Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: GCH1
• Condition: GCH-1 associated dopa-responsive dystonia
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• GCH1 ⇔ 0007495 (dystonia 5): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: GCH1 ⇔ 0007495 (OMIM:128230)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Neuromuscular dysfunction / Surveillance by specialist to guide levodopa and decarboxylase inhibitor therapy	1	3C	3C	3	10CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

GCH1-associated dopa-responsive dystonia (GCH1-DRD), also called GTP cyclohydrolase I deficiency (GTPCHD) or dystonia 5, is a rare disorder. GCH1-DRD is the most common cause of dopa-responsive dystonia. In Serbia, prevalence was estimated to be 2.96 per million. The precise global prevalence of GCH1-DRD remains unknown and great variance can be found among different countries. [1, 2]

Clinical Features

GCH1-DRD is characterized by dystonia that typically presents with gait disturbance caused by foot dystonia, typically flexion-inversion (equinovarus posture) of the foot, and a tendency to fall. Diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep) are also characteristic, though variable, and often attenuate with age and disease progression. 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 striatal toe (dystonic extension of the big toe) is often present. Rapid fatiguing with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. If not treated, focal or segmental dystonia typically progresses to multifocal or generalized dystonia. Later in the course of disease, some, especially those with later onset in adolescence or adulthood, develop parkinsonism. Without treatment, adults may suffer from limb contractures. Some individuals demonstrate only exercise-induced exacerbation or manifestation of dystonia. In general, intellectual, cerebellar, sensory, and autonomic disturbances do not occur. In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported.
There are two types of adult-onset parkinsonism in families with GCH1-DRD. Individuals with adult-onset “benign” parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. When treated these individuals remain functionally normal for a long period of time. The other type is “neurodegenerative” parkinsonism, including Parkinson disease. [1, 2, 3, 4]

Natural History

GCH1-DRD typically presents during the first decade of life, mainly between 3 to 12 years of age, following normal early motor development. Very rarely individuals may present with dystonia and/or developmental delay in the first 12 to 18 months. Disease onset in the second decade is common. In one review that included 488 individuals (one third of whom were males), age of onset ranged from 0 to 68 years with a median of 8 years. Only 11% presented after the age of 40 years. The median age of onset in females (8 years) was lower than the median age of onset in males (19 years). Diurnal fluctuation is a very characteristic finding in the first three decades. Later, fluctuations become less prominent. The clinical presentation in the second decade of life is characterized by action dystonia of the upper limbs, sometimes associated with cervical impairment, asymmetric tremor and parkinsonism. After the age of 20 years the predominant presentation is parkinsonism, isolated or combined with dystonia. Individuals with a later disease onset have a milder phenotype and disease progression is slower. In general, gradual progression to generalized dystonia is observed in those with childhood onset. The progression of the dystonia and the diurnal fluctuation of symptoms subside with age and the disease becomes almost stable in the fourth decade. Symptoms in individuals with adolescent onset are usually milder than in those with childhood onset and disease progression is slower. Individuals with adolescent onset seldom develop severe generalized dystonia; such individuals may become more symptomatic in mid-adulthood due to development of overt parkinsonism. A predominance of clinically affected females is observed, with reported female-to-male ratios ranging from 1.3:1 to 8.3:1. Females may also have a younger age at onset than males with more frequent onset of dystonia in the lower limbs. There is no decrease in life expectancy. [1, 2, 3, 5]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual diagnosed with GCH1-DRD, a neurologic examination to assess the severity of symptoms and a clinical genetics consultation are recommended. (Tier 4) [2]

Involvement of a broad team with specialists in physiotherapy, speech therapy, occupational therapy, and (neuro-) psychological treatment should always be part of the complex care provided to individuals with GCH1-DRD to improve care, prevent secondary complications, and promote neurological development. All individuals or parents should be offered genetic counseling. Begin planning early for transition to adult care in specialized centers. Multidisciplinary care should be continued. (Tier 2) [1]

Levodopa should always be given in combination with a decarboxylase (DC) inhibitor (4:1 ratio) and should be the first line of treatment in GCH1-DRD. The levodopa/DC inhibitor (carbidopa or benserazide) starting dose should be low, distributed in several daily dosages and slowly titrated depending on the clinical symptoms. The timing and dosing of medication may be adjusted individually. Most individuals with GCH1-DRD obtain complete symptom control with lower doses of levodopa/DC inhibitor. (Tier 2) [1]

