Early more than 36 CAG repeats develop the disease.

Early symptoms of Huntington’s are classified in
three domains: psychiatric, cognitive and motor. The motor symptoms are gradual
and occur during early stages of the disease. The symptoms are mostly muscle
“spasms” with involuntary movements of chorea. These involuntary movements are
of ‘small degree’ (Peggy C 2016) which
gradually get worse. In early stages of the disease, motor symptoms tend to
only be hyperkinetic however as the disease progresses, motor symptoms are
hyperkinetic with dystonia and bradykinesia. In terms of cognitive dysfunction,
HD causes a major decline in the ability to making decisions, organisation,
plan and multitask. Both short term and long-term memory is also impaired. As
the disease persists, cognitive deficits results in the diagnosis of dementia.

Psychiatric symptoms at early stages of HD are in the domain of frontal
disinhibition. The symptoms include, irritability which results in severe
outbursts of anger, alterations in mood, impulsivity and poor attention. Family
members often recognise personality change. Later in the disease family members
usually interpret the symptoms as depression. Huntington’s disease is caused by
a mutation in chromosome 4, that encodes for Huntingtin’s protein, of a
person’s DNA. Huntingtin gene contains CAG trinucleotide sequence which codes
for glutamine hence adds glutamines to the Huntingtin protein. In people
without HD, CAG is repeated fewer that 35 times. People with more than 36 CAG
repeats develop the disease. This then results in an increase in glutamine blocks.

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For example, a person has 43 CAG repeats will produce a huntingtin protein with
43 glutamine blocks at the start. (UCL
2011) If a huntingtin protein consists of too many glutamine blocks it
results in a different shape and behaves differently from the normal protein.

The mutated protein has an impact on neuronal health and tends to fold
inaccurately then accumulate as inclusion bodies. These bodies also contain proteins
that control transcription, protein synthesis, folding and degradation. Also,
the number of CAG repeats determines how the huntingtin protein interacts with
its interactor proteins: HIP-1 and HAP-1. As CAG repeats increase in number,
the huntingtin protein binds more to HAP-1 and less to HIP-1. (Liou 2010) The abnormal huntingtin
protein binds tightly to HAP-1 than the normal huntingtin protein which causes
harm to cells and primarily affects striatal and cortical neurons that are
involved in controlling voluntary movement, cognition and motor planning. When
nerve cells in the striatum malfunction and die it causes over-stimulation of
the motor cortex. As this progressively occurs, patients develop irregular involuntary
movements of chorea. It also causes other symptoms of HD for example, gradual
neuronal loss throughout the frontal lobe and cortex results in cognitive
dysfunction. (Driver-Duckley, N. Caviness