Autosomal Recessive Dopa-Responsive Dystonia

Genetic MONDO:0011551 Pathograph 27 Dopa-responsive dystonia Inborn Error of Metabolism Movement Disorder

Autosomal recessive dopa-responsive dystonia is a very rare neurometabolic disorder, classically caused by biallelic TH pathogenic variants, in which tyrosine hydroxylase deficiency limits catecholamine and dopamine synthesis. The phenotype ranges from levodopa-responsive childhood dystonia to infantile parkinsonism with motor delay and progressive infantile encephalopathy. Orphanet also lists loss-of-function TSPOAP1 variants for this disease entry, linking presynaptic active-zone dysfunction to recessive dystonia.

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1
Inheritance
4
Pathophys.
33
Phenotypes
27
Pathograph
2
Genes
2
Treatments
3
Subtypes
7
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:20301610 SUPPORT Other
"TH deficiency is inherited in an autosomal recessive manner."
GeneReviews states autosomal recessive inheritance.
◆

Subtypes

3
TH-deficient dopa-responsive dystonia
Mild TH deficiency with childhood lower-limb dystonia, gait disturbance, possible diurnal fluctuation, and complete levodopa responsiveness.
TH-deficient infantile parkinsonism with motor delay
Severe TH deficiency presenting in infancy with motor delay, hypotonia, and parkinsonian signs including hypokinesia, rigidity, and tremor.
TH-deficient progressive infantile encephalopathy
Very severe early-onset TH deficiency with marked motor delay, hypotonia, hyperreflexia, oculogyric crises, ptosis, intellectual disability, lethargy, irritability, sweating, and drooling.
⚙

Pathophysiology

4
TH Enzymatic Deficiency
Biallelic pathogenic variants in TH reduce tyrosine hydroxylase activity, the rate-limiting enzymatic step for catecholamine biosynthesis, thereby limiting dopamine production in central motor circuits.
TH link
catecholamine biosynthetic process link ↓ DECREASED
tyrosine 3-monooxygenase activity link ↓ DECREASED
Downstream
Central Dopamine Biosynthesis Impairment
Show evidence (4 references)
PMID:9703425 SUPPORT Human Clinical
"This report concerns one new mutation in the tyrosine hydroxylase (TH) gene in three patients originating from three unrelated Dutch families with autosomal recessive L-DOPA-responsive dystonia (DRD)."
Human mutation evidence supports TH as a causative gene for autosomal recessive L-DOPA-responsive dystonia.
PMID:20301610 SUPPORT Other
"The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in TH by molecular genetic testing."
GeneReviews supports biallelic TH pathogenic variants as the diagnostic molecular lesion.
PMID:34834538 SUPPORT Other
"TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment."
Expert review supports the biochemical role of TH and links THD to the clinical spectrum.
+ 1 more reference
Central Dopamine Biosynthesis Impairment
Reduced TH activity impairs dopamine synthesis, causing dystonia, parkinsonism, hypokinesia, rigidity, tremor, and oculogyric crises that may improve when levodopa supplies a downstream dopamine precursor.
dopaminergic neuron link
dopamine biosynthetic process link ↓ DECREASED
Downstream
Limb Dystonia
Parkinsonism
Hypokinesia
Rigidity
Postural Tremor
Oculogyric Crisis
Decreased CSF Homovanillic Acid
Infantile Dopamine Deficiency Encephalopathy
Show evidence (3 references)
PMID:34834538 SUPPORT Other
"Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis."
Expert review links DRD to defective dopamine synthesis.
PMID:20301610 SUPPORT Other
"Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor)."
GeneReviews links TH deficiency to parkinsonian motor signs downstream of dopamine synthesis impairment.
PMID:34054692 SUPPORT Human Clinical
"Conclusions: Most DRD patients showed satisfactory treatment outcomes after long-term levodopa, whereas few patients with TH variants presented motor symptoms, which is considered to be related to dopamine insufficiency."
Human DRD cohort links TH-variant motor symptoms to dopamine insufficiency and levodopa responsiveness.
Infantile Dopamine Deficiency Encephalopathy
Severe early-onset TH deficiency can extend beyond focal dystonia to infantile parkinsonism and progressive infantile encephalopathy, with motor delay, hypotonia, ptosis, hyperreflexia, lethargy, irritability, excessive sweating, and drooling.
Downstream
Motor Delay
Hypotonia
Ptosis
Brisk Reflexes
Lethargy
Irritability
Excessive Salivation
Night Sweats
Feeding Difficulties
Progressive Encephalopathy
Show evidence (2 references)
PMID:20301610 SUPPORT Other
"In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months."
GeneReviews supports very early onset in the severe phenotype.
PMID:20301610 SUPPORT Other
"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)..."
GeneReviews supports the infantile encephalopathy clinical consequences.
TSPOAP1 Presynaptic Active-Zone Dysfunction
Biallelic TSPOAP1 variants disrupt RIMBP1-dependent presynaptic active-zone neurotransmitter release; loss-of-function alleles can reduce synaptic transmission and produce juvenile generalized dystonia with intellectual disability and cerebellar atrophy.
Purkinje cell link
TSPOAP1 link
neurotransmitter secretion link ↕ DYSREGULATED
Downstream
Focal Dystonia
Generalized Dystonia
Mild Intellectual Disability
Show evidence (4 references)
PMID:33539324 SUPPORT Human Clinical
"Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families."
Human genetic evidence supports TSPOAP1 as an autosomal recessive dystonia gene.
PMID:33539324 SUPPORT Model Organism
"In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses."
Mouse evidence supports presynaptic active-zone disruption and cerebellar motor network effects.
PMID:33539324 SUPPORT In Vitro
"In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks."
In vitro evidence supports altered neurotransmitter release as a TSPOAP1 disease mechanism.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Recessive Dopa-Responsive Dystonia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

