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Autosomal recessive DOPA responsive dystonia

MedGen UID:
382128
Concept ID:
C2673535
Disease or Syndrome
Synonyms: Autosomal Recessive Infantile Parkinsonism; DYT-TH; Segawa syndrome, autosomal recessive; TH-deficient dopa-responsive dystonia; Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TH (11p15.5)
 
Monarch Initiative: MONDO:0011551
OMIM®: 605407
Orphanet: ORPHA101150

Disease characteristics

Excerpted from the GeneReview: Tyrosine Hydroxylase Deficiency
Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by pathogenic variants in TH are divided into (1) TH-deficient dopa-responsive dystonia (the mild form of TH deficiency), (2) TH-deficient infantile parkinsonism with motor delay (the severe form), and (3) TH-deficient progressive infantile encephalopathy (the very severe form). In individuals with TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present. In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor). In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability. [from GeneReviews]
Authors:
Yoshiaki Furukawa  |  Stephen Kish   view full author information

Additional descriptions

From OMIM
Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, and the other shows a less severe course with onset in the first year of life of a progressive hypokinetic-rigid syndrome and generalized dystonia. The less severe type shows a better response to levodopa compared to the more severe type (summary by Stamelou et al., 2012). See also infantile parkinsonism-dystonia syndrome (613135), caused by mutation in the SLC6A3 gene (126455).  http://www.omim.org/entry/605407
From MedlinePlus Genetics
Tyrosine hydroxylase (TH) deficiency is a disorder that primarily affects movement. There are three forms of tyrosine hydroxylase deficiency, and they are categorized based on the severity of their symptoms and their response to treatment. The three forms range in severity from mild to severe.

For those with the mild form of tyrosine hydroxylase deficiency (also called TH-deficient dopa-responsive dystonia), symptoms usually appear during childhood. Affected individuals may have difficulties walking and running, which can sometimes lead to falls. Some people with the disorder may walk on their toes because of stiffness in the leg muscles. Additional signs and symptoms may include involuntary muscle contractions (dystonia) that lead to abnormal repetitive movements in the legs, tremor when holding a position (postural tremor), or involuntary upward-rolling movements of the eyes. Symptoms tend to worsen later in the day for some people with TH-deficient dopa-responsive dystonia. Affected individuals may experience more pronounced movement difficulties as they age, but these symptoms almost always get better with medical treatment.

The more severe forms of tyrosine hydroxylase deficiency are often called TH-deficient infantile parkinsonism or TH-deficient progressive infantile encephalopathy. These forms of the disorder appear soon after birth and are more difficult to treat.

The most severe form of tyrosine hydroxylase deficiency (also called TH-deficient progressive infantile encephalopathy) is characterized by brain dysfunction that leads to profound physical and intellectual disabilities. Signs and symptoms typically begin in the first six months of life. Babies with this form of tyrosine hydroxylase deficiency often have feeding difficulties and delayed growth. Additional features include hypokinesia and abnormal eye movements. This form of tyrosine hydroxylase deficiency is difficult to treat, as affected infants tend to be more likely to experience harmful side effects from the medicine.

Signs and symptoms of TH-deficient infantile parkinsonism typically begin in the first year of life. Affected infants often have delayed development of motor skills such as sitting unsupported or reaching for a toy. Some signs and symptoms may resemble those seen in people with Parkinson disease: stiffness of the muscles in the arms and legs, slow or diminished movements (hypokinesia), and tremors. Additional signs and symptoms may include droopy eyelids (ptosis), involuntary upward-rolling eye movements, and intellectual disabilities. People with TH-deficient infantile parkinsonism may respond to treatment, though treatment may not work right away and may not resolve all of the symptoms of the condition.  https://medlineplus.gov/genetics/condition/tyrosine-hydroxylase-deficiency
From MedlinePlus Genetics
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.

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.

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.

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).

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).  https://medlineplus.gov/genetics/condition/dopa-responsive-dystonia

Clinical features

From HPO
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Limb dystonia
MedGen UID:
152944
Concept ID:
C0751093
Sign or Symptom
A type of dystonia (abnormally increased muscular tone causing fixed abnormal postures) that affects muscles of the limbs.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased CSF homovanillic acid concentration
MedGen UID:
1813045
Concept ID:
C5676596
Finding
Decreased concentration of homovanillic acid (HVA) in the cerebrospinal fluid. HVA is a metabolite of dopamine.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Mask-like facies
MedGen UID:
140860
Concept ID:
C0424448
Finding
A lack of facial expression often with staring eyes and a slightly open mouth.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Autosomal recessive DOPA responsive dystonia 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

Recent clinical studies

Diagnosis

Feng B, Sun G, Kong Q, Li Q
Medicine (Baltimore) 2018 Nov;97(44):e12870. doi: 10.1097/MD.0000000000012870. PMID: 30383639Free PMC Article
Fossbakk A, Kleppe R, Knappskog PM, Martinez A, Haavik J
Hum Mutat 2014 Jul;35(7):880-90. Epub 2014 Jun 3 doi: 10.1002/humu.22565. PMID: 24753243Free PMC Article
Haugarvoll K, Bindoff LA
J Parkinsons Dis 2011;1(1):119-22. doi: 10.3233/JPD-2011-11006. PMID: 23939262
Abeling NG, Duran M, Bakker HD, Stroomer L, Thöny B, Blau N, Booij J, Poll-The BT
Mol Genet Metab 2006 Sep-Oct;89(1-2):116-20. Epub 2006 May 2 doi: 10.1016/j.ymgme.2006.03.010. PMID: 16650784

Therapy

Feng B, Sun G, Kong Q, Li Q
Medicine (Baltimore) 2018 Nov;97(44):e12870. doi: 10.1097/MD.0000000000012870. PMID: 30383639Free PMC Article
Abeling NG, Duran M, Bakker HD, Stroomer L, Thöny B, Blau N, Booij J, Poll-The BT
Mol Genet Metab 2006 Sep-Oct;89(1-2):116-20. Epub 2006 May 2 doi: 10.1016/j.ymgme.2006.03.010. PMID: 16650784

Prognosis

Royo M, Daubner SC, Fitzpatrick PF
Proteins 2005 Jan 1;58(1):14-21. doi: 10.1002/prot.20293. PMID: 15468323Free PMC Article
Bräutigam C, Steenbergen-Spanjers GC, Hoffmann GF, Dionisi-Vici C, van den Heuvel LP, Smeitink JA, Wevers RA
Clin Chem 1999 Dec;45(12):2073-8. PMID: 10585338

Clinical prediction guides

Royo M, Daubner SC, Fitzpatrick PF
Proteins 2005 Jan 1;58(1):14-21. doi: 10.1002/prot.20293. PMID: 15468323Free PMC Article
Bräutigam C, Steenbergen-Spanjers GC, Hoffmann GF, Dionisi-Vici C, van den Heuvel LP, Smeitink JA, Wevers RA
Clin Chem 1999 Dec;45(12):2073-8. PMID: 10585338

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