Movement Disorders

Question 1

List the types of movement disorders and examples of each.

Answer 1

excess movement (dystonia, myoclonus, tics, tremor, and chorea)
decreased movement (PD)
ataxias (cerebellar dysfunction

Question 2

Describe excessive movement disorders.

Answer 2

movement disorders characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both

Question 3

What is prevalence of dystonia?

Answer 3

isolated: 1 in 6,000 based on meta-analysis (about 5% is DYT1)
generalized early-onset dystonia: 1 in 30,000 (about 70% is DYT1)
adult-onset isolated idiopathic or hereditary in Finland is 1 in 2,500
most common type is adult-onset neck (“cervical dystonia” or “torticollis”)

Question 4

What are the key features of the history and physical exam with potential prognosis and treatment implications?

Answer 4

age of onset
first part of the body affected (site onset)
spread: final body regions affected (distribution)
coexistance of other movement disorders
presence of other neurological manifestations
presence of nervous system pathology (e.g. on MRI)
genetic versus acquired

Question 5

What correlations are normally seen in movement disorders between age-onset, site-onset, and distribution?

Answer 5

childhood onset correlates with leg onset and generalized spread
as age onset increases, sit of onset ascends to the neck and cranial muscles
dystonia tends to remain localized

Question 6

What are the types/distribution of dystonia?

Answer 6

focal (blepharospasm, oromandibular/Meige syndrome, torticollis, spasmodic dysphonia, writer’s cramp)
segmental
generalized

Question 7

Describe the kinds of involuntary movements.

Answer 7

dystonia- directional, presents with specific actions (NOT uncomfortable or painful, however cervical dystonia is seen with hypertrophy)
tremor- regular oscillation (may co-occur with dystonia)
tics- tend to be suppressible and may be complex, noisy, intermittent
myoclonus- fast jerks, not posture assuming
chorea- random, flowing

Question 8

Describe the early generalized DYT1 (TOR1A) phenotype.

Answer 8

classic cases have childhood or adolescent onset (average 12 years; range 4-64) in an arm or leg, often spreading to other body parts but rarely to the face

Question 9

Describe the late focal DYT1 (TOR1A) phenotype.

Answer 9

family members may have a milder presentation e.g. late onset writers cramp or neck dystonia

Question 10

What general features are seen in all kinds of DYT1 (TOR1A) patients?

Answer 10

early onset, particularly in a leg, correlates with greater chance of spread
normal brain MRIs, blood/urine tests
normal intelligence

Question 11

What are the guidelines for testing in patients suspected to have a DYT1 (TOR1A) phenotype?

Answer 11

onset < 26 years old in proband or family member

Question 12

Describe the genetics of DYT1.

Answer 12

autosomal dominant with reduced penetrance (30-40%)
TOR1A (DYT1) gene- GAG deletion in all but one known case
males and females affected equally
TorsinA protein is an ATPase and functions as an ER protein chaperone

Question 13

How are TOR1A (DYT1) patients treated?

Answer 13

oral medications, especially anticholinergics (drugs that block the action of acetylcholine)
botulinum toxin injections
surgery (GPi deep brain stimulation- success rate is high for DYT1 with most seeing 50% improvement and many having better than that)
education and support

Question 14

What is the role of TOR1A in early onset dystonia in the AJ population?

Answer 14

> 80% if early onset and >90% of generalized dystonia
founder mutation
GAG mutation is about 10 times more common in AJ

Question 15

what is the role of TOR1A in early onset dystonia in non-Jewish populations?

Answer 15

about 50% of early onset and about 60% of generalized dystonia
no significant DYT1 founder effect, multiple DYT1 mutation events
early-onset non-DYT1 may mimic DYT1

Question 16

What are some counseling issues surrounding DYT1?

Answer 16

autosomal dominant inheritance
reduced penetrance (30%)
variable expression (chance of having severe case unknown but may be about 10% for carriers)
>80% of AJ early onset and 50% Non-Jewish
factors influencing penetrance/expression largely unknown modifiers
inverse relationship between age onset and severity (unlikely to be severe if onset occurs after 26 years)
each case is different (occasionally early leg onset cases do not generalize)
oral medications are moderately effective and have side effects vs DBS surgery works well (risk vs benefit)

Question 17

What is the familial risk for late-onset dystonia?

Answer 17

most common form of dystonia (usually focal involving the neck)
genes mostly not known yet
low penetrance of about 15% in most families
evidence of risk:
chance of an affected relative- 5-35% of late-onset isolated dystonia patients have an affected relative
risk to first degree relatives of probands with focal/adult-onset

Question 18

What is DOPA-responsive dystonia?

Answer 18

GTP cyclohydrolase-1 (GCH1) gene
very rare but treatable
0.5-1.0 per million (likely higher)
autosomal dominant with reduced penetrance and sex dependent expression  (3 to 1 female/male)
over 100 mutations reported

Question 19

How does DOPA-responsive dystonia present?