33
Digestive 2
Constipation FREQUENT Constipation (HP:0002019)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002019 | Constipation | Frequent (79-30%) |"
Orphanet lists constipation as frequent.
Feeding Difficulties FREQUENT Feeding difficulties (HP:0011968)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0011968 | Feeding difficulties | Frequent (79-30%) |"
Orphanet lists feeding difficulties as frequent.
Eye 1
Ptosis FREQUENT Ptosis (HP:0000508)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0000508 | Ptosis | Frequent (79-30%) |"
Orphanet lists ptosis as frequent.
Head and Neck 1
Excessive Salivation FREQUENT Excessive salivation (HP:0003781)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0003781 | Excessive salivation | Frequent (79-30%) |"
Orphanet lists excessive salivation as frequent.
Limbs 2
Pes Cavus FREQUENT Pes cavus (HP:0001761)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001761 | Pes cavus | Frequent (79-30%) |"
Orphanet lists pes cavus as frequent.
Talipes Equinovarus FREQUENT Talipes equinovarus (HP:0001762)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001762 | Talipes equinovarus | Frequent (79-30%) |"
Orphanet lists talipes equinovarus as frequent.
Metabolism 1
Fever OCCASIONAL Fever (HP:0001945)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001945 | Fever | Occasional (29-5%) |"
Orphanet lists fever as occasional.
Musculoskeletal 3
Hypotonia FREQUENT Hypotonia (HP:0001252)
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"| HP:0001252 | Hypotonia | Frequent (79-30%) |"
Orphanet lists hypotonia as frequent.
PMID:20301610 SUPPORT Other
"Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor)."
GeneReviews directly supports hypotonia in the infantile TH deficiency spectrum.
Generalized Hypotonia VERY_RARE Generalized hypotonia (HP:0001290)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001290 | Generalized hypotonia | Very rare (<4-1%) |"
Orphanet lists generalized hypotonia as very rare.
Rigidity FREQUENT Rigidity (HP:0002063)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002063 | Rigidity | Frequent (79-30%) |"
Orphanet lists rigidity as frequent.
Nervous System 10
Irritability FREQUENT Irritability (HP:0000737)
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"| HP:0000737 | Irritability | Frequent (79-30%) |"
Orphanet lists irritability as frequent.
PMID:20301610 SUPPORT Other
"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)..."
GeneReviews supports irritability in severe TH deficiency.
Delayed Speech and Language Development FREQUENT Delayed speech and language development (HP:0000750)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0000750 | Delayed speech and language development | Frequent (79-30%) |"
Orphanet lists delayed speech and language development as frequent.
Ataxia FREQUENT Ataxia (HP:0001251)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001251 | Ataxia | Frequent (79-30%) |"
Orphanet lists ataxia as frequent.
Lethargy FREQUENT Lethargy (HP:0001254)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001254 | Lethargy | Frequent (79-30%) |"
Orphanet lists lethargy as frequent.
Mild Intellectual Disability OCCASIONAL Mild intellectual disability (HP:0001256)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001256 | Intellectual disability, mild | Occasional (29-5%) |"
Orphanet lists mild intellectual disability as occasional.
Motor Delay FREQUENT Motor delay (HP:0001270)
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"| HP:0001270 | Motor delay | Frequent (79-30%) |"
Orphanet lists motor delay as frequent.
PMID:20301610 SUPPORT Other
"In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form."
GeneReviews supports motor delay in severe TH deficiency.
Parkinsonism FREQUENT Parkinsonism (HP:0001300)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001300 | Parkinsonism | Frequent (79-30%) |"
Orphanet lists parkinsonism as frequent.
Myoclonus FREQUENT Myoclonus (HP:0001336)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001336 | Myoclonus | Frequent (79-30%) |"
Orphanet lists myoclonus as frequent.
Gait Ataxia FREQUENT Gait ataxia (HP:0002066)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002066 | Gait ataxia | Frequent (79-30%) |"
Orphanet lists gait ataxia as frequent.
Bradykinesia FREQUENT Bradykinesia (HP:0002067)
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"| HP:0002067 | Bradykinesia | Frequent (79-30%) |"
Orphanet lists bradykinesia as frequent.
PMID:30383639 SUPPORT Human Clinical
"RATIONALE: Autosomal-recessive dopa-responsive dystonia (DRD) is a rare clinical disorder presenting as bradykinesia, dystonia, tremor and even severe encephalopathy, and caused by tyrosine hydroxylase deficiency (THD)."
Case-report abstract supports bradykinesia in AR DRD.
Constitutional 1
Night Sweats FREQUENT Night sweats (HP:0030166)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0030166 | Night sweats | Frequent (79-30%) |"
Orphanet lists night sweats as frequent.
Other 12
Brisk Reflexes FREQUENT Brisk reflexes (HP:0001348)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0001348 | Brisk reflexes | Frequent (79-30%) |"
Orphanet lists brisk reflexes as frequent.
Extrapyramidal Motor Dysfunction FREQUENT Abnormality of extrapyramidal motor function (HP:0002071)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002071 | Abnormality of extrapyramidal motor function | Frequent (79-30%) |"
Orphanet lists abnormal extrapyramidal motor function as frequent.
Postural Tremor FREQUENT Postural tremor (HP:0002174)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002174 | Postural tremor | Frequent (79-30%) |"
Orphanet lists postural tremor as frequent.
Hypokinesia FREQUENT Hypokinesia (HP:0002375)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002375 | Hypokinesia | Frequent (79-30%) |"
Orphanet lists hypokinesia as frequent.
Lower Limb Hyperreflexia FREQUENT Lower limb hyperreflexia (HP:0002395)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002395 | Lower limb hyperreflexia | Frequent (79-30%) |"
Orphanet lists lower limb hyperreflexia as frequent.
Progressive Encephalopathy VERY_RARE Progressive encephalopathy (HP:0002448)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0002448 | Progressive encephalopathy | Very rare (<4-1%) |"
Orphanet lists progressive encephalopathy as very rare.
Limb Dystonia FREQUENT Limb dystonia (HP:0002451)
Show evidence (2 references)
ORPHA:101150 SUPPORT Other
"| HP:0002451 | Limb dystonia | Frequent (79-30%) |"
Orphanet lists limb dystonia as frequent.
PMID:20301610 SUPPORT Other
"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."
GeneReviews supports lower-limb dystonia as a typical initial symptom.
Babinski Sign FREQUENT Babinski sign (HP:0003487)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0003487 | Babinski sign | Frequent (79-30%) |"
Orphanet lists Babinski sign as frequent.
Decreased CSF Homovanillic Acid FREQUENT Decreased CSF homovanillic acid concentration (HP:0003785)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0003785 | Decreased CSF homovanillic acid concentration | Frequent (79-30%) |"
Orphanet lists decreased CSF homovanillic acid concentration as frequent.
Focal Dystonia FREQUENT Focal dystonia (HP:0004373)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0004373 | Focal dystonia | Frequent (79-30%) |"
Orphanet lists focal dystonia as frequent.
Generalized Dystonia OCCASIONAL Generalized dystonia (HP:0007325)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0007325 | Generalized dystonia | Occasional (29-5%) |"
Orphanet lists generalized dystonia as occasional.
Oculogyric Crisis FREQUENT Oculogyric crisis (HP:0010553)
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0010553 | Oculogyric crisis | Frequent (79-30%) |"
Orphanet lists oculogyric crisis as frequent.
🧬

