ATAXIA Flashcards
What does ataxia mean?
Without order
What are the symptoms of ataxia?
Incoordination Imbalance Wide base Speech disturbances (dysarthria) Eye disturbances (nystagmus)
What are the clinical symptoms if the vestibulocerebellum is damaged?
- eye disturbances
- wide stance that indicates difficulty balancing
What are the clinical symptoms if the spinocerebellum is damaged?
- wide based irregular steps with lateral veering
- action tremor of limbs
What are the clinical symptoms if the cerebrocerebellum is damaged?
- delayed initiation and termination of movement
- slow to initiate a movement on command
- tendency to overshoot a target (dysmetria)
- inability to perform continuous repetitive movements (dysdiadochokinesia)
What causes cerebellar ataxia?
dysfunction of cerebellum and its connecting pathways
Describe labyrinthine ataxia
- vestibular disorders
- signals from the inner ear do not reach the brainstem and the cerebellum
- no speech defects
- limb movements are coordinated
- impaired gait and balance
Describe sensory ataxia
- malfunction of sensory input
- failure of transmission of proprioception to the CNS
- no eye disturbances
- incoordiation increases dramatically when eyes closed
Describe acquired ataxia
Where symptoms develop suddenly as a result of: Cerebellar haemorrhage Toxins and nutritional deficiencies Tumours Endocrine disease Infectious causes Inflammation Cerebral palsy Parneoplastic syndrome Cerebellar ischemic stroke
Describe hereditary ataxia
It develops slowly over many years. 3 types: X linked ataxias Autosomal dominant Autosomal recessive
Describe x-linked ataxia
Type of hereditary ataxia.
Fragile x-associated tremor and ataxia syndrome
Describe autosomal dominant ataxia
Type of hereditary ataxia.
Two types:
- spinocerebellar ataxia
-episodic ataxia (2 types)
What are the different autosomal recessive ataxias?
- Freidreich’s ataxia
- Ataxia telangiesctasia
- Ataxia with Vitamin E deficiency (treatable)
- Ataxia with coenzyme Q10 deficiency (treatable)
How is ataxia diagnosed?
- History of symptoms and family history required
- neurological exams
- laboratory tests
- brain imaging scans
What neurological exams are used to diagnose ataxia?
Tandem walk - test for drunk drivers, gait needs to be narrowed to achieve this
Test for dysmetria - evaluation of point to point movement
Test for dysdiadochokinesis - evaluation of rapidly alternating movement
What laboratory tests are used to diagnose ataxia?
Measure blood pressure, blood tests for drugs,
vitamin levels, thyroid function, toxins and metals,
HIV and other infections, parneoplastic antibodies
Lumbar puncture
Brain imaging scans
Genetic tests
Describe CT scans
Computerised tomography scan series of X-rays are taken and assembled into 3-D image of brain takes 5 mins half the price of an MRI scan
Describe MRI scans
Magnetic resonance imaging scan
strong magnetic fields and radio waves to produce
detailed scans of the soft tissue of brain
What are symptomatic treatment options for ataxia?
- Physical therapy
- Speech therapy
- Diet modifications - it becomes more difficult to swallow so diet is often modified for maximum consumption. Often a feeding tube is required
- Action tremor may respond with drug treatment
- Use of walking aids/wheelchair will give individual freedom of movement
What type of hereditary ataxias are treatable?
- Ataxia with vitamin E deficiency
- Ataxia with coenzyme Q10 deficiency
- Episodic ataxia type 2
How is acquired ataxia treated?
Depends on underlying cause and how much damage
Complication of infection - antibiotics or anti-virals
Stroke or haemorrhage - correct high blood pressure,
thinning of blood to prevent further clots
Alcohol or toxins - avoid
Tumour - surgery
What tissues are affected in Friedreich’s ataxia?
- Primary sensory neurons in dorsal root ganglion
- Cerebellum (superior cerebellar peduncle)
- Heart (hypertrophic cardiomyopathy)
- Pancreas (diabetes)
Describe Friedreich’s ataxia
- First described in 1860s by Nicholaus Friedreich
- Recessively inherited form of ataxia
- Onset of symptoms between 5 and 15 years
- Progressively lethal
- Gait disturbances/difficulty walking (ataxia)
- Curving of spine to one side (scoliosis)
- Slowness and slurring of speech (dysarthria)
- Hearing and vision loss
Describe the inheritance of Friedreich’s ataxia
Most common inherited ataxia
Affects about 1 in 50,000
Carrier frequency between 1:60 and 1:100
What causes Friedreich’s ataxia?