All individuals with GCH1-DRD demonstrate a dramatic and sustained complete or near-complete response of symptoms to relatively low doses of levodopa. Even individuals who have been untreated for more than 50 years can show a remarkable response to levodopa. One study included 66 individuals with presumed DRD (no genetic testing). The mean age at onset was 6.5 years (range 1.2 to 12 years). All individuals had an immediate benefit from levodopa. Eighteen individuals who remained untreated for over 20 years still showed an impressive response at initiation of therapy. There was more than 10 years of continuous levodopa therapy in 26 individuals, with the longest treatment duration at 22 years. Examination of these individuals while on treatment revealed minor abnormalities of gait, mild scoliosis, slowed foot tapping, or mild postural instability. Nine of the younger individuals were completely normal on exam. Most individuals in whom the duration of levodopa treatment was longer than 5 years were observed to have clinical stability with normal or near normal function. (Tier 3) [2, 4]

One review included 488 individuals from 278 families with GCH1-DRD. Most individuals were white European (39%) or Asian (26%), and 67% were female. In this cohort, 89% of individuals received levodopa and 87% had a positive response. Residual motor signs (mostly dystonia or tremor) after levodopa treatment were reported in 36 individuals (8%). (Tier 5) [5]

A second review of treatment outcome in individuals with DRD, included 408 individuals with genetically confirmed GCH1-DRD. Benefit was reported in 403 of 406 individuals treated with levodopa/DC inhibitor. (Tier 5) [6]

A third review of 352 symptomatic individuals with GCH1-DRD treated with levodopa found that, among individuals with available clinical information, residual motor symptoms were observed with 20% having remaining dystonia and 11% having residual parkinsonism. The residual motor signs included subtle motor signs that did not necessarily interfere with the individuals’ activities of daily life but were detectable on neurologic examination. (Tier 5) [7]

Intensive supervision during and after pregnancy by a multidisciplinary team should be provided. It is important to control disease-related symptoms and adjust the levodopa treatment if needed. (Tier 2) [1]

In 20 pregnancies reported in 12 individuals with GCH1-DRD, levodopa was continued without adverse effect in most. Two women 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. (Tier 3) [2]

Anesthesia recommendations for individuals with GCH1-DRD include strict continuation of levodopa treatment and stress prevention with anxiolytic medication, since delayed intake of dopamine and any kind of stress can cause an amplification of symptoms. Succinylcholine should be avoided in immobilized (e.g., wheelchair-bound) individuals due to the risk of hyperkalemic cardiac arrest and rhabdomyolysis. (Tier 4) [8]

Surveillance

Life-long, systematic follow-up is recommended to achieve optimal development, to prevent or avoid treatment side-effects, and to evaluate quality of life. Individuals should be seen at least yearly by a (child) neurologist with experience in movement disorders or neurometabolic disease, ideally in a multidisciplinary setting. Young children should be seen more frequently; older children at least every 6 months. Follow-up visits should include the evaluation of current medication, neurological symptoms, and general medical history. Feeding and nutritional assessments should always be a part of the care provided to individuals. (Tier 2) [1]

Consider cerebrospinal fluid (CSF) analysis of metabolites homovanillic acid, 5-hydroxyindoleacetic acid, and 5-methyltetrahydrofolate for clarification of otherwise unexplainable clinical irregularities, especially for younger children in whom the spectrum of (neurological) symptoms can be broader or more difficult to assess. (Tier 2) [1]

Circumstances to Avoid

Drugs with antiemetic and antipsychotic properties, acting as central dopamine antagonists, should be avoided since they have the potential to worsen symptoms of dopamine deficiency. Metoclopramide should not be used for the treatment of nausea. Trimethoprim/sulfamethoxazole should be avoided. (Tier 2) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [2, 4]

Prevalence of Genetic Variants

More than 250 pathogenic variants have been reported in individuals with GCH1-DRD. A sequence variant is found in approximately 87% of individuals with GCH1-DRD, and a deletion/duplication in approximately 13%. (Tier 3) [2]

