GENETICS/BASIC DEFECTS Dystonia

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Dystonia is a diverse movement disorder with a complex but not fully understood pathophysiology. It is characterized by involuntary sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures.

GENETICS/BASIC DEFECTS

1. Genetically defined forms of the primary dystonias and dystonia-plus syndromes: at least 13 different types of dystonia can be distinguished genetically as follows:

a. Dystonia type 1 (early onset primary generalized torsion dystonia, Oppenheim dystonia)

i. Autosomal dominant inheritance with reduced penetrance of about 30–40%

ii. Locus: DYT1 on chromosome 9q34 iii. Mutations

a) GAG deletion in the DYT1 gene resulting in loss of Glutamic-acid residues in the C- terminus of a novel ATP-binding protein, torsin A

b) 18 base pair deletion resulting in loss of 6 amino acids (F323-Y328del) in a novel ATP-binding protein, torsin A

b. Dystonia 2 (autosomal recessive torsion dystonia) i. Autosomal recessive inheritance

ii. Locus: DYT2 (chromosome map unknown) c. Dystonia 3 (X-linked dystonia parkinsonism, ‘lubag’)

i. X-linked recessive inheritance ii. Locus: DYT3 on chromosome Xq13.1 d. Dystonia 4 (whispering dysphonia)

i. Autosomal dominant inheritance

ii. Locus: DYT4 (chromosome map unknown) e. Dystonia 5 (dopa-responsive dystonia- parkinsonism)

i. Common autosomal dominant inheritance a) Locus: GCH1 on chromosome 14q22.1-q22.2 b) Caused by mutation in the guanosine

ii. Rare autosomal recessive form (Segawa syndrome)

a) Associated with mutations in the tyrosine hydroxylase gene, TH

b) Locus: TH on chromosome11p15.5

f. Dystonia 6 (adolescent-onset torsion dystonia of mixed type)

i. Autosomal dominant inheritance

ii. Locus: DYT6 on chromosome 8p21-8q22 g. Dystonia 7 (adult-onset focal torsion dystonia)

i. Autosomal dominant inheritance ii. Locus: DYT7 on chromosome 18p

h. Dystonia 8 (paroxysmal dystonic choreoathetosis) i. Autosomal dominant inheritance

ii. Locus: DYT8 on chromosome 2q33-q25

i. Dystonia 9 (paroxysmal choreoathetosis with episodic ataxia and spasticity)

i. Autosomal dominant inheritance

ii. Locus: DYT9 on chromosome 1p21-p13.3 j. Dystonia 10 (paroxysmal kinesigenic choreoathetosis)

i. Locus: DYT10 on chromosome 16p11.2-q12.1 ii. Autosomal dominant inheritance

k. Dystonia 11 (myoclonus-dystonia) i. Autosomal dominant inheritance ii. Locus: DYST11 on chromosome 7q21

iii. Caused by mutations in the ε-sarcoglycan gene in most families

l. Dystonia 12 (rapid-onset dystonia-parkinsonism) i. Autosomal dominant inheritance

ii. Locus: DYT12 on chromosome 19q m. Dystonia 13 (multifocal/segmental dystonia)

i. Autosomal dominant inheritance ii. Locus: DYT13 on chromosome 1p36 2. Secondary dystonia

a. Association with a number of disorders

i. Hepatolenticular degeneration (Wilson disease) a) Dystonia in over a third of the patients b) Associated with lesions in the putamen in

80% of cases

ii. Hallervorden-Spatz disease (pantothenate kinase- associated neurodegeneration)

iii. Huntington chorea iv. Lesch-Nyhan disease

v. Metachromatic leukodystrophy vi. Methylmalonic acidemia vii. Mitochondrial disorders viii. Ceroid lipofucinosis

ix. Gangliosidoses x. Glutaric aciduria xi. Ataxia telangiectasia

xii. Niemann-Pick disease type C xiii. Early-onset parkinsonism

xiv. Corticobasal degeneration

xv. Certain forms of spinocerebellar ataxia

a) Spinocerebellar ataxia 3 (Machado-Joseph dis- ease): the severity of the dystonic symptoms is related to the length of the trinucleotide repeat b) Spinocerebellar ataxia 17 (caused by muta- tions in the thymine-adenine-thymine- adenine binding protein: Dystonia may be the presenting sign of the disorder

b. Other causes i. Psychogenic

ii. Vascular lesions such as carotid occlusive disease and hemorrhagic stroke

iii. Anoxic brain injury (cerebral anoxia/hypoxia): a

well-known cause of secondary dystonia

iv. Acute disseminated encephalomyelitis v. Trauma

a) Head trauma: dystonia is among the most common movement disorders following severe head injury

b) Peripheral trauma causing segmental dystonia vi. Both acute and chronic use of dopamine blocking

medications and other medications a) Haloperidol

b) Resperidol c) Fluphenazine d) Thioridazine e) Chlorpromazine

f) Metoclopramide g) Phenytoin h) Stonatrioran

3. Pathophysiology: a new interpretive hypothesis involving multiple levels of the nervous system

a. Spinal cord: increased spinal motor neuron excitabil- ity in patients with generalized dystonia due to reduced presynaptic inhibition and compromised supraspinal inhibition systems

b. Basal ganglia: disturbed pattern of basal ganglia output neurons

c. Thalamus: disorganization of input–output properties and hyperactivity in thalamic neurons in two dystonic cynomolgus monkeys

d. Somato-sensory system: increased temporal discrimi- nation thresholds for tactile stimuli

e. Sensorimotor integration and motor cortical function i. Abnormal somatotopic arrangement of sensori-

motor interaction

ii. Abnormal functioning of cortico-subcortical loops causing abnormalities of both intracortical inhibition and cortical excitability

