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A. Description

  1. Disorder causing variable muslce tone and recurrent muscle spasm
  2. Movement disorder causing sustained muscle contractions, repetitive twisting movements, and abnormal postures of trunk, neck face, or arms and legs
  3. Results from involvuntary concomitant contraction of agonist and antagonist muscles, with overflow of unwanted muslce contractions into adjacent muscles
  4. Movements may be either slow or rapid, and can change during different activities or postures, and may become fixed in advanced cases

B. Localization

  1. Generalized: more common in children, usually congenital / hereditary, dystonia throughout
  2. Focal: more common in adults and more common overall, dystonia usually 1-2 regions only
  3. Segmental: two or more adjacent regions
  4. Multifocal: two or more nonadjacent regions
  5. Hemidystonia: ipsilateral arm and leg

C. Genetic Classification (Table 2, Ref [1])

  1. Dystonia 1
    1. Other names: primary or idiopathic torsion dystonia, dystonia musculorum deforans 1
    2. Genetic Locus and Chromosome (chr): DYT1, chr 9q34
    3. Gene and function: Torsin A, unknown function
    4. Inheritance and Penetrance: autosomal dominant (AD); 10-40% penetrance
    5. Age at onset: usually childhood; before age 26
    6. Clinical features: usually focal limb dystonia, usually one foot; then generalizes
  2. Dystonia 2
    1. Other names: autosomal recessive (AR) primary torsion dystonia
    2. Genetic Locus and chr: DYT2, unknown chr
    3. Gene and function: unkown
    4. Inheritance and penetrance: AR; unknown penetrance
    5. Age at onset: childhood
    6. Clinical features: segmental or generalized
  3. Dystonia 3
    1. Other names: X-linked dystonia-parkinsonism; lubag
    2. Genetic Locus and Chr: DYT3, chr Xq13.1
    3. Gene and function: TAF1, transcription factor, may regulate dopamine D2 receptors
    4. Inheritance and penetrance: X-linked; 100% penetrance by 5th decade
    5. Age at onset: 12-52 (mean 48) years
    6. Clinical features: focal dystonia then segmental or genalized; parkinsonism in ~50%
  4. Dystonia 4
    1. Other names: torsion dystonia 4; non-DYT1 primary torsion dystonia
    2. Genetic Locus and Chr: DYT4, unknown chr
    3. Gene and function: unkonwn
    4. Inheritance and penetrance: AD; affects 40% of patients' offspring >40 years
    5. Age at onset: 13-37 years
    6. Clinical features: primarily laryngeal (whispering) dystonia
  5. Dystonia 5 [3]
    1. Dopa responsive dystonia
    2. Type 5a: autosomal dominant, mutations in GCH1 (chr 14q22.1-22.2), encodes GTPCH1
    3. GTPCH1 converts GTP to dihydroneopterin triphosphate (tryptophan synthetic pathway)
    4. GTPCH1 is guanosine triphosphate (GTP) cyclohydrolase 1
    5. Type 5b: autosomal recessive, mutations in TH (tyrosine hydroxylase) gene chr 11p15.5
    6. TH hydroxylates tyrosine to L-dopa (then converted to dopamine)
    7. Onset in childhood
    8. Foot affected early; progression to multifocal or generalized
    9. Psychiatric problems
    10. Lack of other neurologic or cognitive abnormalities
    11. Dramatic response to L-Dopa
  6. Dystonia 6
    1. Other names: adolescent onset primary torsion dystonia of mixed type
    2. Genetic Locus and Chr: DYT6, chr 8p21-22
    3. Gene and function: unknown
    4. Inheritance and penetrance: AD; 30% penetrance
    5. Age at onset: 19 years
    6. Clinical features: focal (cervical, cranial, limb) or segmental, may become generalized
  7. Dystonia 7
    1. Other names: adult onset focal primary torsion dystonia
    2. Genetic Locus and Chr: DYT7, chr 8p11.3
    3. Gene and function: unknown
    4. Inheritance and penetrance: AD, incomplete (<40%) penetrance
    5. Age at onset: 28-70 years
    6. Clinical features: focal (cervical or laryngeal dystonia, writers cramp), hand tremors
  8. Dystonia 8
    1. Other names: paroxysmal dystonic choreoathetosis; paroxysmal nonkinesogenic dyskinesia, Mount-Reback syndrome
    2. Genetic Locus and Chr: DYT8, chr 2q33-36
    3. Gene and function: uknown
    4. Inheritance and penetrance: AD; incomplete
    5. Age at onset: childhood to early adulthood
    6. Clinical features: episodes of dystonia and chorea or dyskinesias lasting 2 min to 4 hours, triggered by stress, alcohol, caffeine, nicotine
  9. Dystonia 9
    1. Other names: paroxysmal choreoathetosis with episodic ataxia and spasticity; choreoathetosis, spasticity and episodic ataxia
    2. Genetic Locus and Chr: DYT9 (CSE); chr 1p13.3-21
    3. Gene and function: unknown
    4. Inheritance and penetrance: AD
    5. Age at onset: childhood (2-15 years)
    6. Clinical features: chronic spastic paraplegia plus episodes of dystonia, choreoathetosis, paresthesias, diplopia triggered by alcohol, exercise, stress
  10. Dystonia 10
    1. Other names: paroxysmal kinesogenic choreoathetosis, periodic dystonia
    2. Genetic Locus and Chr: DYT10, chr 16p11.2-12.1
    3. Gene and function: unknown
    4. Inheritance and penetrance: AD, incomplete penetrance
    5. Age at onset: 6-16 years
    6. Clinical features: episodes of dystonia and choreoathetosis triggered by sudden movements
  11. Dystonia 11
    1. Other names: myoclonus-dystonia; alcohol responsive dystonia
    2. Genetic Locus and Chr: DYT11, chr 7q21-31
    3. Gene and function: e-sarcoglycan, muscle structure
    4. Inheritance and penetrance: AD, incomplete penetrance
    5. Age at onset: variable, including early childhood
    6. Clinical features: myoclonus plus dystonia, improves with alcohol ingestion
  12. Dystonia 12
    1. Other names: rapid-onset dystonia with parkinsonism
    2. Genetic Locus and Chr: DYT12, chr 19q13
    3. Gene and function: Na+/K+ ATPase alpha3 subunit (ATP1A3)
    4. Inheritance and penetrance: AD, incomplete penetrance
    5. Age at onset: variable (childhood to adulthood)
    6. Clinical features: acute or subacute onset of generalized dystonia with parkinsonism
  13. Dystonia 13
    1. Other names: focal dystonia with craniocervical features
    2. Genetic Locus and Chr: DYT13, chr 1p36.13-32
    3. Gene and function: unknown
    4. Inheritance and penetrance: AD, ~60% penetrance
    5. Age at onset: 5 year to adulthood; average 15 year
    6. Clinical features: focal or segmental dystonia (cranial, cervical, upper limb), usually mild and rarely generlized
  14. Dystonia DFN-1/MTS
    1. Other names: deafness-dystonia syndrome 1, Morh-Tranebjaerg syndrome, XL dystonia optic atrophy
    2. Genetic Locus and Chr: DDP, chr Xq22
    3. Gene and function: dystonia-deafness peptide; mitochondrial protein import
    4. Inheritance and penetrance: X-linked, incomplete penetrance
    5. Age at onset: childhood
    6. Clinical features: dystonia, sensorineural hearing loss, spasticity, mental retardation, cortical blindness; female carriers may present with adult onset focal dystonia
  15. LHON Dystonia
    1. Other names: Leber's Hereditary Optic Neuropathy plus Dystonia
    2. Genetic Locus and Chr: mitochondrial DNA
    3. Gene and function: NADH-ubiquinone oxidoreductase subunit ND6, complex I
    4. Inheritance and penetrance: maternal, incomplete
    5. Age at onset: variable
    6. Clinical features: dystonia, optic atrophy or both