Penetrance

Penetrance in individuals with GCH1-DRD has been reported to be higher in females than in males. Estimates in females range from 87-100% while estimates in males range from 35-55%. (Tier 3) [2]

In a series of 570 individuals with GCH1-DRD, diurnal fluctuation of symptoms, dystonia (postural or action-induced), and gait difficulties were reported in 50% or more of individuals, while hypertonia and hyperreflexia were reported in 25-49% of individuals. (Tier 3) [1]

One review included 488 symptomatic individuals from 278 families with GCH1-DRD. Most individuals were white European (39%) or Asian (26%). Reported signs and symptoms included:
•Dystonia without parkinsonism 70%
•Dystonia-parkinsonism 17%
•Parkinsonism without dystonia 11%
•Diurnal fluctuation of symptoms 31%
•Dyskinesia 6%
•Spasticity 5%
The review also included 151 heterozygous asymptomatic GCH1 pathogenic variant carriers. In females, 25% were symptomatic by 5 years of age and 75% by 15 years of age. In males, 25% were symptomatic by 6 years of age and 75% by 52 years of age. At the age of 30 years, 53% of males were symptomatic and 85% of females. (Tier 5) [5]

Relative Risk

Information on relative risk was not available.

Expressivity

Wide intra- and interfamilial variations in expressivity have been reported in GCH1-DRD. The clinical phenotypic spectrum has been extended to include adult-onset “benign” parkinsonism, various types of focal dystonia, DRD-simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism. (Tier 3) [2]

Age of onset, severity and type of symptoms, or rate of disease progression can differ between family members. (Tier 4) [2]

Due to gender-related incomplete penetrance (i.e., higher penetrance in women than in men), not everyone will display the condition phenotype. (Tier 4) [2, 3]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified in this report include neurological exams, regular evaluations with a movement disorder specialist, and the administration of levodopa/DC inhibitor. Treatment with levodopa/DC inhibitor is burdensome (doses must be divided into 2-6 doses per day) and lifelong. Adverse effects of levodopa treatment include negative motor effects manifested mainly as dyskinesia and as motor fluctuations with on/off phenomenon. Dyskinesias subside following dose reduction and do not reappear when the dose is slowly increased later. Other movement disorders (tremor, chorea, myoclonic jerks) are observed less frequently. Non-motor side effects of levodopa/DC inhibitor include behavioral and psychiatric symptoms such as anxiety, delusions, impulsivity, irritability, hyperactivity, mood fluctuations, panic attacks, sleep disturbances, gastrointestinal problems such as nausea, vomiting, diarrhea and headaches. One study that included 66 individuals with presumed DRD (no genetic testing) reported that at least 10 individuals experienced dyskinesias at the initiation of therapy which disappeared following dose reduction and did not reappear with later dose increase. [1, 2, 3]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

There seems to be a high rate of undiagnosed individuals. The clinical phenotype may overlap with numerous other disorders, e.g., cerebral palsy. The average delay in diagnosis has been stated to be around 10 years. (Tier 3) [1]

One review included 488 individuals from 278 families with GCH1-DRD. There was a median diagnostic delay of 8 years with a wide range from 0 to 61 years. Misdiagnoses were found in 41 individuals (8%), with cerebral palsy and orthopedic conditions being the most prominent. (Tier 5) [5]

Date of Search: 04.04.2017 (updated 01.15.2025)

Reference List

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4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. DYSTONIA, DOPA-RESPONSIVE; DRD. MIM: 128230: 2020 Apr 01. World Wide Web URL: http://omim.org.

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6. Kim R, Jeon B, Lee WW. A Systematic Review of Treatment Outcome in Patients with Dopa-responsive Dystonia (DRD) and DRD-Plus. Mov Disord Clin Pract. (2016) 3(2330-1619):435-442.

7. Tadic V, Kasten M, Bruggemann N, Stiller S, Hagenah J, Klein C. Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs. Arch Neurol. (2012) 69(12):1558-62.

8. Warnecke T, Kamm C, Zafeiriou D. Anaesthesia recommendations for patients suffering from Seqawa's dystonia. Orphan Anesthesia. (2016) Website: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/segawa%E2%80%99s-dystonia/270-segawa%E2%80%99s-dystonia/file.html