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GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia

Synonyms: Autosomal Dominant Dopa-Responsive Dystonia, Autosomal Dominant Segawa Syndrome, DYT5, GTP Cyclohydrolase 1-Deficient DRD, GTPCH1-Deficient DRD, Hereditary Progressive Dystonia with Marked Diurnal Fluctuation
, MD, PhD
Chairman, Department of Neurology
Juntendo Tokyo Koto Geriatric Medical Center
Professor, Department of Neurology, Faculty of Medicine
University & Postgraduate University of Juntendo
Tokyo, Japan

Initial Posting: ; Last Revision: May 3, 2012.

Summary

Disease characteristics. GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. The average age of onset is approximately six years. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms. Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, or autonomic disturbances do not occur.

Diagnosis/testing. The diagnosis of GTPCH1-deficient DRD is established by clinical findings and response to oral administration of levodopa. GCH1, the gene encoding the enzyme GTPCH1, is currently the only gene in which mutations are known to cause GTPCH1-deficient DRD. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), the essential cofactor for tyrosine hydroxylase (TH). The concentrations of total biopterin (BP, most of which exists as BH4) and total neopterin (NP, the byproduct of the GTPCH1 reaction) in cerebrospinal fluid are low in GTPCH1-deficient DRD.

Management. Treatment of manifestations: Children: initial suggested dose of ≤25 mg/day levodopa/decarboxylase inhibitor (DCI). Adults: initial suggested dose of 50 mg levodopa/DCI 1x-2x/day. For both, dose should be gradually increased as needed. Motor benefit occurs immediately or within a few days of starting levodopa; full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is usually achieved by <300-400 mg/day of levodopa/DCI or by <20-30 mg/kg/day of levodopa without a DCI. Although dyskinesias may appear at the beginning of levodopa therapy, they subside following dose reduction and do not reappear when the dose is gradually increased. Motor adverse effects of chronic levodopa therapy do not occur.

Agents/circumstances to avoid: Discontinuation of levodopa treatment.

Evaluation of relatives at risk: Because onset is typically between ages one and 12 years and treatment is available, testing at-risk relatives during childhood may be appropriate if the GCH1 mutation in the family is known; however, molecular genetic testing cannot predict the occurrence of symptoms, or if they do occur, the age of onset, severity and type of symptoms, or rate of disease progression.

Genetic counseling. GTPCH1-deficient DRD is inherited in an autosomal dominant manner. Affected individuals often have a parent with typical GTPCH1-deficient DRD or adult-onset parkinsonism caused by a GCH1 mutation. One of the parents may have a GCH1 mutation but be asymptomatic because of incomplete penetrance. A proband with GTPCH1-deficient DRD may have the disorder as the result of a de novo mutation. Every child of an individual with autosomal dominant GTPCH1-deficient DRD has a 50% chance of inheriting the mutation. However, because of sex-influenced incomplete penetrance (i.e., higher penetrance in women than in men), it is not possible to predict if offspring with a GCH1 mutation will develop symptoms.

Diagnosis

Clinical Diagnosis

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]:

  • Onset usually between ages one and 12 years (mean: 6 years) following normal early motor development
  • Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance
  • Later development of parkinsonism (tremor is mainly postural)
  • Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals
  • In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances
  • Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable.
  • Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course
  • Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression
  • A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is usually achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI.
  • Absence of motor adverse effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa
  • Female predominance among clinically affected individuals

Note: In contrast to individuals with autosomal recessive GTPCH1 deficiency (GTPCH1-deficient hyperphenylalaninemia [HPA]), tetrahydrobiopterin (BH4) administration and 5-hydroxytryptophan therapy are not necessary for individuals with autosomal dominant GTPCH1 deficiency (GTPCH1-deficient DRD).

Testing

CSF pterins. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase, and phenylalanine hydroxylase. Concentrations of total biopterin (BP, most of which exists as BH4) and total neopterin (NP, the byproducts of the GTPCH1 reaction) in cerebrospinal fluid (CSF) are reduced in individuals with GTPCH1 deficiencies. Measurement of both BP and NP in CSF is useful for the diagnosis of GTPCH1-deficient DRD [Furukawa et al 1996b].