Genetic Associations

2
TH biallelic pathogenic variants (Causative biallelic pathogenic variants)
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301610 SUPPORT Other
"The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in TH by molecular genetic testing."
Supports biallelic TH pathogenic variants as diagnostic.
ORPHA:101150 SUPPORT Other
"| TH | tyrosine hydroxylase | hgnc:11782 | Disease-causing germline mutation(s) in |"
Orphanet lists TH as a disease-causing gene.
TSPOAP1 biallelic loss-of-function variants (Biallelic loss-of-function variants)
Show evidence (2 references)
PMID:33539324 SUPPORT Human Clinical
"Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families."
Human genetic evidence supports TSPOAP1 biallelic variants.
ORPHA:101150 SUPPORT Other
"| TSPOAP1 | TSPO associated protein 1 | hgnc:16831 | Disease-causing germline mutation(s) (loss of function) in |"
Orphanet lists TSPOAP1 for this disease entry.
💊

Treatments

2
Levodopa with decarboxylase inhibitor
Action: Pharmacotherapy NCIT:C15986
Agent: levodopa ↗
Levodopa, typically paired with a decarboxylase inhibitor, bypasses the TH enzymatic block by supplying a downstream dopamine precursor; dosing is usually low and titrated carefully because severe TH deficiency can be levodopa-sensitive.
Mechanism Target:
BYPASSES Central Dopamine Biosynthesis Impairment
Target Phenotypes: Limb dystonia ↗ Parkinsonism ↗ Rigidity ↗
Show evidence (3 references)
PMID:20301610 SUPPORT Other
"All individuals with TH-deficient DRD demonstrate complete responsiveness of symptoms to levodopa (with a decarboxylase inhibitor)."
GeneReviews supports levodopa with a decarboxylase inhibitor for TH-deficient DRD.
PMID:20301610 SUPPORT Other
"Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa."
GeneReviews supports marked levodopa response in the severe motor-delay subtype.
PMID:30383639 SUPPORT Human Clinical
"INTERVENTIONS: The patient was administrated low-dose levodopa. OUTCOMES: The treatment resulted in the substantial improvement of dystonia."
Human case report supports low-dose levodopa improving dystonia.
Agents/Circumstances to Avoid
Action: supportive care MAXO:0000950
The prokinetic agent metoclopramide (Reglan) and other related antidopaminergic agents should be avoided because they can acutely worsen the dopamine deficiency that underlies TH-deficient dopa-responsive dystonia.
Show evidence (1 reference)
PMID:20301610 SUPPORT Other
"Agents/circumstances to avoid: The prokinetic agent Reglan® and other related antidopaminergic agents."
GeneReviews explicitly lists the prokinetic agent metoclopramide (Reglan) and other related antidopaminergic agents as agents to avoid in tyrosine hydroxylase deficiency, since they can exacerbate the underlying dopamine deficit.
🔬

Biochemical Markers

1
CSF homovanillic acid (DECREASED)
Context: Low CSF homovanillic acid is a neurotransmitter-metabolite clue to central dopamine synthesis impairment in TH deficiency.
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"| HP:0003785 | Decreased CSF homovanillic acid concentration | Frequent (79-30%) |"
Orphanet lists decreased CSF homovanillic acid as frequent.
{ }