4. Dystonia with unknown etiology

CLINICAL FEATURES

1. Dystonia describes a symptom that may be part of many disorders with a variety of causes

a. An abnormal sustained posture that is often writhing or twisting in quality

b. Can be rapid or slow c. Often painful

2. Classifications of dystonia

a. Classification based on distribution of dystonia i. Primary/generalized dystonia

a) Occurs in childhood

b) Often begins focally in the legs and pro- gresses to a generalized symptom involving the entire body

ii. Focal dystonia

a) May occur at any age b) Typically starts in adulthood

c) Affects an isolated body area, such as hand and arm (writer’s cramp), neck (cervical dystonia, previously known as spasmodic torticollis), vocal/laryngeal apparatus (dystonic adductor dysphonia or whispering dysphonia), mouth

(oromandibular dystonia, musician’s cramp), or eyelids (blepharospasm)

d) Multifocal dystonia (two or more noncon- tiguous parts affected)

iii. Segmental dystonia a) May occur at any age b) Typically starts in adulthood

c) Involves only the right or left side of the body d) Cranial (two or more parts of cranial and

neck musculature affected) e) Axial (neck and trunk affected)

f) Brachial (one arm and axial; both arms, with or without neck, with or without trunk) g) Crural (one leg and trunk; both legs, with or

without trunk)

iv. Hemidystonia: affects ipsilateral arm and leg v. Secondary dystonia

a) Can be generalized, focal, or segmental b) Induced by a disease or ingested substance c) Can occur at any time

d) Treated by identifying the underlying med- ical disorder or substance

b. Classification based on age of onset of dystonia i. Early-onset dystonia

a) Often starts in a limb

b) Tends to generalize and frequently has a genetic origin

ii. Adult-onset dystonia

a) Usually spares the lower extremities b) Frequently involves cervical or cranial

muscles

c) A tendency to remain focal d) Sporadic in most cases

3. Clinical characteristic in genetically defined forms of dystonia and dystonia-plus

a. Dystonia type 1 (early onset generalized primary tor- sion dystonia)

i. Early-onset torsion dystonia (onset usually childhood)

ii. May present as focal, usually in the limbs iii. Often generalizes to other body parts as the dis-

ease progresses

b. Dystonia type 2 (autosomal recessive torsion dystonia) i. Early-onset

ii. Generalized or segmental torsion dystonia c. Dystonia type 3 (X-linked dystonia parkinsonism,

‘lubag’ meaning ‘twist’ in a local dialect in the Island of Panay in the Philippines)

i. Only described in individuals from the Philippines

ii. Usually males

iii. Onset usually adulthood iv. Usually generalized dystonia

v. Parkinsonism (50% of cases) unresponsive to L- dopa

vi. Progressive neurodegenerative syndrome d. Dystonia type 4 (whispering dysphonia)

i. Described in a single large Australian family ii. Laryngeal and cervical dystonia

iii. Age of onset: 13–37 years

e. Dystonia type 5 (dopa-responsive dystonia- parkinsonism)

i. Childhood onset of dystonia

ii. Onset of dystonia in a limb, typically a leg, resulting in gait disturbance

iii. Gradual progression to generalized dystonia (usually more pronounced in the legs)

iv. Dystonia with concurrent or subsequent parkin- sonism

v. Diurnal worsening of symptoms

a) Aggravation of symptoms toward the evening b) Alleviation of symptoms in the morning

after sleep

vi. A variety of atypical presentations a) Generalized hypotonia b) Proximal weakness c) Gait disturbance d) ‘Atypical cerebral palsy’

vii. A dramatic response to L-dopa

f. Dystonia type 6 (adolescent-onset torsion dystonia of mixed type)

i. Described in two Mennonite families ii. Adolescent-onset

iii. Mostly segmental torsion dystonia iv. Focal or generalized (rare)

v. Cranial, cervical or limb dystonia

g. Dystonia type 7 (adult-onset focal torsion dystonia) i. Described in a single German family

ii. Adult-onset focal dystonia iii. Torticollis

iv. Writer’s cramp v. Spasmodic dysphonia vi. Blepharospasm

h. Dystonia type 8 (paroxysmal dysphonic choreoathetosis) i. Variable age of onset (early childhood, adoles-

cence or early adulthood)