Note: (1) NP concentration in CSF is not decreased in other BH4 deficiency disorders, including sepiapterin reductase (SR) deficiency. (2) NP concentration in CSF is not decreased in individuals with other forms of dystonia, early-onset parkinsonism, or idiopathic Parkinson disease. (3) Both BP and NP concentrations in CSF are normal in TH-deficient DRD (the mild form of TH deficiency) [Furukawa et al 2005].

GTPCH1 enzyme activity. Activity of the enzyme GTPCH1 in phytohemagglutinin-stimulated mononuclear blood cells was reported to be reduced in individuals with GTPCH1-deficient DRD [Ichinose et al 1994].

Using cultured lymphoblasts, however, Bezin et al [1998] have suggested that phytohemagglutinin induction alone may misrepresent the actual status of GTPCH1 enzyme activity; nonstimulated GTPCH1 enzyme activity in mononuclear blood cells is too low to be measured.

Measurement of GTPCH1 enzyme activity in cytokine-stimulated fibroblasts may be useful for the diagnosis of GTPCH1-deficient DRD; however, it is unknown why activity levels are lower in most individuals with GTPCH1-deficient DRD (heterozygotes) than in individuals with GTPCH1-deficient HPA (homozygotes with more severe symptoms) [Bonafé et al 2001a, Van Hove et al 2006].

Note: The phenylalanine loading test (see Clinical Description) can be performed in most hospitals; however, both false negative and false positive results have been reported.

Molecular Genetic Testing

Gene. The only gene in which mutations are currently known to cause GTPCH1-deficient DRD is GCH1 (encoding GTPCH1, the rate-limiting enzyme in BH4 biosynthesis) [Ichinose et al 1994, Furukawa 2004].

Evidence for locus heterogeneity. For information on locus heterogeneity in DRD, see Nomenclature and Differential Diagnosis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in GTPCH1-Deficient DRD

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
GCH1Sequence analysisSequence variants 2~60% (20%-80%) 3
Deletion / duplication analysis 4Exonic or whole-gene deletions/ duplications~5%-10% 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. In genetic reports on DRD, in which conventional genomic DNA sequencing of GCH1 was conducted in a relatively large number of families, mutations in the coding region (including the splice sites) of this gene were found in ~60% (mean) of DRD pedigrees.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. After conducting GCH1 analysis that included both sequence analysis and deletion/duplication analyses, Furukawa [2004], Hagenah et al [2005], and Clot et al [2009] identified GCH1 mutations in 80%-90% of their families with DRD. Zirn et al [2008] found GCH1 mutations in 62% (54% with point mutations and 8% with exon deletions) of individuals with clinically confirmed DRD.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

For "coding region mutation-negative" GTPCH1-deficient DRD pedigrees, possible explanations include the following:

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

  • A therapeutic trial with low doses of levodopa based on clinical suspicion is still the most practical approach to the diagnosis of DRD; it is generally agreed that individuals with childhood-onset dystonic symptoms of unknown etiology should be treated initially with levodopa.
  • Although the results of molecular genetic and biochemical studies described above are, at this time, unlikely to significantly alter clinical management of the individual, these analyses could be useful in providing information on prognosis (i.e., GTPCH1-deficient DRD vs progressive neurodegenerative disorders or more severe metabolic disorders).
    • For the diagnosis of GTPCH1-deficient DRD, molecular genetic testing first by sequence analysis followed by deletion/duplication analysis if a disease-causing mutation is not identified of GCH1 should be performed.
    • In individuals with no identifiable GCH1 mutations, a finding of reduced concentrations of both BP and NP in CSF is useful for the diagnosis of GTPCH1-deficient DRD (see Differential Diagnosis).
    • If CSF sampling is not available, evaluation of GTPCH1 enzyme activity in cytokine-stimulated fibroblasts may be useful. Although measurement of GTPCH1 enzyme activity in phytohemagglutinin-stimulated mononuclear blood cells may also be useful, this measurement should be performed within 20 hours after blood sampling.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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.

Initial symptoms in most individuals with childhood-onset GTPCH1-deficient DRD are gait difficulties attributable to dystonia in the leg, typically flexion-inversion (equinovarus posture) of the foot. Affected individuals have a tendency to fall. A small number of individuals have onset with arm dystonia, postural tremor of the hand, or slowness of movements. Standing position with equinovarus posture of the feet can induce increased lumbar lordosis.

A variable degree of rigidity and slowness of movements are recognized in the affected limbs. Tremor is usually postural especially in the early course of illness. Rapid fatiguing of effort with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed.

