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Disease Profile

GTPCH1-deficient DRD

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Childhood

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ICD-10

G24.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

DYT-GCH1; Dopa-responsive dystonia autosomal dominant Segawa syndrome; DOPA-responsive dystonia, with or without hyperphenylalaninemia;

Categories

Congenital and Genetic Diseases; Nervous System Diseases

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 98808

Definition
A rare neurometabolic disorder characterized by childhood-onset dystonia that shows a dramatic and sustained response to low doses of levodopa (L-dopa) and that may be associated with parkinsonism at an older age.

Epidemiology
The estimated European prevalence of dopa-responsive dystonia (DRD) ranges from 1/1,000,000-1/200,000. DYT5a occurs more frequently than autosomal recessive DRD (DYT5b).

Clinical description
Onset usually occurs in childhood (average age 6 years), and females are 2-4 times more likely to suffer from this disease than males. At onset, DYT5a is typically characterized by lower limb dystonia, most commonly with flexion-inversion of the foot (equinovarus posture) resulting in gait disturbances (that can result in stumbling and falling) with diurnal fluctuations, with symptoms worsening in the evening and improving after sleep. Physical exercise may also aggravate the symptoms. Rarely, arm dystonia, postural tremor of the hands, slowness of movements (bradykinesia) or cervical dystonia are presenting symptoms. In many patients, brisk deep-tendon reflexes and/or dystonic extension of the big toe (striatal toe) are obvious at examination. The disease usually progresses to generalized dystonia, and some patients, especially those with onset in adolescence or adulthood, also develop parkinsonism (manifesting with bradykinesia, rigidity and mainly postural tremor). There is no effect on cognitive or intellectual functioning. Patients with a later disease onset have a milder phenotype. In rare cases depression, anxiety, sleep disturbances and obsessive-compulsive disorder have been reported. Without treatment, adults may suffer from limb contractures.

Etiology
DYT5a is caused by mutations in the GCH1 gene (14q22.1-q22.2), encoding the enzyme GTP cyclohydrolase 1 (GTPCH1). This enzyme is essential in the biosyntheisis of tetrahydrobiopterin (the essential co-factor for tyrosine hydroxylase), which is the rate-limiting enzyme in the biosynthesis of dopamine.

Diagnostic methods
Diagnosis is based on the presence of characteristic clinical symptoms and the dramatic and sustained improvement of symptoms with the administration of low doses of oral L-dopa. Reduced levels of both total biopterin and neopterin in cerebrospinal fluid (CSF) are typically found in DYT5a patients. Reduced GTPCH1 activity in blood cells is also noted. Molecular genetic testing can identify a mutation in the GCH1 gene.

Differential diagnosis
Differential diagnoses include other forms of DRD (e.g. autosomal recessive DRD), early onset torsion dystonia, myoclonic dystonia, hyperphenylalaninemia, hereditary spastic paraplegia, young adult-onset parkinsonism or cerebral palsy.

Antenatal diagnosis
Prenatal diagnosis is possible in families with a known GCH1 mutation.

Genetic counseling
DYT5a is inherited in an autosomal dominant manner, but due to gender-based incomplete penetrance, not everyone with a mutation will display the disease phenotype. Approximately 30-50% of patients with DRD do not report a family history of dystonia. De novo mutations are also possible.

Management and treatment
This form of dystonia shows a dramatic and sustained response to L-dopa therapy. The current suggested initial dosage of L-dopa/decarboxylase inhibitor for children is 25 mg or less, once a day, and in adults 50 mg once or twice a day. These dosages can be increased in small increments if needed, with typical optimal or maximum doses of approximately 10-20 mg/kg/day. If dyskinesia appears after administration of L-dopa, dosage should be decreased. Treatment is life-long, and alleviation of symptoms can usually be noted after a few weeks to a few months.

Prognosis
There is no decrease in life expectancy, and typically there is a complete or almost complete resolution of symptoms with the administration of L-dopa.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
30%-79% of people have these symptoms
Abnormal substantia nigra morphology
0045007
Anxiety
Excessive, persistent worry and fear
0000739
Babinski sign
0003487
Brisk reflexes
0001348
Decreased CSF homovanillic acid
0003785
Depressivity
Depression
0000716
Fatigue
Tired
Tiredness

[ more ]

0012378
Gait ataxia
Inability to coordinate movements when walking
0002066
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Limb dystonia
0002451
Lower limb hyperreflexia
Overactive lower leg reflex
0002395
Parkinsonism
0001300
Pes cavus
High-arched foot
0001761
Postural tremor
0002174
Rigidity
Muscle rigidity
0002063
Sleep disturbance
Difficulty sleeping
Trouble sleeping

[ more ]

0002360
Talipes equinovarus
Club feet
Club foot
Clubfeet
Clubfoot

[ more ]

0001762
Torticollis
Wry neck
0000473
Transient hyperphenylalaninemia
0008297
5%-29% of people have these symptoms
Autosomal recessive inheritance
0000007
Bradykinesia
Slow movements
Slowness of movements

[ more ]

0002067
Generalized dystonia
0007325
Horizontal nystagmus
0000666
Hypertension
0000822
Hypothyroidism
Underactive thyroid
0000821
Impaired vibration sensation in the lower limbs
Decreased lower limb vibratory sense
Decreased vibratory sense in lower limbs
Decreased vibratory sense in the lower extremities
Decreased vibratory sense in the lower limbs
Diminished vibratory sensation in the legs

[ more ]

0002166
Obsessive-compulsive behavior
Obsessive compulsive behavior
0000722
Paresis of extensor muscles of the big toe
0002601
Progressive flexion contractures
0005876
Rheumatoid arthritis
0001370
Scoliosis
0002650
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Childhood onset
Symptoms begin in childhood
0011463
Hyperreflexia
Increased reflexes
0001347
Parkinsonism with favorable response to dopaminergic medication
0002548
Writer's cramp
0002356

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • MedlinePlus Genetics contains information on GTPCH1-deficient DRD. This website is maintained by the National Library of Medicine.
    • The Merck Manual provides information on this condition for patients and caregivers.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.