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Clinical Neuroscience > Genetics of Movement Disorders > Flashcards

Genetics of Movement Disorders Flashcards

MOVEMENT DISORDERS

1
Q

name the 4 Neurological description for abnormal movements (dyskinesias)

A

-Chorea
-ataxia
-dystonia
-bradykinesia

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2
Q

Chorea

A

Ceaseless/constant occurrence of a wide variety of rapid, highly complex, jerky, dyskinetic movements that appear well coordinated but are involuntary. e.g. fidgety

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3
Q

Ataxia

A

Loss of the ability to coordinate muscular
movement. e.g. broad base gait

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4
Q

Dystonia

A

Abnormal tonicity of muscle, characterized by prolonged, repetitive muscle contractions that may cause twisting or jerking movements of the body or a body part.

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5
Q

Bradykinesia

A

Abnormal slowness of muscular movement. e.g. PD

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6
Q

Inherited movement disorders

A
  • Wide variety of inherited movement disorders
  • Present varying combinations of chorea, dystonia, ataxia and bradykinesia
  • Pattern recognition
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7
Q

name examples of chorea

A
  • Huntington’s disease
  • Wilson’s disease
  • Choreacanthocytosis
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8
Q

name examples of ataxia

A
  • Spinocerebellar ataxia (SCA)
  • Friedreich’s ataxia
  • Fragile X tremor ataxia (FXTAS)
  • Neuropathy ataxia retinitis pigmentosa (NARP)
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9
Q

name examples of dystonia

A
  • Primary dystonia early onset
  • Myoclonus dystonia
  • Dopa-responsive dystonia (DRD)
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10
Q

name examples of bradykinesia

A

Parkinson’s disease

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11
Q

Genetic aspects of inherited movement
disorders

A
  • Pedigree interpretation
    • Autosomal dominant
    • Autosomal recessive
    • X-linked
    • Mitochondrial
  • Genetic mechanisms
    • Anticipation (triplet repeat disorder)
    • Imprinting
  • Genetic counselling issues
    • Predictive testing for adult onset disorders
    • Testing children
    • Prenatal testing
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12
Q

CHOREA - Huntington’s disease

A
  • First described in 1872
  • Third most common inherited neurological disorder in the UK after CMT/NF1
  • Autosomal dominant
  • IT15 gene identified in 1993 after international
    collaborative effort
  • CAG repeat expansion in exon 1 of IT15 gene encoding the huntingtin protein (htt)
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13
Q

Prevalence of HD

A
  • Prevalence 4-10 per 100,000
  • Northern European origin of the mutation
  • HD pts have an ancestral origin from healthy carriers of intermediate alleles
  • Frequency due to high proportion of intermediate repeat number allele carriers in the normal population that become unstable during spermatogenesis
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14
Q

clinical features of HD

A
  • Neurological
    • Chorea (>90% individuals)
    • Impaired voluntary movements Gait disturbance
    • Dysphagia/dysarthria
  • Cognitive
    • Cognitive decline
  • Psychiatric
    • Change in personality
    • Anxiety/Depression - most common
    • Increased incidence suicide
    • Problem behaviours
  • Order of symptom presentation
    • Variable, often subtle changes over several years before manifest HD (prodromal)
    • Declining performance in usual employment
    • Depression/anxiety disorder
  • Impact on family and those at risk
    • 40s to 50s
    • 50/50 chance of transmitting
  • Brain imaging:
    • shrunken and atrophied caudate
    • atrophy of brain volume
    • atrophy of cerebellum
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15
Q

allele sizes of HD

A
  • Normal
    • 26 or fewer CAG repeats
  • Intermediate
    • 27-35 CAG repeats
    • Risk of expansion into disease causing range on transmission
    • Especially with paternal transmission
  • Pathological
    • 36 or more CAG repeats
    • Reduced penetrance alleles 36-39 CAG repeats
    • Full penetrance alleles 40 or more CAG repeats
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16
Q

Anticipation OF HD

A
  • Occurs in the germline
  • DNA repair/replication apparatus “slips” on CAG repeats?
    • ancestral haplotype
  • Ova undergo meiosis in utero then pause
  • Sperm precursors constantly replicating
    • mitotic dystrophy (triplet repeat disorder) → maternal germline
  • 70% mutation rate in HD chromosomes
  • 0.7% in normal chromosomes
17
Q

predictive testing OF HD

A
  • Family history and clinic visit
  • Confirm diagnosis
  • Basic explanation
  • Second appointment - counselling
  • May have psychiatric appointment
  • Blood taken with written consent
  • Results given in person in 4 weeks
  • Follow up phone call
  • Why do people take test?
    • Need to know 55%
    • Planning life 51%
    • Reducing uncertainty 19%
    • Family planning 13%
    • Factor in marriage / relationship 13%
18
Q

treatment OF HD

A
  • Chorea-neuroleptics olanzapine, haloperidol,
    tetrabenazine (monoamine depletion)
  • Depression/Psychosisantidepressants/antipsychotis
  • Exercise, physiotherapy
  • Good diet, high calorie as disease progresses
  • Future therapies
    • Gene silencing therapies (RNAi;ASO)
    • Pharmacotherapies to inhibit apoptosis, excitotoxicity, protein aggreggation,
      proteolysis, inflammaiton, oxidative damage,
      HTT phosphorylation, phosphodiesteraseactivity.
19
Q