Some clinical findings suggestive of pyramidal signs in the lower extremities (brisk deep-tendon reflexes, spasticity, ankle clonus, and/or intermittent extensor plantar responses) are detected in many affected individuals. However, normal efferent cortical spinal activity with magneto-electrical stimulation of the motor cortex suggests a non-pyramidal basis for these findings. In fact, after starting levodopa therapy, severe hyperreflexia and spasticity resolve and an extensor plantar response often disappears in individuals with GTPCH1-deficient DRD [Nygaard & Duvoisin 1999, Furukawa et al 2005]. Dystonic extension of the big toe (the striatal toe) may be misinterpreted as an extensor plantar response.

In general, intellectual and cognitive function is normal and there is no evidence of cerebellar, sensory, and autonomic disturbances in individuals with GTPCH1-deficient DRD [Segawa & Nomura 1993, Nygaard & Duvoisin 1999, Furukawa et al 2005].

Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep) is characteristic [Segawa et al 1976]. The degree of fluctuation is variable, with some individuals being normal in the morning and others being only less severely affected in the morning compared to later in the day. Some individuals demonstrate only exercise-induced exacerbation or manifestation of dystonia.

In general, gradual progression to generalized dystonia occurs in individuals with childhood-onset GTPCH1-deficient DRD. Typically, dystonia remains more pronounced in the legs throughout the disease course. Diurnal fluctuation often attenuates with age and disease progression.

Symptoms in adolescent-onset cases are usually milder than in childhood-onset cases and disease progression is slower. Individuals with adolescent-onset GTPCH1-deficient DRD seldom develop severe generalized dystonia. Such individuals may become more symptomatic in mid-adulthood because of development of overt parkinsonism.

All individuals with GTPCH1-deficient DRD demonstrate a dramatic and sustained complete or near-complete response of symptoms to relatively low doses of levodopa (see Treatment of Manifestations). Even individuals who have been untreated for more than 50 years (e.g., persons initially diagnosed with cerebral palsy) can show a remarkable response to levodopa.

At the initiation of levodopa therapy, some individuals with GTPCH1-deficient DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later; note that these transient dyskinesias are different from those with motor response fluctuations observed in persons with early-onset parkinsonism and Parkinson disease during chronic levodopa therapy. Under optimal doses, individuals with GTPCH1-deficient DRD on long-term levodopa treatment do not develop either motor response fluctuations (wearing-off and on-off phenomena) or dopa-induced dyskinesias.

A predominance of clinically affected females is observed, with a reported female-to-male ratio of 2:1 to 6:1. The penetrance of GCH1 mutations in GTPCH1-deficient DRD is higher in females than in males.

Individuals with GTPCH1-deficient DRD never develop hyperphenylalaninemia (HPA). However, a subclinical defect in phenylalanine metabolism caused by partial BH4 deficiency in the liver can often be detected in individuals by the phenylalanine loading test, which analyzes plasma phenylalanine-to-tyrosine ratios for four or six hours following an oral phenylalanine load (100 mg/kg). Note: Both false negative and false positive results of this test have been reported [Furukawa et al 2005].

Phenotypic heterogeneity. Wide intra- and interfamilial variations in expressivity have been reported in GTPCH1-deficient DRD [Nygaard et al 1993b, Bandmann et al 1998, Steinberger et al 1998, Tassin et al 2000, Grimes et al 2002, Klein et al 2002, Uncini et al 2004, Furukawa et al 2005, Wu et al 2008, Trender-Gerhard et al 2009, Ling et al 2011].

The clinical phenotype has been extended to include "benign" adult-onset parkinsonism, various types of focal dystonia, DRD simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism (sometimes with a relapse in the later course of illness). Individuals with adult-onset parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations, freezing episodes, or dopa-induced dyskinesias.

In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [Hahn et al 2001, Van Hove et al 2006, Trender-Gerhard et al 2009].

Leuzzi et al [2002] reported an individual who demonstrated delayed attainment of early motor milestones and involuntary jerky movements that were responsive to levodopa; myoclonus-dystonia as a phenotype of GTPCH1-deficient DRD was found only in this individual [Luciano et al 2009].

Neuroimaging. Brain CT and MRI are normal.

