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Dystonia 5(DRD)

MedGen UID:
342121
Concept ID:
C1851920
Disease or Syndrome
Synonyms: DRD; Dystonia 5, Dopa-responsive type; Dystonia, Dopa-responsive, autosomal dominant; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia; Dystonia, progressive, with diurnal variation; Dystonia-Parkinsonism with diurnal fluctuation; DYT-GCH1; GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia; Segawa syndrome, autosomal dominant
SNOMED CT: Dopa responsive dystonia (230332007); Autosomal dominant dopa responsive dystonia (715768000); Autosomal dominant Segawa syndrome (715768000); Hereditary progressive dystonia with marked diurnal fluctuation (715768000); Segawa dystonia (230332007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): GCH1 (14q22.2)
 
Monarch Initiative: MONDO:0007495
OMIM®: 128230
Orphanet: ORPHA98808

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. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). 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, and autonomic disturbances generally do not occur. [from GeneReviews]
Authors:
Yoshiaki Furukawa   view full author information

Additional descriptions

From OMIM
Autosomal dominant dopa-responsive dystonia (DRD) is characterized by generalized dystonia, diurnal fluctuation of symptoms, and a dramatic therapeutic response to L-dopa. The clinical spectrum can range from subtle neurologic signs and symptoms (e.g., abnormal writing tests) to orthopedic signs (e.g., pes equinovarus), parkinsonism, and even psychiatric manifestations (summary by Steinberger et al., 2007).  http://www.omim.org/entry/128230
From MedlinePlus Genetics
Rarely, the movement problems associated with dopa-responsive dystonia do not appear until adulthood. In these adult-onset cases, parkinsonism usually develops before dystonia, and movement problems are slow to worsen and do not show diurnal fluctuations.

The movement difficulties associated with dopa-responsive dystonia usually worsen with age but stabilize around age 30. A characteristic feature of dopa-responsive dystonia is worsening of movement problems later in the day and an improvement of symptoms in the morning, after sleep (diurnal fluctuation).

Over time, affected individuals often develop a group of movement abnormalities called parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability).

Signs and symptoms of dopa-responsive dystonia usually appear during childhood, most commonly around age 6. The first signs of the condition are typically the development of inward- and upward-turning feet (clubfeet) and dystonia in the lower limbs. The dystonia spreads to the upper limbs over time; beginning in adolescence, the whole body is typically involved. Affected individuals may have unusual limb positioning and a lack of coordination when walking or running. Some people with this condition have sleep problems or episodes of depression more frequently than would normally be expected.

Dopa-responsive dystonia is a disorder that involves involuntary muscle contractions, tremors, and other uncontrolled movements (dystonia). The features of this condition range from mild to severe. This form of dystonia is called dopa-responsive dystonia because the signs and symptoms typically improve with sustained use of a medication known as L-Dopa.  https://medlineplus.gov/genetics/condition/dopa-responsive-dystonia

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Writer cramp
MedGen UID:
57821
Concept ID:
C0154676
Disease or Syndrome
A focal dystonia of the fingers, hand, and/or forearm that appears when the affected person attempts to do a task that requires fine motor movements such as writing or playing a musical instrument.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Postural tremor
MedGen UID:
66696
Concept ID:
C0234378
Sign or Symptom
A type of tremors that is triggered by holding a limb in a fixed position.
Resting tremor
MedGen UID:
66697
Concept ID:
C0234379
Sign or Symptom
A resting tremor occurs when muscles are at rest and becomes less noticeable or disappears when the affected muscles are moved. Resting tremors are often slow and coarse.
Dysdiadochokinesis
MedGen UID:
115975
Concept ID:
C0234979
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to perform rapidly alternating movements, such as pronating and supinating his or her hand on the dorsum of the other hand as rapidly as possible.
Incoordination
MedGen UID:
141714
Concept ID:
C0520966
Finding
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Parkinsonism with favorable response to dopaminergic medication
MedGen UID:
375989
Concept ID:
C1846868
Disease or Syndrome
Parkinsonism is a clinical syndrome that is a feature of a number of different diseases, including Parkinson disease itself, other neurodegenerative diseases such as progressive supranuclear palsy, and as a side-effect of some neuroleptic medications. Some but not all individuals with Parkinsonism show responsiveness to dopaminergic medication defined as a substantial reduction of amelioration of the component signs of Parkinsonism (including mainly tremor, bradykinesia, rigidity, and postural instability) upon administration of dopaminergic medication.
Impaired distal vibration sensation
MedGen UID:
381262
Concept ID:
C1853767
Finding
A decrease in the ability to perceive vibration in the distal portions of the limbs.
Jaw hyperreflexia
MedGen UID:
765822
Concept ID:
C3552908
Finding
Increased intensity of muscle tendon reflexes in jaw.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Cogwheel rigidity
MedGen UID:
57469
Concept ID:
C0151564
Sign or Symptom
A type of rigidity in which a muscle responds with cogwheellike jerks to the use of constant force in bending the limb (i.e., it gives way in little, repeated jerks when the muscle is passively stretched).
Transient hyperphenylalaninemia
MedGen UID:
78679
Concept ID:
C0268464
Disease or Syndrome
A condition of not having consistently high levels of phenylalanine in the blood but of experiencing temporary hyperphenylalaninemia following ingestion of large quantities of phenylalanine (for instance, following an oral loading test with phenylalanine).
Gaze-evoked horizontal nystagmus
MedGen UID:
377895
Concept ID:
C1853394
Finding
Horizontal nystagmus made apparent by looking to the right or to the left.

