Huntingtons Flashcards
What are the genetics of Huntington’s
Autosomal dominant with complete penetrance. Huntingtin gene (HTT) found on short arm of chromosome 4. Length of CAG repeat determines risk. Above 40 repeats is disease, 36-39 is reduced penetrance, 27-35 is intermediate. Relationship between age of onset and length of CAG repeats.
Cellular pathology and mechanisms.
Huntingtin is ubiquitous and cytoplasmic. Many physiological signaling roles. Plaques form in Huntington’s disease. The aggregates interact intracellularly, to cause mitochondrial dysfunction, calcium signalling dysfunction (innhibition of ER stored intracellular Ca), have protein-protein interactions, and cause transcriptional dysfunction. Causes altered NT release, and different receptor expression.
Gross pathology and loss of what neurones in direct/indirect pathway
10-20% reduction in brain weight. decrease in striatal and cortical volume, but increase in ventricle size. loss of GABA and enkephalin-containing medium spiny neurones (MSN) in the striatum. Direct pathway causes loss of substance P- containing MSNs.
Basal ganglia in Huntington’s and the direct/indirect pathway
Basal ganglia made up of putamen, caudate nucleus, globules pallid us (internal and external), subthalamic nucleus, substantia nigra. Direct pathway contains D1 (stimulatory) receptors, indirect pathway contains D2 (inhibitory) receptors. Indirect -movement off. Direct - movement on.
In the direct pathway, upon DA stimulation of D1, GABA and substance P is released from the striatum onto the globus pallidum internal (GPi), which decreases GABA release onto the thalamus, thus increasing function. Here increase in dopamine from substantia nigra stimulates the striatum to release GABA - increasing thalamus activity.
in the indirect pathway, GABA and enkephalin is released to the globus pallidum external (GPe) from the striatum, which releases GABA on the subthalamic nucleus (STN), which then releases glutamate to the GPi. glutamate release increases the release of GABA to the thalamus - decreasing excitation. In this pathway, dopamine from the substantia nigra binds to D2 to decrease the GABA release from the striatum, thus decreasing movement by increasing glutamate release onto the GPi.
In Huntington’s initially it is the loss of the GABA and enkephalin containing MSNs in the indirect pathway that are lost. this increases GPe release of GABA onto the STN which decreases glutamate release onto the GPi, thus decreasing GABA release onto the thalamus - excitation. Dopamine release onto the striatum will increase, but will actually make it worse by further inhibiting the indirect pathway, and stimulating the direct pathway.
In later stages, the GABA and substance P MSNs from the direct pathway are also lost. As such, in later stages the involuntary movements will decrease.
Affected roles of the substructures of the basal ganglia
premotor area, affecting movement (putamen). dorsolat prefrontal cortex and lateral orbitorontal cortex are affected, causing cognitive declines (caudate). The medial orbito-frontal crotex also affected, causing psychiatric symptoms (nucleus accumbens).
Motor symptoms
Early stage: involuntary hand, toe, and eye movements. restlessness.
Mid-stages: involuntary movements, slow abnormal movements with increased muscle tone.
Late-course: impaired voluntary movements: rigidity, bradykinesia, dystonia, convulsions, weight loss. can cause death, e.g., pneumonia, choking, etc…
Can also cause muscle weakness
Cognitive symptoms
Attention deficits
Impaired insight/judgement
Forgetfulness
Language deficits
Stroop test diagnosis
Name of colour written in a different colour, e.g., ‘blue’ in red font. If cannot tell, may have it.
Psychiatric symptoms
irritability
depression
apathy
anxiety
disinhibition
obsessive/compulsive
Rare: hallucinations
differ massively patient to patient
Other symptoms
Weight loss
sleep disturbance