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies using presynaptic dopaminergic markers have demonstrated normal results in the striatum of GTPCH1-deficient DRD [Jeon et al 1998, Kishore et al 1998]. These PET and SPECT findings are supported by normal striatal levels of dopa decarboxylase, dopamine transporter, and vesicular monoamine transporter at autopsy of individuals with GTPCH1-deficient DRD, indicating that striatal dopamine nerve terminals are preserved in this disorder [Furukawa et al 1999, Furukawa et al 2002]. Using [11C]-raclopride PET, elevated D2-receptor binding in the striatum has been found in GTPCH1-deficient DRD [Kishore et al 1998].

Network analysis of [18F]-fluorodeoxyglucose PET images has shown that GTPCH1-deficient DRD is associated with a specific metabolic topography, which is characterized by increases in the dorsal midbrain, cerebellar vermis, and supplementary motor area and by decreases in the putamen as well as lateral premotor and motor cortical regions [Asanuma et al 2005].

Neuropathology. Neuropathologic studies demonstrated a normal population of cells with reduced melanin and no evidence of Lewy body formation in the substantia nigra in three individuals with GTPCH1-deficient DRD and one asymptomatic individual with a GCH1 mutation [Rajput et al 1994, Furukawa et al 1999, Furukawa et al 2002, Wider et al 2008].

Neurochemistry. Neurochemical data are available for GTPCH1-deficient DRD [Rajput et al 1994, Furukawa et al 1999, Furukawa et al 2002]. At autopsy, BP and NP levels in the putamen were substantially lower in two affected individuals (mean: -84% and -62%) than in age-matched normal controls. The caudal portion of the putamen was the striatal subdivision most affected by dopamine loss (-88%). Striatal levels of dopa decarboxylase protein, dopamine transporter, and vesicular monoamine transporter were normal, but tyrosine hydroxylase (TH) protein levels were markedly decreased in the putamen (more than -97%). These biochemical findings suggest that striatal dopamine reduction in GTPCH1-deficient DRD is caused by both decreased TH activity resulting from a low cofactor (BH4) level and actual loss of TH protein without nerve terminal loss. This TH protein reduction in the striatum may be caused by diminished regulatory effect of BH4 on the steady-state level of TH molecules [Furukawa et al 1999, Furukawa et al 2002, Sumi-Ichinose et al 2005, Sato et al 2008].

In an asymptomatic individual with a GCH1 mutation, decreases in BP and NP levels in the putamen (-82% and -57%) paralleled those in the two symptomatic individuals who were autopsied [Furukawa et al 2002]. However, TH protein and dopamine levels in the caudal putamen (-52% and -44%) were not as severely affected as in the symptomatic individuals. Consistent with other postmortem brain data suggesting that greater than 60%-80% striatal dopamine loss is necessary for overt motor symptoms to occur [Furukawa 2003, Furukawa 2004], the maximal 44% dopamine reduction in the striatum of the asymptomatic individual with the GCH1 mutation was not sufficient to produce any symptoms of GTPCH1-deficient DRD.

Genotype-Phenotype Correlations

No correlations between specific clinical features and types of mutations in GCH1 have been established in individuals with GTPCH1-deficient DRD.

Penetrance

Penetrance in individuals with GTPCH1-deficient DRD has been reported to be higher in females than in males: 87% vs 38% [Furukawa et al 1998b], 100% vs 55% [Steinberger et al 1998], and 87% vs 35% [Segawa et al 2003].

Anticipation

Anticipation has been suggested in some families [Segawa 2000].

Nomenclature

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of levodopa. This characteristic levodopa responsiveness and absence of motor-adverse effects from chronic levodopa therapy distinguish DRD from all other forms of dystonia (including dystonia that is partially responsive to levodopa) and from early-onset parkinsonism and Parkinson disease. Diurnal fluctuation of symptoms occurs in approximately 80% of individuals with DRD, and many neurologists owe their awareness of DRD to Drs. Segawa and Nygaard, who have established the clinical concept of this type of dystonia.

Recent advances in the molecular genetics of dystonia have shown locus heterogeneity in DRD and have led to the use of "DRD" to delineate the following disease entities (see Differential Diagnosis):

When Wider et al [2008] restudied a Swiss family with DRD, which Grotzsch et al [2002] had mapped to a locus named DYT14 on chromosome 14q13 (adjacent to the DYT5a locus), they found a heterozygous deletion of GCH1 exons 3 to 6.