Term Hierarchy

Follow this link to review classifications for Dystonia 5 in Orphanet.

Professional guidelines

PubMed

Weissbach A, Pauly MG, Herzog R, Hahn L, Halmans S, Hamami F, Bolte C, Camargos S, Jeon B, Kurian MA, Opladen T, Brüggemann N, Huppertz HJ, König IR, Klein C, Lohmann K
Mov Disord 2022 Feb;37(2):237-252. Epub 2021 Dec 15 doi: 10.1002/mds.28874. PMID: 34908184
Niemann N, Jankovic J
Parkinsonism Relat Disord 2019 Oct;67:74-89. Epub 2019 Jun 30 doi: 10.1016/j.parkreldis.2019.06.025. PMID: 31272925
Luc QN, Querubin J
Paediatr Drugs 2017 Oct;19(5):447-461. doi: 10.1007/s40272-017-0243-3. PMID: 28620849

Recent clinical studies

Etiology

Yoshida K
Clin Oral Investig 2021 Oct;25(10):5755-5764. Epub 2021 May 6 doi: 10.1007/s00784-021-03878-9. PMID: 33956216
Tafreshi AR, Shahrestani S, Lien BV, Ransom S, Brown NJ, Ransom RC, Ballatori AM, Ton A, Chen XT, Sahyouni R, Lee B
Clin Neurol Neurosurg 2021 Jan;200:106372. Epub 2020 Nov 16 doi: 10.1016/j.clineuro.2020.106372. PMID: 33246250
McClelland VM, Cvetkovic Z, Lin JP, Mills KR, Brown P
Clin Neurophysiol 2020 Apr;131(4):967-977. Epub 2020 Feb 4 doi: 10.1016/j.clinph.2020.01.012. PMID: 32067914Free PMC Article
Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ
Neurotox Res 2016 Jan;29(1):105-17. doi: 10.1007/s12640-015-9565-5. PMID: 26467676
Müller U
Brain 2009 Aug;132(Pt 8):2005-25. Epub 2009 Jul 3 doi: 10.1093/brain/awp172. PMID: 19578124

Diagnosis

Yoshida K
Clin Oral Investig 2021 Oct;25(10):5755-5764. Epub 2021 May 6 doi: 10.1007/s00784-021-03878-9. PMID: 33956216
Tafreshi AR, Shahrestani S, Lien BV, Ransom S, Brown NJ, Ransom RC, Ballatori AM, Ton A, Chen XT, Sahyouni R, Lee B
Clin Neurol Neurosurg 2021 Jan;200:106372. Epub 2020 Nov 16 doi: 10.1016/j.clineuro.2020.106372. PMID: 33246250
Tsuboi T, Wong JK, Okun MS, Ramirez-Zamora A
Parkinsonism Relat Disord 2020 Jan;70:82-93. Epub 2019 Nov 18 doi: 10.1016/j.parkreldis.2019.11.016. PMID: 31767450Free PMC Article
Adams CE, Bergman H, Irving CB, Lawrie S
Cochrane Database Syst Rev 2013 Nov 15;(11):CD003082. doi: 10.1002/14651858.CD003082.pub3. PMID: 24242360
Müller U
Brain 2009 Aug;132(Pt 8):2005-25. Epub 2009 Jul 3 doi: 10.1093/brain/awp172. PMID: 19578124

Therapy

Tafreshi AR, Shahrestani S, Lien BV, Ransom S, Brown NJ, Ransom RC, Ballatori AM, Ton A, Chen XT, Sahyouni R, Lee B
Clin Neurol Neurosurg 2021 Jan;200:106372. Epub 2020 Nov 16 doi: 10.1016/j.clineuro.2020.106372. PMID: 33246250
Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ
Neurotox Res 2016 Jan;29(1):105-17. doi: 10.1007/s12640-015-9565-5. PMID: 26467676
Adams CE, Bergman H, Irving CB, Lawrie S
Cochrane Database Syst Rev 2013 Nov 15;(11):CD003082. doi: 10.1002/14651858.CD003082.pub3. PMID: 24242360
Esper CD, Freeman A, Factor SA
Parkinsonism Relat Disord 2010 Aug;16(7):438-41. Epub 2010 May 21 doi: 10.1016/j.parkreldis.2010.04.007. PMID: 20494607
Lauterbach EC, Spears TE, Price ST
J Neuropsychiatry Clin Neurosci 1992 Fall;4(4):435-9. doi: 10.1176/jnp.4.4.435. PMID: 1422171