Source YAML

click to show 
name: Autosomal Recessive Dopa-Responsive Dystonia
creation_date: "2026-05-06T07:55:00Z"
updated_date: "2026-05-06T07:55:00Z"
category: Genetic
parents:
- Dopa-responsive dystonia
- Inborn Error of Metabolism
- Movement Disorder
disease_term:
  preferred_term: TH-deficient dopa-responsive dystonia
  term:
    id: MONDO:0011551
    label: TH-deficient dopa-responsive dystonia
synonyms:
- Autosomal recessive Segawa syndrome
- DYT5b
- Tyrosine hydroxylase deficiency
- Tyrosine hydroxylase-deficient dopa-responsive dystonia
description: >-
  Autosomal recessive dopa-responsive dystonia is a very rare neurometabolic
  disorder, classically caused by biallelic TH pathogenic variants, in which
  tyrosine hydroxylase deficiency limits catecholamine and dopamine synthesis.
  The phenotype ranges from levodopa-responsive childhood dystonia to infantile
  parkinsonism with motor delay and progressive infantile encephalopathy.
  Orphanet also lists loss-of-function TSPOAP1 variants for this disease entry,
  linking presynaptic active-zone dysfunction to recessive dystonia.
notes: >-
  ORPHA:101150 cross-references this entity to MONDO:0011551, OMIM:605407,
  MeSH:C537537, ICD-10:G24.1, ICD-11:8A02.11, and UMLS:C5700309.
has_subtypes:
- name: TH-deficient DRD
  display_name: TH-deficient dopa-responsive dystonia
  description: >-
    Mild TH deficiency with childhood lower-limb dystonia, gait disturbance,
    possible diurnal fluctuation, and complete levodopa responsiveness.
- name: Infantile parkinsonism
  display_name: TH-deficient infantile parkinsonism with motor delay
  description: >-
    Severe TH deficiency presenting in infancy with motor delay, hypotonia, and
    parkinsonian signs including hypokinesia, rigidity, and tremor.
- name: Progressive infantile encephalopathy
  display_name: TH-deficient progressive infantile encephalopathy
  description: >-
    Very severe early-onset TH deficiency with marked motor delay, hypotonia,
    hyperreflexia, oculogyric crises, ptosis, intellectual disability, lethargy,
    irritability, sweating, and drooling.
references:
- reference: ORPHA:101150
  title: Autosomal recessive dopa-responsive dystonia
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: >-
      Orphanet defines autosomal recessive dopa-responsive dystonia as a very
      rare neurometabolic disorder spanning DRD to progressive infantile
      encephalopathy.
    supporting_text: >-
      A very rare neurometabolic disorder characterized by a spectrum of
      symptoms ranging from those seen in dopa-responsive dystonia (DRD) to
      progressive infantile encephalopathy.
    evidence:
    - reference: ORPHA:101150
      reference_title: "Autosomal recessive dopa-responsive dystonia"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A very rare neurometabolic disorder characterized by a spectrum of
        symptoms ranging from those seen in dopa-responsive dystonia (DRD) to
        progressive infantile encephalopathy.
      explanation: >-
        Orphanet definition supports the disease scope and severity spectrum.
- reference: PMID:20301610
  title: Tyrosine Hydroxylase Deficiency.
  tags:
  - GeneReviews
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: >-
      GeneReviews supports TH deficiency subtypes, biallelic molecular
      diagnosis, autosomal recessive inheritance, and levodopa management.
    supporting_text: >-
      GeneReviews describes TH-deficient DRD, infantile parkinsonism with motor
      delay, and progressive infantile encephalopathy, and states that diagnosis
      is established by biallelic TH pathogenic variants.
- reference: PMID:34834538
  title: Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency.
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: TH deficiency impairs catecholamine and dopamine synthesis.
    supporting_text: >-
      The expert review states that DRD is associated with defective dopamine
      synthesis and that TH catalyzes the rate-limiting step in catecholamine
      biosynthesis.
- reference: PMID:9703425
  title: A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population.
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: Human mutation evidence links TH variants to autosomal recessive L-DOPA-responsive dystonia.
    supporting_text: >-
      The report identified homozygous TH R233H in three unrelated Dutch
      patients with autosomal recessive L-DOPA-responsive dystonia.
- reference: PMID:34054692
  title: Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes.
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: Human DRD cohort evidence includes patients with TH variants and long-term levodopa outcomes.
    supporting_text: >-
      The cohort included 20 genetically diagnosed DRD patients, nine with TH
      variants, and reported mostly satisfactory long-term levodopa outcomes.
- reference: PMID:30383639
  title: "Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report."
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: A Chinese case report supports TH compound heterozygosity, AR DRD symptoms, genetic diagnosis, and low-dose levodopa response.
    supporting_text: >-
      The abstract reports bradykinesia, dystonia, tremor, encephalopathy,
      compound heterozygous TH mutations, low-dose levodopa, and substantial
      dystonia improvement.
- reference: PMID:33539324
  title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
  found_in:
  - Autosomal_Recessive_Dopa_Responsive_Dystonia-deep-research-fallback.md
  findings:
  - statement: TSPOAP1 biallelic variants cause autosomal recessive dystonia through presynaptic active-zone dysfunction.
    supporting_text: >-
      The study describes biallelic TSPOAP1 variants in seven subjects from
      three families, mouse motor abnormalities, and in vitro calcium/transmitter
      release effects.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TH deficiency is inherited in an autosomal recessive manner."
    explanation: GeneReviews states autosomal recessive inheritance.
prevalence:
- population: Europe
  percentage: 1-9 / 1 000 000
  notes: Orphanet records European point prevalence in the one-to-nine per million range.
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| 1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET |"
    explanation: Orphanet lists European point prevalence.
pathophysiology:
- name: TH Enzymatic Deficiency
  description: >-
    Biallelic pathogenic variants in TH reduce tyrosine hydroxylase activity,
    the rate-limiting enzymatic step for catecholamine biosynthesis, thereby
    limiting dopamine production in central motor circuits.
  genes:
  - preferred_term: TH
    term:
      id: hgnc:11782
      label: TH
  molecular_functions:
  - preferred_term: tyrosine 3-monooxygenase activity
    term:
      id: GO:0004511
      label: tyrosine 3-monooxygenase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: catecholamine biosynthetic process
    term:
      id: GO:0042423
      label: catecholamine biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Central Dopamine Biosynthesis Impairment
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:9703425
    reference_title: "A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report concerns one new mutation in the tyrosine hydroxylase (TH)
      gene in three patients originating from three unrelated Dutch families
      with autosomal recessive L-DOPA-responsive dystonia (DRD).
    explanation: >-
      Human mutation evidence supports TH as a causative gene for autosomal
      recessive L-DOPA-responsive dystonia.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of TH deficiency is established in a proband by
      identification of biallelic pathogenic variants in TH by molecular genetic
      testing.
    explanation: >-
      GeneReviews supports biallelic TH pathogenic variants as the diagnostic
      molecular lesion.
  - reference: PMID:34834538
    reference_title: "Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TH is a key enzyme that catalyzes the rate-limiting step in catecholamine
      biosynthesis, and THD patients often present with complex and variable
      phenotypes, which results in frequent misdiagnosis and lack of appropriate
      treatment.
    explanation: >-