Location of defect mapped to chromosome 9 in 1988
Frataxin gene was identified in 1996
The defect is a mutation - an unstable expansion of GAA repeat (repeated 66-1700 times) in the first intron resulting in a shortage of frataxin produced (13-30& of normal levels)
Where is the frataxin protein found?
In the mitochondria
What happens as a result of loss of frataxin?
Deficiency Fe-S containing proteins/ Mitochondria overloaded with iron
Inefficient electron transfer chain
increase reactive oxygen species
Impaired energy production
Damage to cells of nervous system, heart, pancreatic β-cells
How can protein expression be increased as a therapeutic option for FA
Recombinant human erythropoietin:
- improvement of ataxia and cardioprotective effects
- reduced DNA damage and oxidative damage
- increase in frataxin protein is post-transcriptional
Histone deacetylase (HDAC) inhibitors:
- alter heterochromatin structure (acetylation of histones associated with
higher levels of transcription)
- Compound 106 restored frataxin levels in mouse model
- Picked up by pharmaceutical company to carry out further animal and
safety trials
What antioxidants can be used as therapeutic treatment for FA?
Idebenone
Mitoquinone
Coenzyme Q10-vitamine E hybrid (EPI –A0001)
EGb 761 (Ginkgo bilboa extract)
What iron chelators can be used as therapeutic treatment for FA?
Deferiprone
PCTH (2-pyridylcarboxaldehyde 2-thiophencarboxyl hydrazone)
What is the function of frataxin?
It is required for efficient regulation of cellular iron homeostasis.
It is involved in assembly of iron-sulfur clusters.
Describe Autosomal dominant spinocerebellar ataxias (SCAs)
- Group of inherited neurodegenerative disorders
- Different genetic defects and variable phenotypes
- All characterized by postural abnormalities, progressive motor incoordination, cerebellar degeneration
- Autosomal dominant; family history
- Some forms of SCA are fatal but not all
What are the 5 types of SCA by clinical phenotype?
Type I - Ataxia + degeneration of other neuronal systems
Type II - Ataxia + degeneration of retina
Type III - Pure cerebellar ataxia
Type IV - Ataxia + myoclonus
What are the loci associated with SCA?
There are more than 40 different loci associated with SCA
What are the genes and mutations that cause SCA?
- poly glutamine (CAG) expansions
- Non coding CAG and non CAG repeat expansions
- Conventional mutations
What are the symptoms of SCA1?
They begin in early adulthood.
- Ataxia
- eye disturbances
- speech/swallowing difficulties
- cognitive impairment
What is the pathology of SCA1?
- severe loss of Purkinje cells (greatest in vermis)
- some loss of granule cells
- loss of olivary neurons in brain stem
- loss of afferent fibers in middle and inferior cerebellar peduncles
- loss of neurons in spinal cord
What causes SCA1?
Polyglutamine expansion results in increased levels of phosphorylated protein in nucleus; alters gene expression; Purkinje cell’s protein repertoire altered; cerebellar output and survival of Purkinje cells altered glutamine expansion affects folding, interaction with other transcription factors and post translational modification of ataxin-1
How does expanded CAG (polyglutamine) repeat cause SCA1?
Presence of expanded polyglutamine repeat in protein alters interaction of ataxin 1 with other transcription factors
Reduced expression of proteins involved in calcium
signaling/buffering, glutamate removal (EAAT4; excitatory amino acid
transporter 4)
Loss of calcium buffering proteins and ability to remove glutamate may cause disease
What are the symptoms of SCA6?
Pure cerebellar symptoms (abnormal eye movements, slurred speech, progressive imbalance and limb incoordination)
What causes SCA6?
Alternative splicing results in high level of mutant protein with expanded glutamine being expressed in Purkinje cells; explains cell selectivity but not mechanism; not known if changes in calcium levels occur.
What causes SCA13?
Mutations affect potassium channel properties; unable to sense change in membrane potential or result in slow closure of channels; takes longer for Purkinje cell to regain resting membrane potential after action potential; slows Purkinje cell firing frequency; cerebellar output reduced
What are the clinical symptoms of SCA13?
Dysarthria, nystagmus and gait ataxia Cerebellar atrophy without brainstem involvement Epilepsy and mental retardation