Prevalence

Prevalence of DRD (as defined in Clinical Description) in both England and Japan has been estimated at 0.5 per million [Nygaard et al 1993b].

DRD (as defined in Clinical Description) is observed worldwide with no increased prevalence in any ethnic group.

Differential Diagnosis

For a differential diagnosis of dystonia, see Dystonia Overview.

Individuals with dystonia and/or parkinsonism or unexplained gait disorders during childhood should be treated initially with low doses of levodopa because of the possibility that their symptoms result from DRD [Nygaard et al 1991, Furukawa & Kish 1999].

The major differential diagnoses of DRD include early-onset parkinsonism (see Parkinson Disease Overview), early-onset primary dystonia (see DYT1 dystonia), and cerebral palsy or spastic paraplegia (see Hereditary Spastic Paraplegia Overview).

Mutations in several different genes were reported to result in the clinical phenotype of DRD (see Clinical Description). These findings have led to the use of the term "DRD" to delineate disease entities, namely, autosomal dominant GTPCH1-deficient DRD (DYT5a), autosomal recessive TH-deficient DRD (DYT5b), autosomal recessive SR-deficient DRD (rare), and autosomal dominant SR-deficient DRD (very rare; see Nomenclature).

Approximately 30%-50% of individuals with DRD have no family history of dystonia [Nygaard et al 1993a, Segawa & Nomura 1993, Nygaard & Duvoisin 1999]. In some of these individuals, de novo mutations in GCH1 or recessively inherited mutations in TH are identified [Furukawa 2003].

Autosomal recessive tyrosine hydroxylase (TH)-deficient DRD (the mild form of TH deficiency). More than ten individuals with genetically proven TH-deficient DRD have been reported [Ludecke et al 1995, Swaans et al 2000, Furukawa et al 2001, Schiller et al 2004, Verbeek et al 2007, Willemsen et al 2010, Yeung et al 2011]. A dramatic and sustained response to levodopa treatment and the absence of motor-adverse effects for a period of more than 30 years has been confirmed in several families. Female predominance (which is confirmed in GTPCH1-deficient DRD) may not be a clinical characteristic in TH-deficient DRD; further experience with TH-deficient DRD is necessary to establish the clinical features of this treatable disorder. Autosomal recessive TH deficiency is associated with a broad clinical phenotypic spectrum ranging from TH-deficient DRD (the mild form) to infantile parkinsonism with motor delay or progressive infantile encephalopathy (the severe form) [Hoffmann et al 2003, Furukawa et al 2004b, Willemsen et al 2010, Najmabadi et al 2011, Yeung et al 2011, Giovanniello et al 2012]. Analyses of both GCH1 and TH demonstrated mutations in 86% of families with DRD or dystonia with motor delay [Furukawa 2004].

Autosomal recessive BH4-related enzyme deficiencies. Individuals with autosomal recessive BH4-related enzyme deficiencies (so called BH4 deficiencies [Blau et al 2002]), including recessively inherited GTPCH1 deficiency (see Genetically Related Disorders), develop BH4-dependent HPA in the first six months of life; an exception is autosomal recessive SR deficiency (in this case, BH4 is synthesized through the salvage pathway in peripheral tissue). These individuals typically present with severe neurologic dysfunction (e.g., psychomotor retardation, convulsions, microcephaly, swallowing difficulties, hypersomnia, cognitive impairment, truncal hypotonia, limb hypertonia, paroxysmal stiffening, involuntary movements, oculogyric crises); diurnal fluctuation of symptoms and dystonia partially responding to levodopa can be seen in some individuals, especially those with SR deficiency [Hanihara et al 1997, Furukawa & Kish 1999, Bonafé et al 2001b, Furukawa 2004, Neville et al 2005, Abeling et al 2006, Roze et al 2006, Arrabal et al 2011, Dill et al 2012, Marras et al 2012]. (see Autosomal recessive SR-deficient DRD). For individuals with autosomal recessive SR deficiency, oral administration of both levodopa and 5-hydroxytryptophan is necessary because of very low levels of the neurotransmitter metabolites homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in CSF. BH4 treatment and neurotransmitter replacement therapy (levodopa and 5-hydroxytryptophan) are indispensable for those with other autosomal recessive BH4-related enzyme deficiencies.

