Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Incomplete (WARNING: Incomplete Stage 2 curation.)

GENE/GENE PANEL: GCH1
Condition: Dopa-Responsive Dystonia
GENEDISEASE PAIRS: GCH1128230
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
GCH1-deficient dopa-responsive dystonia (DRD) is a rare disorder. It is observed worldwide with no increased prevalence in any ethnic group. Prevalence estimates range from 0.5 to 9 per million.
1 2
Clinical Features
(Signs / symptoms)
DRD typically presents with gait disturbance caused by dystonia in the leg, most commonly due to flexion-inversion of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, slowness of movements, or cervical dystonia resulting in stumbling and falling. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe) may be present. Rapid fatiguing with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. 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. 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. 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.
 
The clinical phenotype 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 (sometimes with a relapse in the later course of illness). Individuals with adult-onset “benign” parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood.
1 2 3
Natural History
(Important subgroups & survival / recovery)
DRD typically presents in childhood, with an average age of onset of approximately 6 years (range 1-12 years) following normal early motor development. Though age of onset has been reported as late as 54 years. Patients 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. 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 a female-to-male ratio estimated from 2:1 to 6:1. Women may also have a younger age at onset than men with more frequent onset of dystonia in the lower limbs. There is no decrease in life expectancy.
1 2 3 4
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with DRD, a neurologic examination to assess the severity of motor disturbances and a clinical genetics consultation are recommended. (Tier 4)
1
All individuals with DRD, including those with adult-onset “benign” parkinsonism, 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 (e.g., persons initially diagnosed with cerebral palsy) can show a remarkable response to levodopa. Appropriate levodopa therapy can reverse symptoms and signs. 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. Treatment is lifelong. (Tier 3)
1
There is some evidence that residual symptoms may still occur following the initiation of levodopa. A literature review of 352 symptomatic cases found that, among patients with available clinical information, residual motor symptoms were observed with 32% having remaining dystonia and 16% having residual parkinsonism. However, the authors note that these findings should be interpreted with caution as multiple biases are likely present in the literature. The summarized studies were not population-based and within the clinic samples there may be a selective reporting of atypical or severe cases. In addition, the residual motor signs also included subtle motor signs that did not necessarily interfere with the patients’ activities of daily life, but were detectable on neurologic examination. (Tier 5)
3
There is a marked delay in diagnosis of DRD, which could have consequences on the disability of patients. A literature review of 352 symptomatic cases reported a long delay in diagnosis, where the mean age of onset was 11.6 (SD=13.4) years and the average delay in diagnosis was 13.5 (SD=13.3) years. Complications related to a delay in diagnosis (i.e., contractures, secondary orthopedic deformities, and unnecessary surgical procedures) were identified among 8% of cases; however clinical information was not available for all patients. (Tier 5)
3
There are no definite recommendations for general or regional anesthesia. Due to lack of experience with this exceptionally rare disease, the patient should be monitored at intensive or intermediate care unit post-operatively. The delayed intake of dopamine and any kind of stress could cause an amplification of the symptoms. Levodopa treatment should strictly be continued, and side effects should be considered and monitored. Stress should be strictly prevented with anxiolytic medications. Succinylcholine should be avoided in immobilized (e.g., wheelchair-bound) patients due to the risk of hyperkalemic cardiac arrest and rhabdomyolysis. Monitoring of the neuromuscular blockade is strictly recommended if any neuromuscular blocking agent is used. The temperature should be monitored as usual. (Tier 3)
5
Surveillance
Examination by a movement disorder specialist at least several times yearly is recommended. (Tier 4)
1
Family Management
It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives; 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. (Tier 4)
1
Circumstances to Avoid
Exacerbation of symptoms after taking oral contraceptives (OC) has been reported in some women with DRD. One case report described onset of tremor following OC commencement. Tremor improved significantly when OC was discontinued and recurred when it was recommenced. A second report also reported marked exacerbation of dystonia following OC use in one woman. A third study of 19 women indicated that of the 13 who reported taking OC, 3 reported marked worsening of symptoms during use. (Tier 3)
1
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
The prevalence of pathogenic variants in GCH1 should be similar to the prevalence of GCH1-deficient DRD, which has been estimated from 0.5 per million (Tier 3) to 9 per million (Tier 4). However, given reduced penetrance particularly in males, the prevalence of individuals with symptomatic DRD may be lower.
1 2
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Penetrance in individuals with 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% when defined by symptoms of dystonia with a positive responsive to levodopa. (Tier 3)
1
Information on relative risk was not available.
 
 
Expressivity
Wide intra- and interfamilial variations in expressivity have been reported in DRD. (Tier 3)
1
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. At the initiation of levodopa therapy, some individuals with DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later. Under optimal doses, individuals with DRD on long-term levodopa treatment do not develop either motor response fluctuations (wearing-off and on-off phenomena) or dopa-induced dyskinesias.
1
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
There is a marked delay in diagnosis of DRD, which could have consequences on the disability of patients. A literature review of 352 symptomatic cases reported a long delay in diagnosis, where the average delay in diagnosis was 13.5 (SD=13.3) years. (Tier 5)
3

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Neuromuscular dysfunction / Regular examinations and surveillance by a movement disorder specialist
2
3C
0D
3
8CD
Neuromuscular dysfunction / Levodopa therapy
2
3C
3C
3
11CC
Neuromuscular dysfunction / Avoidance of oral contraceptives
2
3C
2C
2
9CC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Y Furukawa. Gtp cyclohydrolase 1-deficient dopa-responsive dystonia. 2002 Feb 21 [Updated 2015 Mar 05]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1508
2. Autosomal dominant dopa-responsive dystonia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=98808
3. 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.
4. Wijemanne S, Jankovic J. Dopa-responsive dystonia--clinical and genetic heterogeneity. Nat Rev Neurol. (2015) 11(7):414-24.
5. Warnecke T. Anaesthesia recommendations for patients suffering from segawa’s dystonia. Orpananesthesia. (2016) Accessed: 2017-04-05. Website: https://www.orpha.net/data/patho/Ans/en/AutosomalDominantDopa-responsiveDystonia_DE_en_ANS_ORPHA98808.pdf
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