Answer 19

typically childhood onset limb dystonia
often with Parkinson-like features (tremor, slowness, rigidity, instability, and diurnal variation
adult family members have increased risk of adult onset parkinsonism (i.e. age-dependent expression like DYT1)
can mimic cerebral palsy, spastic paraplegia, parkinsonism, DYT1 dystonia
Hallmark: Dramatic sustained response to low doses of levo-dopa (l-dopa)

Question 20

What counseling issues may arise with Dopa-Responsive Dystonia?

Answer 20

highly treatable
autosomal dominant with reduced, sex-influenced penetrance (M=15%, F=45%)
rare and sometimes missed by physicians
diagnosis is generally made on the basis of dramatic l-dopa response
found in all ethnicities
up to 50% may be new mutations
NO KNOWN G/P correlation

Question 21

What is Myoclonus Dystonia?

Answer 21

M-D, DYT11
e-sarcoglycan (SGCE) gene
male and female equally affected
autosomal dominant with imprinting (reduced penetrance especially when transmitted through the MOTHER)
likelihood of SGCE mutation in patients with M-D is 30-40% overall and 60% if familial

Question 22

Describe the clinical continuum of ATP1A3 syndromes.

Answer 22

1. Rapid dystonia Parkinsonism (RDP)
2. Alternateting hemiplegia in childhood (AHC)
3. CAPOS (Cerebellar ataxia, areflezia, pes cavus, optic atrophy, and SNHL)
4. Intermediate/variant/combo forms

Question 23

What is Rapid dystonia Parkinsonism?

Answer 23

abrupt onset of dystonia over days to weeks along with Parkinsonism
treatment with Levo-dopa gives minimal benefit; DBS IS NOT EFFECTIVE

Question 24

Describe the genetics of ATP1A3.

Answer 24

encodes alpha-3 subunit of the sodium/potassium-transporting ATPase (Na, K-ATPase)
mutations are most commonly missense
De novo or dominantly inherited
dystonia panel or WES

Question 25

What are the acquired causes of dystonia?

Answer 25

perinatal cerebral injury
encephalitis (infectious and post-infectious)
head or cervical cord trauma
stroke
tumor
MS
peripheral injury
drugs
toxins
psychogenic

Question 26

What are some general themes in dystonia?

Answer 26

basal ganglia involvement
autosomal dominant, reduced penetrance, variable expression (sensory tricks)
sex dependent phenotypes (seen in DRD and adult dystonia)
age dependent phenotypes (seen in DYT1 and DRD)
mutation dependent phenotypes (seen in RDP/AHC/CAPOS)
role for cell membrane channels and ATPases that regulate cell membrane polarization (seen in RDP and peisodic dystonias)

Question 27

What are some testing strategies that can be used when dystonias are suspected?

Answer 27

Dystonia panel (eg. Invitae, GeneDx, MNG, EGL) including varied genes

Question 28

What is the pathophysiology ofParkinson Disease?

Answer 28

impaired function of nigrostriatal dopamine system
loss of dopamine neurons
formation of Lewy bodies

Question 29

What are the cardinal features of Parkinson disease?

Answer 29

bradykinesia (overall slowness of movements), resting tremor, rigidity, postural instability
other: shuffling gait, soft voice, small writing, loss of smell, constipation, depression, autonomic dysfunction, REM sleep behavior disorder, late stage dementia

Question 30

How can Parkinson disease be treated?

Answer 30

oral medications: replace dopanine (levodopa precursor converted to dopamine), mimic dopamine (dopamine agonists bind to dopamine receptors), preserve dopamine (MAO-B inhibitors prevent degradation of dopamine; COMT-inhibitors prevent degradation of levodopa medication)

surgery: deep brain stimulation alters signaling to improve movement
therapies: physical, speech/swallowing, and occupational

Question 31

What genes have been associated with Parkinson disease?

Answer 31

PARKIN (Park 2)- autosomal recessive,
gene product is E3 ubiquitin ligase (NO LEWY BODIES), accounts for 49% of early onset AR PD and 18% of sporadic PD with onset <45 years
SCNA (PARK1)- autosomal dominant, gene for a-Synuclein, rare cause of PD, highly penetrant
LRRK2, GBA- leucine risk repeat kinase and glucocerebrosidase, most common monogenic cause of PD, low penetrance (1/3 of AJ with PD; <1% of non-AJ individuals are carriers of a GBA mutation; 1 in 18 AJ individuals are carriers of a GBA mutation)

Question 32

What counseling issues could come up regarding Parkinson disease?

Answer 32

most cases are “sporadic” without a known genetic cause (most is late onset and genes we do know have low penetrance)
greater likelihood of genetic cause if familial and/or early onset
more likely identifiable gene if AJ, Berber, or Basque
other genetic causes are more likely in patient siwth atypical features (e.g. ataxia gene)
23 and Me offers testing for 2 AJ founder mutations in LRRD2 and GBA)
treatment is not changed based on genetic diagnosis YET but the promise and imminence of gene-specific clinical trials have changed that equation for patients considering testing

Question 33

What other risk factors are there for Parkinson Disease?

Answer 33

adults with 22q11.2 deletions have 20-70x increased risk

carriers and affected patients with Gaucher disease