      Expert review supports the biochemical role of TH and links THD to the
      clinical spectrum.
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| TH | tyrosine hydroxylase | hgnc:11782 | Disease-causing germline mutation(s) in |"
    explanation: Orphanet lists TH as a disease-causing gene.
- name: Central Dopamine Biosynthesis Impairment
  description: >-
    Reduced TH activity impairs dopamine synthesis, causing dystonia,
    parkinsonism, hypokinesia, rigidity, tremor, and oculogyric crises that may
    improve when levodopa supplies a downstream dopamine precursor.
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  biological_processes:
  - preferred_term: dopamine biosynthetic process
    term:
      id: GO:0042416
      label: dopamine biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Limb Dystonia
    causal_link_type: DIRECT
  - target: Parkinsonism
    causal_link_type: DIRECT
  - target: Hypokinesia
    causal_link_type: DIRECT
  - target: Rigidity
    causal_link_type: DIRECT
  - target: Postural Tremor
    causal_link_type: DIRECT
  - target: Oculogyric Crisis
    causal_link_type: DIRECT
  - target: Decreased CSF Homovanillic Acid
    causal_link_type: DIRECT
  - target: Infantile Dopamine Deficiency Encephalopathy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34834538
    reference_title: "Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dopa-responsive dystonia (DRD) is a rare movement disorder associated
      with defective dopamine synthesis.
    explanation: Expert review links DRD to defective dopamine synthesis.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected infants demonstrate truncal hypotonia and parkinsonian symptoms
      and signs (hypokinesia, rigidity of extremities, and/or tremor).
    explanation: >-
      GeneReviews links TH deficiency to parkinsonian motor signs downstream of
      dopamine synthesis impairment.
  - reference: PMID:34054692
    reference_title: "Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conclusions: Most DRD patients showed satisfactory treatment outcomes
      after long-term levodopa, whereas few patients with TH variants presented
      motor symptoms, which is considered to be related to dopamine
      insufficiency.
    explanation: >-
      Human DRD cohort links TH-variant motor symptoms to dopamine
      insufficiency and levodopa responsiveness.
- name: Infantile Dopamine Deficiency Encephalopathy
  description: >-
    Severe early-onset TH deficiency can extend beyond focal dystonia to
    infantile parkinsonism and progressive infantile encephalopathy, with motor
    delay, hypotonia, ptosis, hyperreflexia, lethargy, irritability, excessive
    sweating, and drooling.
  downstream:
  - target: Motor Delay
    causal_link_type: DIRECT
  - target: Hypotonia
    causal_link_type: DIRECT
  - target: Ptosis
    causal_link_type: DIRECT
  - target: Brisk Reflexes
    causal_link_type: DIRECT
  - target: Lethargy
    causal_link_type: DIRECT
  - target: Irritability
    causal_link_type: DIRECT
  - target: Excessive Salivation
    causal_link_type: DIRECT
  - target: Night Sweats
    causal_link_type: DIRECT
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Progressive Encephalopathy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In individuals with TH-deficient progressive infantile encephalopathy,
      onset is before age three to six months.
    explanation: GeneReviews supports very early onset in the severe phenotype.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: >-
      GeneReviews supports the infantile encephalopathy clinical consequences.
- name: TSPOAP1 Presynaptic Active-Zone Dysfunction
  description: >-
    Biallelic TSPOAP1 variants disrupt RIMBP1-dependent presynaptic active-zone
    neurotransmitter release; loss-of-function alleles can reduce synaptic
    transmission and produce juvenile generalized dystonia with intellectual
    disability and cerebellar atrophy.
  genes:
  - preferred_term: TSPOAP1
    term:
      id: hgnc:16831
      label: TSPOAP1
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: neurotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
    modifier: DYSREGULATED
  downstream:
  - target: Focal Dystonia
    causal_link_type: DIRECT
  - target: Generalized Dystonia
    causal_link_type: DIRECT
  - target: Mild Intellectual Disability
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33539324
    reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe homozygous frameshift, nonsense, and missense variants
      in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1),
      as a genetic cause of autosomal recessive dystonia in 7 subjects from 3
      unrelated families.
    explanation: >-
      Human genetic evidence supports TSPOAP1 as an autosomal recessive dystonia
      gene.
  - reference: PMID:33539324
    reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, complete loss of RIMBP1, known to reduce neurotransmission, led
      to motor abnormalities reminiscent of dystonia, decreased Purkinje cell
      dendritic arborization, and reduced numbers of cerebellar synapses.
    explanation: >-
      Mouse evidence supports presynaptic active-zone disruption and cerebellar
      motor network effects.
  - reference: PMID:33539324
    reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked
      calcium transients and enhanced neurotransmission, suggesting that
      RIMBP1-linked dystonia can be caused by either reduced or enhanced rates
      of spike-evoked release in relevant neural networks.
    explanation: >-
      In vitro evidence supports altered neurotransmitter release as a TSPOAP1
      disease mechanism.
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | TSPOAP1 | TSPO associated protein 1 | hgnc:16831 | Disease-causing
      germline mutation(s) (loss of function) in |
    explanation: Orphanet lists TSPOAP1 loss-of-function variants for this entry.
phenotypes:
- category: Ophthalmologic
  name: Ptosis
  description: Ptosis is frequent in the severe TH deficiency spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000508 | Ptosis | Frequent (79-30%) |"
    explanation: Orphanet lists ptosis as frequent.
- category: Neurologic
  name: Irritability
  description: Irritability is frequent and may alternate with lethargic episodes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0000737 | Irritability | Frequent (79-30%) |"
    explanation: Orphanet lists irritability as frequent.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: GeneReviews supports irritability in severe TH deficiency.
- category: Developmental
  name: Delayed Speech and Language Development
  description: Delayed speech and language development is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0000750 | Delayed speech and language development | Frequent
      (79-30%) |
    explanation: >-
      Orphanet lists delayed speech and language development as frequent.
- category: Neurologic
  name: Ataxia
  description: Ataxia is a frequent neurologic feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001251 | Ataxia | Frequent (79-30%) |"
    explanation: Orphanet lists ataxia as frequent.
- category: Neurologic
  name: Hypotonia
  description: Hypotonia is frequent, especially in infantile TH deficiency.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001252 | Hypotonia | Frequent (79-30%) |"
    explanation: Orphanet lists hypotonia as frequent.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected infants demonstrate truncal hypotonia and parkinsonian symptoms
      and signs (hypokinesia, rigidity of extremities, and/or tremor).
    explanation: >-
      GeneReviews directly supports hypotonia in the infantile TH deficiency
      spectrum.
- category: Neurologic
  name: Lethargy
  description: Lethargy is frequent in severe TH deficiency.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001254 | Lethargy | Frequent (79-30%) |"
    explanation: Orphanet lists lethargy as frequent.
- category: Neurologic
  name: Mild Intellectual Disability
  description: Mild intellectual disability is reported occasionally.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001256 | Intellectual disability, mild | Occasional (29-5%) |"
    explanation: Orphanet lists mild intellectual disability as occasional.
- category: Neurologic
  name: Motor Delay