Autosomal recessive sepiapterin reductase (SR)-deficient DRD (rare). Arrabal et al [2011] reported one family with a strikingly mild phenotype (without motor and cognitive delay) of SR deficiency associated with compound heterozygosity for SPR (the gene encoding SR) mutations; one was a missense mutation and the other was a partially penetrant splicing mutation. Even in this family with the very mild form of autosomal recessive SR deficiency, an affected family member showed markedly decreased concentrations of HVA and 5-HIAA in CSF. Both levodopa and 5-hydroxytriptophan were administered orally for this affected individual but 5-hydroxytriptophan was not tolerated.

Autosomal dominant sepiapterin reductase (SR)-deficient DRD (very rare). Steinberger et al [2004] found a heterozygous mutation in the untranslated region of SPR in one of 95 individuals who presented with dystonia responsive to levodopa and did not have a GCH1 mutation; they concluded that haploinsufficiency of SPR can be a rare cause of autosomal dominant DRD [Zirn et al 2008].

Early-onset parkinsonism. Individuals with early-onset parkinsonism responding to levodopa, especially those with onset before age 20 years, often develop gait disturbance attributable to foot dystonia as the initial symptom [Furukawa et al 1996a]. Thus, in the early course, the clinical differentiation between individuals with early-onset parkinsonism with dystonia and individuals with GTPCH1-deficient DRD is difficult.

  • The most reliable clinical distinction between early-onset parkinsonism and GTPCH1-deficient DRD is the subsequent occurrence of motor-adverse effects of chronic levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) in early-onset parkinsonism. Under optimal doses, individuals with GTPCH1-deficient DRD on long-term levodopa treatment do not develop these motor complications. However, this is a retrospective difference.
  • An investigation of the nigrostriatal dopaminergic terminals by PET or SPECT can differentiate early-onset parkinsonism (markedly reduced) from GTPCH1-deficient DRD (normal or near-normal) [Jeon et al 1998, Kishore et al 1998, Furukawa et al 2005].
  • Measurement of concentration of both BP and NP in CSF is useful in distinguishing the following three disorders responsive to levodopa [Furukawa & Kish 1999]:

Early-onset primary dystonia (DYT1). A GAG deletion in TOR1A (the gene in which mutation causes DYT1) that results in loss of a glutamic acid residue in a novel ATP-binding protein (torsin A) has been identified in many individuals with chromosome 9q34-linked early-onset primary dystonia, irrespective of ethnic background. This heterozygous deletion cannot be found in some families with typical DYT1 phenotype (early-onset limb dystonia spreading to at least one other limb but not to cranial muscles). However, a dramatic and sustained response to low doses of levodopa in DRD distinguishes this clinical syndrome from all other forms of dystonia, including DYT1. (See Early-Onset Primary Dystonia.)

Myoclonus-dystonia (M-D). Inherited M-D and DRD are differentiated from primary dystonias and are classified under the dystonia-plus category [Fahn et al 1998]. At least two genes are associated with M-D: SGCE, encoding ε-sarcoglycan, and an as-yet undetermined gene that maps to 18p11 (DYT15) [Furukawa & Rajput 2002, Han et al 2007]. In M-D, myoclonic jerks affect predominantly the neck, shoulders, and arms. Dystonic symptoms are mainly torticollis and writer's cramp. In addition to these involuntary movements, psychiatric problems (e.g., alcohol abuse, obsessive-compulsive disorder, and panic attacks) occur. It remains uncertain which psychiatric problems are caused by the underlying gene defect; alcohol dependence could be attributable to the role of alcohol in alleviating myoclonus. (See Myoclonus-Dystonia.)

Cerebral palsy or spastic paraplegia. Some individuals with GTPCH1-deficient DRD are initially diagnosed as having cerebral palsy or spastic paraplegia [Tassin et al 2000, Grimes et al 2002, Furukawa et al 2005]. Although clinical findings suggestive of pyramidal signs in the lower extremities are detected in many affected individuals, normal efferent cortical spinal activity with magneto-electrical stimulation of the motor cortex suggests a non-pyramidal basis for these findings. Dystonic extension of the big toe (the striatal toe), which occurs spontaneously or is induced by plantar stimulation, may be misinterpreted as the Babinski response. (See Hereditary Spastic Paraplegia Overview.)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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.