ii. Attacks of dystonia/choreoathetosis

iii. Precipitated by stress, hunger, fatigue, alcohol, caffeine, nicotine, and chocolate

i. Dystonia type 9 (paroxysmal choreoathetosis with episodic ataxia and spasticity)

i. Age of onset: 2–15 years

ii. Attacks of dystonia, paresthesias, and double vision iii. Precipitated by exercise, fatigue, stress, alcohol

iv. Spastic paraplegia between attacks

j. Dystonia type 10 (paroxysmal kinesigenic choreoa- thetosis)

i. Attacks of dystonia/choreoathetosis

ii. Precipitated by sudden unexpected movements iii. Respond to anticonvulsant therapy

k. Dystonia type 11 (myoclonus-dystonia)

i. Onset usually in the first or second decade of life ii. Rapid, jerk-like movements

iii. Responsive to alcohol

iv. Combined with variable degrees of dystonia l. Dystonia type 12 (rapid-onset dystonia-parkinsonism)

i. Acute or subacute onset (develop over hours or weeks) of generalized dystonia

ii. In combination with parkinsonism

m. Dystonia type 13 (multifocal/segmental dystonia) i. Described in a single Italian family

ii. Juvenile or early adult onset of segmental dystonia iii. With prominent cranial-cervical and upper limb

involvement

iv. Some focal dystonia, some generalized dystonia

DIAGNOSTIC INVESTIGATIONS

1. Electromyography shows a simultaneous contraction of both agonist and antagonist muscles

2. Neuroimaging

a. Lacks signs of structural abnormality

b. Inconsistent results of functional imaging studies 3. Dopa-responsive dystonia

a. GTPCH1-deficient dopa-responsive dystonia i. Decreased concentration of both total biopterin

(BP) and neopterin (NP) in cerebrospinal fluid in patients with GTPCH1 deficiencies

ii. Phenylalanine loading test to detect a subclinical defect in phenylalanine metabolism

iii. DNA mutation analysis to detect GCH1 mutation b. TH-deficient dopa-responsive dystonia

i. Normal BP and NP, and reduced-3-methoxy-4- hydroxy-phenylethyleneglycol in CSF

ii. DNA mutation analysis to detect TH mutation

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib

i. Autosomal recessive inheritance: 25%

ii. Autosomal dominant inheritance: not increased unless one of the parent carries a mutant allele in which case, there is a 50% risk of having an affected sib

iii. X-linked recessive inheritance; 50% of male sib will be affected given the mother is a carrier iv. Secondary dystonias: risk depending on the

etiology b. Patient’s offspring

i. Autosomal recessive inheritance: not increased (all offspring are carriers) unless the spouse is also a carrier in which case, there is a 50% risk of having an affected offspring

ii. Autosomal dominant inheritance: 50%

iii. X-linked recessive inheritance: none of the sons will be affected; all of the daughters will be carriers iv. Secondary dystonias: risk depending on the

etiology

2. Prenatal diagnosis is possible for some forms of dystonia by DNA analysis of the fetal blood obtained from amnio- centesis of CVS provided the disease-causing allele(s) of an affected family member have been identified

3. Management

a. Generalized idiopathic dystonia i. Medical therapy

a) Anticholinergic agents (trihexyphenidyl):

first choice (a moderate response in about

40–50% of dystonia patients)

b) Benzodiazepines (diazepam, clonazepam) c) Dopamine depletors (tetrabenazine) d) γ-aminobutyric acidergics (baclofen) e) Atypical neuroleptics (clozapine, olanzapine) ii. Intrathecal baclofen infusion

iii. Ablative therapies, reserved for patients in whom medical therapies fail

a) Pallidotomy b) Thalamotomy b. Dopa-responsive dystonia

i. A dramatic response to small dosages of lev- odopa (100 mg/day) (confirms the diagnosis) ii. Maintenance with low-dose levodopa for life

may improve from severe inability to completely normal function

c. Focal dystonias

i. Unresponsive to systemic drug treatment in most case

ii. Frequently well controlled by periodic botu- linum toxin (BTX) injections into the muscles directly involved in the dystonia

iii. Try with intrathecal baclofen and surgery if oral medications fail

d. Cervical dystonias resistant to BTX: selective peripheral denervation

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Fig. 1. A 7-year-old girl with progressive dystonia showing dystonic posturing with gait locking of the knees and swiveling of the hips to propel the legs forward. She developed normally until age 6 when she started to have loss of balance, falling, unable to get the foot off the ground, stiffing of lower and upper extremities, and slurring of speech.

Plasma amino acids, urine organic acids, blood chemistry, lactate/ pyru- vate, ceruloplasmin, copper, arsenic, lead, 5-methyltetrahydrofolate, neurotransmitter metabolites/amines, tetrahydrobiopterin/ neopterine, and various lysosomal enzymes were all normal. No mutations were detected on mitochondrial myopathy mtDNA, DYT1, and PANK2.

MRI of the brain showed bilateral hyperdense basal ganglia lesions.

Use of levodopa/dopamine agonists has at best, been minimally bene- ficial.