  description: Motor delay is frequent in the infantile forms.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001270 | Motor delay | Frequent (79-30%) |"
    explanation: Orphanet lists motor delay as frequent.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In contrast to TH-deficient DRD, motor milestones are overtly delayed in
      this severe form.
    explanation: GeneReviews supports motor delay in severe TH deficiency.
- category: Neurologic
  name: Generalized Hypotonia
  description: Generalized hypotonia is reported very rarely by Orphanet.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001290 | Generalized hypotonia | Very rare (<4-1%) |"
    explanation: Orphanet lists generalized hypotonia as very rare.
- category: Neurologic
  name: Parkinsonism
  description: Parkinsonism is frequent, particularly in infantile motor-delay cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001300 | Parkinsonism | Frequent (79-30%) |"
    explanation: Orphanet lists parkinsonism as frequent.
- category: Neurologic
  name: Myoclonus
  description: Myoclonus is a frequent movement feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001336 | Myoclonus | Frequent (79-30%) |"
    explanation: Orphanet lists myoclonus as frequent.
- category: Neurologic
  name: Brisk Reflexes
  description: Brisk reflexes and hyperreflexia are frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Brisk reflexes
    term:
      id: HP:0001348
      label: Brisk reflexes
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001348 | Brisk reflexes | Frequent (79-30%) |"
    explanation: Orphanet lists brisk reflexes as frequent.
- category: Musculoskeletal
  name: Pes Cavus
  description: Pes cavus is a frequent foot phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001761 | Pes cavus | Frequent (79-30%) |"
    explanation: Orphanet lists pes cavus as frequent.
- category: Musculoskeletal
  name: Talipes Equinovarus
  description: Talipes equinovarus is a frequent foot posture abnormality.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001762 | Talipes equinovarus | Frequent (79-30%) |"
    explanation: Orphanet lists talipes equinovarus as frequent.
- category: Constitutional
  name: Fever
  description: Fever is reported occasionally.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0001945 | Fever | Occasional (29-5%) |"
    explanation: Orphanet lists fever as occasional.
- category: Gastrointestinal
  name: Constipation
  description: Constipation is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002019 | Constipation | Frequent (79-30%) |"
    explanation: Orphanet lists constipation as frequent.
- category: Neurologic
  name: Rigidity
  description: Rigidity is a frequent parkinsonian sign.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002063 | Rigidity | Frequent (79-30%) |"
    explanation: Orphanet lists rigidity as frequent.
- category: Neurologic
  name: Gait Ataxia
  description: Gait ataxia is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002066 | Gait ataxia | Frequent (79-30%) |"
    explanation: Orphanet lists gait ataxia as frequent.
- category: Neurologic
  name: Bradykinesia
  description: Bradykinesia is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bradykinesia
    term:
      id: HP:0002067
      label: Bradykinesia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002067 | Bradykinesia | Frequent (79-30%) |"
    explanation: Orphanet lists bradykinesia as frequent.
  - reference: PMID:30383639
    reference_title: "Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RATIONALE: Autosomal-recessive dopa-responsive dystonia (DRD) is a rare
      clinical disorder presenting as bradykinesia, dystonia, tremor and even
      severe encephalopathy, and caused by tyrosine hydroxylase deficiency
      (THD).
    explanation: Case-report abstract supports bradykinesia in AR DRD.
- category: Neurologic
  name: Extrapyramidal Motor Dysfunction
  description: Extrapyramidal motor dysfunction is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of extrapyramidal motor function
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0002071 | Abnormality of extrapyramidal motor function | Frequent
      (79-30%) |
    explanation: Orphanet lists abnormal extrapyramidal motor function as frequent.
- category: Neurologic
  name: Postural Tremor
  description: Postural tremor is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002174 | Postural tremor | Frequent (79-30%) |"
    explanation: Orphanet lists postural tremor as frequent.
- category: Neurologic
  name: Hypokinesia
  description: Hypokinesia is frequent in the parkinsonian TH deficiency spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypokinesia
    term:
      id: HP:0002375
      label: Hypokinesia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002375 | Hypokinesia | Frequent (79-30%) |"
    explanation: Orphanet lists hypokinesia as frequent.
- category: Neurologic
  name: Lower Limb Hyperreflexia
  description: Lower limb hyperreflexia is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lower limb hyperreflexia
    term:
      id: HP:0002395
      label: Lower limb hyperreflexia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002395 | Lower limb hyperreflexia | Frequent (79-30%) |"
    explanation: Orphanet lists lower limb hyperreflexia as frequent.
- category: Neurologic
  name: Progressive Encephalopathy
  description: Progressive encephalopathy is reported very rarely in the severe spectrum.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Progressive encephalopathy
    term:
      id: HP:0002448
      label: Progressive encephalopathy
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002448 | Progressive encephalopathy | Very rare (<4-1%) |"
    explanation: Orphanet lists progressive encephalopathy as very rare.
- category: Neurologic
  name: Limb Dystonia
  description: Limb dystonia is frequent and often begins in the lower limbs.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Limb dystonia
    term:
      id: HP:0002451
      label: Limb dystonia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0002451 | Limb dystonia | Frequent (79-30%) |"
    explanation: Orphanet lists limb dystonia as frequent.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      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.
    explanation: GeneReviews supports lower-limb dystonia as a typical initial symptom.
- category: Neurologic
  name: Babinski Sign
  description: Babinski sign is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0003487 | Babinski sign | Frequent (79-30%) |"
    explanation: Orphanet lists Babinski sign as frequent.
- category: Autonomic
  name: Excessive Salivation
  description: Excessive salivation and drooling are frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Excessive salivation
    term:
      id: HP:0003781
      label: Excessive salivation
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0003781 | Excessive salivation | Frequent (79-30%) |"
    explanation: Orphanet lists excessive salivation as frequent.
- category: Biochemical
  name: Decreased CSF Homovanillic Acid
  description: >-
    Decreased CSF homovanillic acid reflects impaired central dopamine
    metabolism and is listed as frequent by Orphanet.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased CSF homovanillic acid concentration
    term:
      id: HP:0003785
      label: Decreased CSF homovanillic acid concentration
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0003785 | Decreased CSF homovanillic acid concentration | Frequent
      (79-30%) |
    explanation: >-
      Orphanet lists decreased CSF homovanillic acid concentration as frequent.
- category: Neurologic
  name: Focal Dystonia
  description: Focal dystonia is frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Focal dystonia
    term:
      id: HP:0004373
      label: Focal dystonia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0004373 | Focal dystonia | Frequent (79-30%) |"
    explanation: Orphanet lists focal dystonia as frequent.
- category: Neurologic
  name: Generalized Dystonia
  description: Generalized dystonia is reported occasionally.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0007325
      label: Generalized dystonia
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0007325 | Generalized dystonia | Occasional (29-5%) |"