Treatment of Manifestations

Children. Although an initial dose of 25 mg levodopa/decarboxylase inhibitor (DCI) two to three times a day was recommended by Nygaard et al [1991], an initial dose of 25 mg or less of levodopa/DCI once a day is currently suggested [Furukawa et al 2005] because some children with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) demonstrated a remarkable response to smaller doses and a child with the dystonia with motor delay phenotype manifested very severe dyskinesia (lasting 4 days) after receiving a single 50-mg dose of levodopa/DCI. Changing the dose slowly and by small increments is recommended.

Adults. An initial dose of 50 mg levodopa/DCI once or twice a day is suggested [Furukawa et al 2005]. Gradual increase to higher doses is recommended.

Motor benefit can be recognized immediately or within a few days of starting levodopa therapy; full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is usually achieved by less than 300-400 mg/day of levodopa/DCI or by less than 20-30 mg/kg/day of levodopa without a DCI [Nygaard et al 1993a, Segawa & Nomura 1993, Steinberger et al 2000, Grimes et al 2002, Furukawa et al 2005]. According to Nygaard & Duvoisin [1999], no dose of levodopa/DCI greater than 400 mg/day has been necessary for individuals with GTPCH1-deficient DRD.

At the initiation of levodopa treatment, some individuals with GTPCH1-deficient DRD develop dyskinesias. However, these dyskinesias subside following dose reduction and do not reappear with later gradual increment in dose. It is important to note that such transient dyskinesias are different from those observed in early-onset parkinsonism and idiopathic Parkinson disease during chronic levodopa therapy. A continued stable response to levodopa therapy and no motor-adverse effects for more than 30 years have been confirmed in GTPCH1-deficient DRD [Furukawa et al 2005].

Prevention of Primary Manifestations

As described in Treatment of Manifestations, appropriate levodopa therapy can reverse symptoms and signs of GTPCH1-deficient DRD; levodopa therapy from infancy may not be required to prevent disease manifestations.

Prevention of Secondary Complications

Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment.

Surveillance

Examination by a movement disorder specialist several times yearly is recommended.

Agents/Circumstances to Avoid

Discontinuation of levodopa treatment usually results in return of symptoms.

Exacerbation of symptoms after taking oral contraceptives has been reported in some women with GTPCH1-deficient DRD [Furukawa et al 1998a, Postuma et al 2003, Trender-Gerhard et al 2009].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In 20 pregnancies reported in 12 affected individuals, levodopa was continued without adverse effect in most. Two woman experienced remission resulting in a reduction or cessation of therapy. Two women reported mild deterioration of dystonia; an increase in dose was required in one. No fetal abnormalities were identified [Trender-Gerhard et al 2009].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Although individuals with GTPCH1-deficient DRD may respond to trihexyphenidyl and bromocriptine, levodopa is more effective in the treatment of this disorder [Nygaard et al 1991, Segawa & Nomura 1993].

Acute BH4 administration appears to be much less effective in GTPCH1-deficient DRD than levodopa therapy [Furukawa et al 2005]; the reduction of striatal TH protein observed at autopsy in GTPCH1-deficient DRD can be expected to limit a stimulatory effect of acute BH4 administration on dopamine biosynthesis in this disorder [Furukawa et al 1999].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Individuals diagnosed with autosomal dominant GTPCH1-deficient DRD often have a parent with classic GTPCH1-deficient DRD or adult-onset parkinsonism caused by a GCH1 mutation.
  • One of the parents may have a GCH1 mutation but be asymptomatic as a result of gender-related incomplete penetrance (i.e., higher penetrance in women than in men).
  • A proband with autosomal dominant GTPCH1-deficient DRD may have the disorder as the result of a de novo GCH1 mutation. It has been suggested that GCH1 has a relatively high spontaneous mutation rate [Furukawa et al 1998b, Wu-Chou et al 2010].
  • Because of the possibility that one of the parents of an affected individual with no known family history of GTPCH1-deficient DRD will develop "benign" adult-onset parkinsonism in the future, evaluation of both parents is recommended.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If one of the parents has a GCH1 mutation, each sib has a 50% chance of inheriting the mutant allele at conception. Because of gender-related incomplete penetrance, a sib who inherits a GCH1 mutation may be asymptomatic.
  • If neither parent has a GCH1 mutation, the risk to the sibs of the proband is usually very low.

