Autosomal dominant dopa-responsive dystonia

General Information (adopted from Orphanet):

Synonyms, Signs: DYSTONIA-PARKINSONISM WITH DIURNAL FLUCTUATION
DOPA-RESPONSIVE DYSTONIA, AUTOSOMAL DOMINANT
SEGAWA SYNDROME, AUTOSOMAL DOMINANT
DYSTONIA 5
DYSTONIA, PROGRESSIVE, WITH DIURNAL VARIATION
DYSTONIA, DOPA-RESPONSIVE, AUTOSOMAL DOMINANT
DRD
DYT5
HPD with marked diurnal fluctuation
GTPCH1-deficient DRD
GTPCH1-deficient dopa-responsive dystonia
DYT5a
Autosomal dominant Segawa syndrome
Hereditary progressive dystonia with marked diurnal fluctuation
Number of Symptoms 31
OrphanetNr: 98808
OMIM Id: 128230
ICD-10: G24.1
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: > 0.1 of 100 000
Inheritance:
Age of onset:

Disease classification (adopted from Orphanet):

Parent Diseases: Disorder of pterin metabolism
 -Rare genetic disease
Dopa-responsive dystonia
 -Rare genetic disease
 -Rare neurologic disease

Comment:

DRD due to adGTPCH (GCH1) deficiency typically presents insidiously between the ages of 1 and 9 years, (PMID: 17368676) The phenotypic spectrum of GTPCH type I deficiency can be regarded as a continuum between the milder dominant and the severe recessive forms. (PMID: 18276179)

Symptom Information: Sort by abundance 

1
(HPO:0000473) Torticollis 15390021 IBIS 42 / 7739
2
(HPO:0002307) Drooling 17368676 IBIS 43 / 7739
3
(HPO:0002356) Writer's cramp 15390021 IBIS 16 / 7739
4
(HPO:0100543) Cognitive impairment 21556877 IBIS 230 / 7739
5
(HPO:0007034) Generalized hyperreflexia 17368676 IBIS 33 / 7739
6
(HPO:0001288) Gait disturbance 15390021 IBIS 318 / 7739
7
(HPO:0002067) Bradykinesia 17368676; 15390021 IBIS 62 / 7739
8
(HPO:0004373) Focal dystonia 15390021 IBIS 9 / 7739
9
(HPO:0002548) Parkinsonism with favorable response to dopaminergic medication 15390021 IBIS 13 / 7739
10
(HPO:0003487) Babinski sign 17368676 IBIS 179 / 7739
11
(HPO:0100022) Abnormality of movement 17368676 IBIS 129 / 7739
12
(HPO:0001347) Hyperreflexia 17368676 IBIS 363 / 7739
13
(HPO:0001300) Parkinsonism 15390021 IBIS 75 / 7739
14
(HPO:0002174) Postural tremor 15390021 IBIS 22 / 7739
15
(HPO:0002063) Rigidity 17368676 IBIS 92 / 7739
16
(HPO:0003785) Decreased CSF homovanillic acid 17368676 IBIS 7 / 7739
17
(HPO:0100710) Impulsivity 21556877 IBIS 16 / 7739
18
(HPO:0002066) Gait ataxia 15390021 IBIS 327 / 7739
19
(HPO:0002921) Abnormality of the cerebrospinal fluid 17368676 IBIS 6 / 7739
20
(HPO:0000870) Prolactin excess 12391354 IBIS 10 / 7739
21
(HPO:0002938) Lumbar hyperlordosis 15390021 IBIS 73 / 7739
22
(HPO:0001762) Talipes equinovarus 15390021 IBIS 309 / 7739
23
(HPO:0002650) Scoliosis 15390021 IBIS 705 / 7739
24
(HPO:0008297) Transient hyperphenylalaninemia 16624273 IBIS 4 / 7739
25
(HPO:0008936) Muscular hypotonia of the trunk 17368676 IBIS 77 / 7739
26
(OMIM) Postural dystonia (onset is restricted to 1 extremity, usually lower, with foot dystonia) 15390021 IBIS 1 / 7739
27
(OMIM) Action dystonia 21556877 IBIS 1 / 7739
28
(OMIM) Decreased tetrahydrobiopterin (BH4) in CSF 17368676; 21556877 IBIS 1 / 7739
29
(OMIM) Decreased GTP cyclohydrolase I activity (about 20% of normal) 15303002; 21556877 IBIS 1 / 7739
30
(OMIM) 5-HIAA CSF may be normal or decreased 12391354 IBIS 2 / 7739
31
(OMIM) Asymmetry of symptoms 15390021 IBIS 1 / 7739

Associated genes:

GCH1;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Diagnosis OMIM Hyland et al. (1997, 1999) demonstrated that oral phenylalanine loading can identify both symptomatic and asymptomatic carriers of the gene for autosomal dominant GTP cyclohydrolase deficiency. Patients with heterozygous mutations showed significantly increased plasma phenylalanine after loading compared ...
Clinical Description OMIM Segawa et al. (1976) reported 9 patients in 6 families with postural and motor disturbances showing marked diurnal fluctuation. Dystonic posture or movement of one limb appeared insidiously between ages 1 and 9 years. All limbs were involved ...
Molecular genetics OMIM In affected members of 4 families with DRD, Ichinose et al. (1994) identified 4 different mutations in the GCH1 gene (600225.0001-600225.0004).

In 58 patients with dopa-responsive dystonia, Steinberger et al. (2000) identified mutations in the GCH1 ...

Diagnosis GeneReviews The following are characteristics of classic autosomal dominant GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD; also known as DYT5), the major form of DRD [Furukawa et al 2005]:...
Clinical Description GeneReviews The average age of onset of typical GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the major form of DRD, is approximately six years (range: age 1-12 years) [Nygaard et al 1993a, Segawa & Nomura 1993, Furukawa et al 2005]. The perinatal and postnatal periods are normal, as is early motor development. ...
Genotype-Phenotype Correlations GeneReviews No correlations between specific clinical features and types of mutations in GCH1 have been established in individuals with GTPCH1-deficient DRD. ...
Differential Diagnosis GeneReviews For a differential diagnosis of dystonia, see Dystonia Overview....
Management GeneReviews To establish the extent of disease in an individual diagnosed with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), neurologic examination is recommended....
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....