    explanation: Orphanet lists generalized dystonia as occasional.
- category: Neurologic
  name: Oculogyric Crisis
  description: Oculogyric crises are frequent in severe early-onset TH deficiency.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Oculogyric crisis
    term:
      id: HP:0010553
      label: Oculogyric crisis
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0010553 | Oculogyric crisis | Frequent (79-30%) |"
    explanation: Orphanet lists oculogyric crisis as frequent.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: Feeding difficulties are frequent in the infantile disease spectrum.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0011968 | Feeding difficulties | Frequent (79-30%) |"
    explanation: Orphanet lists feeding difficulties as frequent.
- category: Autonomic
  name: Night Sweats
  description: Night sweats are frequent.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| HP:0030166 | Night sweats | Frequent (79-30%) |"
    explanation: Orphanet lists night sweats as frequent.
biochemical:
- name: CSF homovanillic acid
  biomarker_term:
    preferred_term: CSF homovanillic acid
    term:
      id: CHEBI:545959
      label: homovanillic acid
  presence: DECREASED
  context: >-
    Low CSF homovanillic acid is a neurotransmitter-metabolite clue to central
    dopamine synthesis impairment in TH deficiency.
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0003785 | Decreased CSF homovanillic acid concentration | Frequent
      (79-30%) |
    explanation: Orphanet lists decreased CSF homovanillic acid as frequent.
genetic:
- name: TH biallelic pathogenic variants
  gene_term:
    preferred_term: TH
    term:
      id: hgnc:11782
      label: TH
  association: Causative biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301610
      reference_title: "Tyrosine Hydroxylase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "TH deficiency is inherited in an autosomal recessive manner."
      explanation: GeneReviews supports autosomal recessive inheritance.
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of TH deficiency is established in a proband by
      identification of biallelic pathogenic variants in TH by molecular genetic
      testing.
    explanation: Supports biallelic TH pathogenic variants as diagnostic.
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| TH | tyrosine hydroxylase | hgnc:11782 | Disease-causing germline mutation(s) in |"
    explanation: Orphanet lists TH as a disease-causing gene.
- name: TSPOAP1 biallelic loss-of-function variants
  gene_term:
    preferred_term: TSPOAP1
    term:
      id: hgnc:16831
      label: TSPOAP1
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Orphanet lists TSPOAP1 loss-of-function variants for this disease entry;
    the primary TSPOAP1 study reports biallelic variants causing autosomal
    recessive dystonia.
  evidence:
  - reference: PMID:33539324
    reference_title: "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe homozygous frameshift, nonsense, and missense variants
      in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1),
      as a genetic cause of autosomal recessive dystonia in 7 subjects from 3
      unrelated families.
    explanation: Human genetic evidence supports TSPOAP1 biallelic variants.
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | TSPOAP1 | TSPO associated protein 1 | hgnc:16831 | Disease-causing
      germline mutation(s) (loss of function) in |
    explanation: Orphanet lists TSPOAP1 for this disease entry.
diagnosis:
- name: Molecular genetic testing
  presence: Positive
  description: >-
    Diagnosis is established by identifying biallelic pathogenic variants in TH;
    TSPOAP1 should be considered when a recessive dystonia phenotype and genetic
    findings indicate presynaptic active-zone disease.
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of TH deficiency is established in a proband by
      identification of biallelic pathogenic variants in TH by molecular genetic
      testing.
    explanation: GeneReviews supports molecular genetic testing for TH deficiency.
  - reference: PMID:30383639
    reference_title: "Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LESSONS: Gene mutation analysis is helpful and necessary to diagnose DRD
      and has important guiding significance for the subsequent treatment.
    explanation: Case-report abstract supports genetic testing for AR DRD diagnosis.
- name: CSF neurotransmitter metabolite testing
  presence: Positive
  description: >-
    Decreased CSF homovanillic acid can support a central dopamine-synthesis
    defect consistent with TH deficiency.
  evidence:
  - reference: ORPHA:101150
    reference_title: "Autosomal recessive dopa-responsive dystonia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | HP:0003785 | Decreased CSF homovanillic acid concentration | Frequent
      (79-30%) |
    explanation: Orphanet supports decreased CSF homovanillic acid as a frequent diagnostic clue.
- name: Levodopa responsiveness
  presence: Positive
  description: >-
    Clinical response to levodopa helps distinguish TH-deficient DRD from other
    early-onset movement disorders, though severe infantile forms may respond
    incompletely or be limited by dyskinesias.
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      All individuals with TH-deficient DRD demonstrate complete responsiveness
      of symptoms to levodopa (with a decarboxylase inhibitor).
    explanation: GeneReviews supports levodopa responsiveness in the mild subtype.
  - reference: PMID:34054692
    reference_title: "Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most DRD patients showed satisfactory treatment outcomes after long-term
      levodopa, whereas few patients with TH variants presented motor symptoms,
      which is considered to be related to dopamine insufficiency.
    explanation: Human cohort supports long-term levodopa response in DRD.
treatments:
- name: Levodopa with decarboxylase inhibitor
  description: >-
    Levodopa, typically paired with a decarboxylase inhibitor, bypasses the TH
    enzymatic block by supplying a downstream dopamine precursor; dosing is
    usually low and titrated carefully because severe TH deficiency can be
    levodopa-sensitive.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_phenotypes:
  - preferred_term: Limb dystonia
    term:
      id: HP:0002451
      label: Limb dystonia
  - preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  - preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  target_mechanisms:
  - target: Central Dopamine Biosynthesis Impairment
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      All individuals with TH-deficient DRD demonstrate complete responsiveness
      of symptoms to levodopa (with a decarboxylase inhibitor).
    explanation: GeneReviews supports levodopa with a decarboxylase inhibitor for TH-deficient DRD.
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with TH-deficient infantile parkinsonism with motor delay
      demonstrate a marked response to levodopa.
    explanation: GeneReviews supports marked levodopa response in the severe motor-delay subtype.
  - reference: PMID:30383639
    reference_title: "Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTERVENTIONS: The patient was administrated low-dose levodopa. OUTCOMES:
      The treatment resulted in the substantial improvement of dystonia.
    explanation: Human case report supports low-dose levodopa improving dystonia.
- name: Agents/Circumstances to Avoid
  description: >-
    The prokinetic agent metoclopramide (Reglan) and other related
    antidopaminergic agents should be avoided because they can acutely
    worsen the dopamine deficiency that underlies TH-deficient
    dopa-responsive dystonia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301610
    reference_title: "Tyrosine Hydroxylase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: The prokinetic agent Reglan® and other related antidopaminergic agents."
    explanation: >-
      GeneReviews explicitly lists the prokinetic agent metoclopramide
      (Reglan) and other related antidopaminergic agents as agents to avoid
      in tyrosine hydroxylase deficiency, since they can exacerbate the
      underlying dopamine deficit.
📚

