Genetics of Movement Disorders Flashcards
MOVEMENT DISORDERS
name the 4 Neurological description for abnormal movements (dyskinesias)
-Chorea
-ataxia
-dystonia
-bradykinesia
Chorea
Ceaseless/constant occurrence of a wide variety of rapid, highly complex, jerky, dyskinetic movements that appear well coordinated but are involuntary. e.g. fidgety
Ataxia
Loss of the ability to coordinate muscular
movement. e.g. broad base gait
Dystonia
Abnormal tonicity of muscle, characterized by prolonged, repetitive muscle contractions that may cause twisting or jerking movements of the body or a body part.
Bradykinesia
Abnormal slowness of muscular movement. e.g. PD
Inherited movement disorders
- Wide variety of inherited movement disorders
- Present varying combinations of chorea, dystonia, ataxia and bradykinesia
- Pattern recognition
name examples of chorea
- Huntington’s disease
- Wilson’s disease
- Choreacanthocytosis
name examples of ataxia
- Spinocerebellar ataxia (SCA)
- Friedreich’s ataxia
- Fragile X tremor ataxia (FXTAS)
- Neuropathy ataxia retinitis pigmentosa (NARP)
name examples of dystonia
- Primary dystonia early onset
- Myoclonus dystonia
- Dopa-responsive dystonia (DRD)
name examples of bradykinesia
Parkinson’s disease
Genetic aspects of inherited movement
disorders
- 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
CHOREA - Huntington’s disease
- 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)
Prevalence of HD
- 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
clinical features of HD
- 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
allele sizes of HD
- 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
Anticipation OF HD
- 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
predictive testing OF HD
- 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%
treatment OF HD
- 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.
CHOREA - Wilson’s disease
- 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
ATAXIA - Spinocerebellar ataxia (SCA)
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
Friedreich’s ataxia
- 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)
Fragile X tremor ataxia (FXTAS)
- 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
Mitochondrial disorders eg NARP
- 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
Early onset primary dystonia
- 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
Dystonia plus: Myoclonus dystonia
- 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
- 100% develop symptoms with paternal
- 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
Dystonia plus: Dopa responsive dystonia
- 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
Bradykinesia - Parkinson’s disease
- 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
summarise genetics of movement disorders
- 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