D. Secondary Dystonias [3]

  1. Drug induced tardive dystonias (dyskinesias)
    1. Antipsychotic drugs: dopamine receptor blocking order typical and newer atypical drugs
    2. Anxiolytic agent: buspirone (rare)
  2. Other Drug Associated Dystonias
    1. Antidepressant Agents: selective serotonin reuptake inhibitors
    2. Dopaminergic drugs: levodopa (L-dopa) and dopamine agonists
    3. Antiemetic drugs: metoclopramide
    4. Antiseizure drugs: phenytoin, carbamazepine, gabapentin
  3. Parkinsonian Disorders
    1. Parkinson's Disease
    2. Juvenile parkinsonism (PARKIN mutations)
    3. Multisystem atrophy
    4. Corticobasal degeneration
    5. Progressive supranuclear palsy
  4. Huntington's Disease
  5. Globus pallidus degeneration
  6. Cerebral palsy
  7. Wilson's Disease
  8. Mitochoncrial encephalo9pathies
  9. Neuroacanthocytosis
  10. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz Disease)
  11. Fahr's Disease
  12. Lysosomal Storage Diseases
  13. Organic Aminoacidurias
  14. Mitochondrial Disorders
  15. Lesch-Nyhan Syndrome
  16. Ataxia-Telangiectasia

E. Symptoms

  1. Twisting postures
  2. Tremors
  3. Pain resulting from sustained muscle contractions
  4. Meige Syndrome - oral and ocular spasm
  5. Laryngeal or pharyngeal spasm
  6. Torticollis - head twisting
  7. Blepharospasm - tremor of the eye (orbicularis oculus muscle)

F. Therapy Overview

  1. Dopamine responsive dystonia - usually with parkinsonism
    1. Dramatic response to L-DOPA
    2. Initiate with carbidopa (25mg) - levodopa (100mg) as Sinamet® bid
    3. May increase dose as warranted for symptoms
  2. Anticholinergics:
    1. Weaker agents: anti-histamines such as diphenhydramine
    2. Stronger agent: cyclobenzaprine (Flexeril®)
    3. Anticholinergics with baclofen (Lioresal®) may be dramatically effective in children
  3. Botulinum Toxin injection - mainly for adults with focal dystonia
  4. Bilateral deep brain stimulation of globus pallidus - good efficacy in refractory dystonia [4]

References

  1. Tarsy D and Simon DK. 2006. NEJM. 355(8):818 abstract
  2. Greene P. 2005. NEJM. 352(5):498 abstract
  3. Venna N, Sims KB, Grant PE. 2006. NEJM. 355(8):831 (Case Record) abstract
  4. Vidailhet M, Vercueil L, H JL, et al. 2005. NEJM. 352(3):459