References & Deep Research

References

7
ORPHA:101150
Autosomal recessive dopa-responsive dystonia
1 finding
Orphanet defines autosomal recessive dopa-responsive dystonia as a very rare neurometabolic disorder spanning DRD to progressive infantile encephalopathy.
"A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy."
Show evidence (1 reference)
ORPHA:101150 SUPPORT Other
"A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy."
Orphanet definition supports the disease scope and severity spectrum.
PMID:20301610
Tyrosine Hydroxylase Deficiency.
1 finding
GeneReviews supports TH deficiency subtypes, biallelic molecular diagnosis, autosomal recessive inheritance, and levodopa management.
"GeneReviews describes TH-deficient DRD, infantile parkinsonism with motor delay, and progressive infantile encephalopathy, and states that diagnosis is established by biallelic TH pathogenic variants."
PMID:34834538
Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency.
1 finding
TH deficiency impairs catecholamine and dopamine synthesis.
"The expert review states that DRD is associated with defective dopamine synthesis and that TH catalyzes the rate-limiting step in catecholamine biosynthesis."
PMID:9703425
A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population.
1 finding
Human mutation evidence links TH variants to autosomal recessive L-DOPA-responsive dystonia.
"The report identified homozygous TH R233H in three unrelated Dutch patients with autosomal recessive L-DOPA-responsive dystonia."
PMID:34054692
Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes.
1 finding
Human DRD cohort evidence includes patients with TH variants and long-term levodopa outcomes.
"The cohort included 20 genetically diagnosed DRD patients, nine with TH variants, and reported mostly satisfactory long-term levodopa outcomes."
PMID:30383639
Compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive dopa-responsive dystonia: A case report.
1 finding
A Chinese case report supports TH compound heterozygosity, AR DRD symptoms, genetic diagnosis, and low-dose levodopa response.
"The abstract reports bradykinesia, dystonia, tremor, encephalopathy, compound heterozygous TH mutations, low-dose levodopa, and substantial dystonia improvement."
PMID:33539324
Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia.
1 finding
TSPOAP1 biallelic variants cause autosomal recessive dystonia through presynaptic active-zone dysfunction.
"The study describes biallelic TSPOAP1 variants in seven subjects from three families, mouse motor abnormalities, and in vitro calcium/transmitter release effects."

Deep Research

1
Autosomal Recessive Dopa-Responsive Dystonia Deep Research Fallback ▸

Autosomal Recessive Dopa-Responsive Dystonia Deep Research Fallback

Provider Attempts

  • just research-disorder falcon Autosomal_Recessive_Dopa_Responsive_Dystonia started and wrote only the startup line before remaining silent during the bounded wait; the process was terminated with signal 15 and produced no usable research artifact.
  • timeout 45s just research-disorder openai Autosomal_Recessive_Dopa_Responsive_Dystonia wrote only the startup line and was terminated by the timeout with signal 15; it produced no usable research artifact.

Literature Scope Used

Because both providers failed, the curation used structured Orphanet evidence plus manually selected PubMed references focused on tyrosine hydroxylase deficiency, dopa-responsive dystonia treatment, and the TSPOAP1/RIMBP1 recessive dystonia mechanism.

Key cached sources:

  • ORPHA:101150 for disease definition, inheritance, European prevalence, TH/TSPOAP1 gene rows, MONDO/OMIM/xref rows, and Orphanet phenotype-frequency rows.
  • PMID:20301610 for GeneReviews statements on TH-deficiency clinical spectrum, biallelic TH molecular diagnosis, autosomal recessive inheritance, and levodopa treatment response.
  • PMID:34834538 for expert-review support that DRD reflects defective dopamine synthesis and that TH catalyzes the rate-limiting step in catecholamine biosynthesis.
  • PMID:9703425 for human mutation evidence linking TH variants to autosomal recessive L-DOPA-responsive dystonia.
  • PMID:34054692 for a genetically diagnosed DRD cohort including TH variants and long-term levodopa outcomes.
  • PMID:30383639 for a human AR DRD case report with TH compound heterozygosity, clinical features, molecular diagnosis, and low-dose levodopa response.
  • PMID:33539324 for TSPOAP1 biallelic variants, human recessive dystonia, mouse RIMBP1-loss motor findings, and in vitro synaptic release evidence.

Curation Conclusions

  • The core TH disease mechanism is biallelic TH pathogenic variation causing decreased tyrosine hydroxylase activity, decreased catecholamine biosynthesis, and impaired central dopamine synthesis.
  • The phenotype spectrum is explicitly broad: mild TH-deficient dopa-responsive dystonia, infantile parkinsonism with motor delay, and progressive infantile encephalopathy.
  • All Orphanet frequent phenotype rows in ORPHA:101150 were represented with exact structured-cache snippets; occasional and very rare Orphanet rows that capture the severe spectrum were also included.
  • Molecular genetic testing, CSF neurotransmitter-metabolite findings, and levodopa responsiveness are the main diagnostic anchors available from the cached evidence.
  • Levodopa with a decarboxylase inhibitor is the evidence-backed treatment anchor; the YAML binds the action to MAXO:0000058 pharmacotherapy and the therapeutic agent to CHEBI:15765 L-dopa.
  • TSPOAP1 was included because ORPHA:101150 lists it as a disease-causing loss-of-function gene and PMID:33539324 provides human, mouse, and in vitro support for an autosomal recessive dystonia mechanism through presynaptic active-zone dysfunction.