CHOREA - Wilson’s disease

A
  • Autosomal recessive disorder
  • Disorder of copper metabolism
  • Gene ATP7B Copper transporting ATPase 2Some common mutations certain populations
  • May present
    • Liver disease – hepatitis/chronic liver disease
    • Neurological disease - chorea/dystonia
    • Psychiatric disturbance - depression/personality change
  • Biochemistry
    • Reduced serum copper & caeruloplasmin
    • Increased urinary copper excretion
  • Copper deposition in basal ganglia/iris
  • Treatment – Chelating agents
20
Q

ATAXIA - Spinocerebellar ataxia (SCA)

A

SCA 1,2,3,6,7,8,12,17
- Many are CAG repeats except SCA8 CTG repeat
- Over 50 causes of hereditary spinocerebellar ataxia
- Tend to test for all triplet repeat forms others are difficult to test.
- Whole genome sequencing may change this
> atrophy of cerebellum
>
- Age of onset and physical findings overlap
- Usually slowly progressive
- Cerebellar atrophy may be seen on neuroimaging
- Additional features:
- slow saccadic eye movements
- sensory axonal neuropathy
- retinopathy
- Some may show reduced penetrance
- Some allelic with other conditions eg CACNA1A
- SCA6
- Hemiplegic migraine
- Episodic ataxia type 2
- different types of mutations or genes ⇒ cause different conditions = allelic disorder
- Anticipation especially with SCA 7
- CAG repeat unstable with paternal transmission
- CTG repeat unstable with maternal transmission

21
Q

Friedreich’s ataxia

A
  • Onset 5-15 years
  • Progressive unsteadiness
  • Dysarthria
  • Decreased ankle and knee jerks with upgoing plantars
  • Kyphoscoliosis
  • Cardiomyopathy
  • FXN gene (intronic GAA triplet repeat not associated with anticipation)
22
Q

Fragile X tremor ataxia (FXTAS)

A
  • Fragile X is the commonest cause of inherited severe intellectual disability in males
  • CGG triplet repeat in FMR1gene
  • Normal 10-50, FRAX >200 full mutation
  • 50-200 pre-mutation
  • FXTAS (pre-mutation carriers)
  • Females – Premature ovarian failure
  • Males- late onset neurodegenerative disorder with gait ataxia and tremor
  • White matter lesions in middle cerebellar peduncle
23
Q

Mitochondrial disorders eg NARP

A
  • Onset often late childhood
  • Ataxia and learning difficulties
  • Neuropathy
  • Dystonia and chorea may occur
  • Retinitis pigmentosa
  • Other features mitochondrial disease
  • May suffer episodic deterioration often with viral illness
  • MRI brain may show basal ganglia lucencies
  • Blood/CSF lactate
  • Muscle biopsy respiratory chain enzymes
  • ATP synthase 6- MTATP6 mitochondrial gene
  • Heteroplasmy wild type vs mutant gene load
  • Maternal inheritance
  • Treatment supportive
24
Q

Early onset primary dystonia

A
  • Presents <21 yrs
    • reduced penetrance
  • Involuntary posturing of a leg, foot or arm
  • Often generalise
  • Postural arm tremor
  • Writer’s cramp
  • AD with 40% penetrance
  • DYT1 TOR1A gene chromosome 9q34
  • 3bp GAG deletion in all individuals
  • Increased in Ashkenazi Jewish pop.
  • Treatment
    • Medication (anticholinergics, benzodiazepines)
    • Botulinum injection
    • Stereotactic surgery
25
Q

Dystonia plus: Myoclonus dystonia

A
  • Myoclonus
    • rapid brief muscle contractions
    • especially neck, trunk, upper limbs
  • Dystonia
  • Writer’s cramp
  • Onset childhood/early adolescence
  • Adults report amelioration with alcohol ingestion
  • Inheritance autosomal dominant; expression of
    disease modified by sex of transmitting parent
    • 100% develop symptoms with paternal
      transmission
    • 5% develop symptoms with maternal
      transmission
  • Imprinted gene SGCE epsilon-sargoglycan
    • imprinting = gene expresses itself or not e.g. maternal gene is silences whereas paternal gene is active
  • Maternal allele methylated
26
Q

Dystonia plus: Dopa responsive dystonia

A
  • DYT5 AD form
  • GCH1
    • AD GTP cyclohydrolase
    • onset ~ 6 yrs often with leg dystonia
    • F:M 3:1
    • 70-80% generalise may resemble dystonic cerebral palsy
  • Response to treatment with Dopa
27
Q

Bradykinesia - Parkinson’s disease

A
  • Bradykinesia, muscle rigidity, tremor
  • Most multifactorial with late onset
    • risk to first degree relative lifetime 3-7%
  • Mendelian forms AD and AR
    • Juvenile onset <20 y
    • Early onset >20 <50y
    • Late onset >50 y
  • AD forms
    • PARK1 SNCA Alpha synuclein Av age 46 y
    • PARK8 LRRK2 Dardarin Av age 50 y
  • AR forms
    • PARK2 PARK2 Parkin Av age 20-40 y
28
Q

summarise genetics of movement disorders

A
  • Inherited movement disorders are clinically and genetically heterogeneous.
  • Consider and exclude non-genetic causes
  • Importance of interpretation of family tree in genetic counselling
    • Consider non-penetrance
    • Consider imprinting
    • Consider anticipation
    • Identify relatives at risk
  • Next generation sequencing technologies greatly enhancing ability to make genetic diagnosis
    • Also facilitating new gene discovery
  • Huntington’s Disease
  • Good model for understanding processes around
    predictive testing for adult onset neurodegenerative
    disease
  • Identification of genes causing movement disorders
    • Better understanding of biological processes may lead to new treatments
    • May help elucidate cause of non-Mendelianneurodegenerative disease

Clinical Neuroscience (27 decks)

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