, treatment, pregnancyWord Count: Abstract: 267 Manuscript (excluding references, tables and figure legends): 3671 References: 36 Number of tables: 3An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). 

Q15. What was the severity of the parkinsonian component in early-onset cases?

Despite longstanding illness and increasing age, the severity of the parkinsonian component in early-onset cases never exceeded the dystonic one.65% of patients developed limb tremor. 

Q16. How many patients had mild progression of dystonia?

Although the maximum benefit since levodopa initiation was usually sustained, mild progression of dystonia was seen in 6 patients despite treatment adjustment. 

Q17. How many patients had a clear improvement in their symptoms?

only 4/18 patients noted a clear worsening in the evening and at night and therefore met the restless legs syndrome diagnostic criteria.[26] 

Q18. What is the effect of levodopa on the patient?

Based on the twenty pregnancies reported here, their data suggest that levodopa retains efficacy during pregnancy and was not associated with any foetal abnormalities. 

Q19. Why do the authors suspect that males are more likely to have a milder pheno?

The authors suspect that this might artificially increase the female predominance among DRD patients, since male patients may be more likely to be misdiagnosed as young-onset Parkinson’s disease or do not come to medical attention due to mild disease severity.