Prognosis

Segar DJ, Tata N, Harary M, Hayes MT, Cosgrove GR
J Neurosurg 2022 Mar 1;136(3):699-708. Epub 2021 Aug 6 doi: 10.3171/2020.12.JNS202572. PMID: 34359029
Yoshida K
Clin Oral Investig 2021 Oct;25(10):5755-5764. Epub 2021 May 6 doi: 10.1007/s00784-021-03878-9. PMID: 33956216
Tsuboi T, Wong JK, Okun MS, Ramirez-Zamora A
Parkinsonism Relat Disord 2020 Jan;70:82-93. Epub 2019 Nov 18 doi: 10.1016/j.parkreldis.2019.11.016. PMID: 31767450Free PMC Article
Volkmann J, Wolters A, Kupsch A, Müller J, Kühn AA, Schneider GH, Poewe W, Hering S, Eisner W, Müller JU, Deuschl G, Pinsker MO, Skogseid IM, Roeste GK, Krause M, Tronnier V, Schnitzler A, Voges J, Nikkhah G, Vesper J, Classen J, Naumann M, Benecke R; DBS study group for dystonia
Lancet Neurol 2012 Dec;11(12):1029-38. Epub 2012 Nov 1 doi: 10.1016/S1474-4422(12)70257-0. PMID: 23123071
Pittock SJ, Parisi JE, McKeon A, Roemer SF, Lucchinetti CF, Tan KM, Keegan BM, Hunter SF, Duncan PR, Baehring JM, Matsumoto JY, Lennon VA
Arch Neurol 2010 Sep;67(9):1109-15. doi: 10.1001/archneurol.2010.209. PMID: 20837856

Clinical prediction guides

Segar DJ, Tata N, Harary M, Hayes MT, Cosgrove GR
J Neurosurg 2022 Mar 1;136(3):699-708. Epub 2021 Aug 6 doi: 10.3171/2020.12.JNS202572. PMID: 34359029
Tafreshi AR, Shahrestani S, Lien BV, Ransom S, Brown NJ, Ransom RC, Ballatori AM, Ton A, Chen XT, Sahyouni R, Lee B
Clin Neurol Neurosurg 2021 Jan;200:106372. Epub 2020 Nov 16 doi: 10.1016/j.clineuro.2020.106372. PMID: 33246250
Tsuboi T, Wong JK, Okun MS, Ramirez-Zamora A
Parkinsonism Relat Disord 2020 Jan;70:82-93. Epub 2019 Nov 18 doi: 10.1016/j.parkreldis.2019.11.016. PMID: 31767450Free PMC Article
Volkmann J, Wolters A, Kupsch A, Müller J, Kühn AA, Schneider GH, Poewe W, Hering S, Eisner W, Müller JU, Deuschl G, Pinsker MO, Skogseid IM, Roeste GK, Krause M, Tronnier V, Schnitzler A, Voges J, Nikkhah G, Vesper J, Classen J, Naumann M, Benecke R; DBS study group for dystonia
Lancet Neurol 2012 Dec;11(12):1029-38. Epub 2012 Nov 1 doi: 10.1016/S1474-4422(12)70257-0. PMID: 23123071
Pittock SJ, Parisi JE, McKeon A, Roemer SF, Lucchinetti CF, Tan KM, Keegan BM, Hunter SF, Duncan PR, Baehring JM, Matsumoto JY, Lennon VA
Arch Neurol 2010 Sep;67(9):1109-15. doi: 10.1001/archneurol.2010.209. PMID: 20837856

Recent systematic reviews

Tsuboi T, Wong JK, Okun MS, Ramirez-Zamora A
Parkinsonism Relat Disord 2020 Jan;70:82-93. Epub 2019 Nov 18 doi: 10.1016/j.parkreldis.2019.11.016. PMID: 31767450Free PMC Article
Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ
Neurotox Res 2016 Jan;29(1):105-17. doi: 10.1007/s12640-015-9565-5. PMID: 26467676
Adams CE, Bergman H, Irving CB, Lawrie S
Cochrane Database Syst Rev 2013 Nov 15;(11):CD003082. doi: 10.1002/14651858.CD003082.pub3. PMID: 24242360

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