Offspring of a proband. Every child of an individual with autosomal dominant GTPCH1-deficient DRD has a 50% chance of inheriting the mutation. However, because of sex-influenced incomplete penetrance, it cannot be predicted whether offspring with a GCH1 mutation will develop symptoms.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent has a GCH1 mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic family members for GTPCH1-deficient DRD is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression will be. When testing at-risk individuals for GTPCH1-deficient DRD, an affected family member should be tested first to confirm the molecular diagnosis in the family. Because onset is typically between ages one and 12 years and treatment is available, testing of at-risk individuals during childhood may be appropriate.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions (like GTPCH1-deficient DRD) that have treatment available are not common.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Pediatric Neurotransmitter Disease Association
    498 Lillian Court
    PO Box 180622
    Delafield WI 53018
    Phone: 603-733-8409
    Email: pnd@pndassoc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia (View All in OMIM)

128230DYSTONIA, DOPA-RESPONSIVE; DRD
600225GTP CYCLOHYDROLASE I; GCH1

Normal allelic variants. GCH1 is composed of six exons spanning approximately 30 kilobases [Ichinose et al 1995]. There are three cDNA isoforms with different 3'-ends as a result of alternative splicing; only type 1 cDNA (having the longest coding region) gives rise to the active enzyme. A full-length cDNA clone encoding human GTPCH1 type 1 from pheochromocytoma consists of 2921 base pairs including a poly(A) tail. One polymorphism in the coding region of GCH1 (Pro23Leu) has been reported [Hauf et al 2000, Furukawa 2004, Clot et al 2009].

Pathologic allelic variants. More than 150 pathologic variants have been reported in individuals with GTPCH1 deficiencies (i.e., GTPCH1-deficient DRD [mild], dystonia with motor delay [moderate], and GTPCH1-deficient HPA [severe]) [Furukawa et al 2005]. The reason for the presence of many independent mutations throughout all of the exons of GCH1 is unclear. See Table A.

Normal gene product. The normal product of GCH1 is the GTPCH1 (GTP cyclohydrolase I; EC 3.5.4.16) protein containing 250 amino acid residues. The enzyme GTPCH1 catalyzes the first step (from GTP to dihydroneopterin triphosphate) in the biosynthetic pathway of BH4, the natural cofactor for TH. The atomic structure of GTPCH1 from Escherichia coli demonstrates that this enzyme is a homodecamer formed by a face-to-face association of two pentamers [Furukawa 2003].

Abnormal gene product. One allele having a pathologic mutation of GCH1 produces dysfunctional GTPCH1 protein and consequently results in decreased synthesis of BH4. Because the other allele usually has no GCH1 mutation, an approximately 50% reduction in striatal levels of the cofactor was expected in individuals with GTPCH1-deficient DRD. However, BP concentrations in the putamen of two autopsied individuals were reduced to 16% of age-matched control means [Furukawa et al 1999]. Enzyme activity of GTPCH1 in phytohemagglutinin-stimulated mononuclear blood cells of affected individuals was decreased to less than 20% that of normal controls [Ichinose et al 1994].

In coexpression studies, abnormal GTPCH1 protein with dominantly inherited GCH1 mutations (but not recessively inherited mutations) inactivated the wild-type enzyme, indicating a role of this dominant-negative effect in GTPCH1-deficient DRD. However, Suzuki et al [1999] have reported that such a dominant-negative effect is unlikely to explain markedly reduced GTPCH1 activity in phytohemagglutinin-stimulated mononuclear blood cells from individuals with GTPCH1-deficient DRD and that a reduction of the amount of GTPCH1 protein found in these cells may contribute to the mechanism of dominant inheritance.

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Chapter Notes

Revision History

  • 3 May 2012 (yf) Revision: information about autosomal recessive sepiapterin reductase (SR)-deficient DRD added
  • 6 October 2011 (me) Comprehensive update posted live
  • 4 August 2009 (me) Comprehensive update posted live
  • 15 February 2007 (me) Comprehensive update posted to live Web site. Note: scope of Dopa-Responsive Dystonia GeneReview changed —> GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia and Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia
  • 15 June 2004 (me) Comprehensive update posted to live Web site
  • 5 March 2004 (me) Comprehensive update posted to live Web site
  • 21 February 2002 (me) Review posted to live Web site
  • 30 June 2001 (yf) Original submission
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