CAG - 3 letters that can change your life

Huntington’s disease (HD) is an inherited neurodegenerative disorder of the central nervous system which affects movement, cognition and behaviour. In 1872 Dr George Huntington, a N.Y. Physician, provided the first thorough description of HD; through studying combined medical history of several generations of Long Island families with similar symptoms. Although the symptoms of HD had been documented prior to 1872, Dr Huntington was the first to characterise the symptoms as one disease.

HD affects 3 to 7 in 100,000 people of European ancestry; the disease is less common in other populations, such as American, African and Japanese. Symptoms tend to develop between 30 and 50 years old. The first symptoms include memory loss, uncontrolled movements, rigidity and mood swings which develop into dementia, involuntary movements, seizures, depression and speech impediments. During the late stages of HD a patient becomes totally dependent, needing full nursing care. The cause of death in HD patients is often from a secondary cause, eg heart failure or pneumonia.

HD is an autosomal dominant disorder. The genetic defect is carried in chromosome 4 and affects the HTT gene encoding the huntingtin protein (Htt). Being homozygous for a dominant disorder usually results in a more severe phenotype, however it appears that the clinical expression for homozygote HD does not differ from heterozygous HD. HD is the first disease discovered that displays complete phenotypic dominance. However there is a direct correlation between the number of CAG repeats and the extent of the phenotype.

Several pathways by which mutated Htt may cause cell death have been identified:-

· Effects on chaperone proteins; which help fold proteins and remove misfolded ones

· Interactions with caspases; which play a role in the process of removing cells

· The toxic effects of glutamine on nerve cells

· Impairment of energy production within cells

· Effects on the expression of genes

The pathogenesis of HD is concentrated in the corpus striatum where selective degeneration of GABAergic spiny neurons are replaced by a proliferation of glial cells.

Huntington's affects the whole brain but certain areas are more vulnerable. These are listed below:-

· Structures of the basal ganglia; caudate nucleus and putamen

· Layers 3,5 and 6 of the cerebral cortex

· The hippocampus

· The purkinje cells in the cerebellum

· The lateral tuberal nuclei of the hypothalamus

· Parts of the thalamus

These are affected due to their structure and the type of neurons they contain, reducing in size as cells are lost. Striatal spiny neurons are the most vulnerable. In particular striatal neurons with projections towards the external globus pallidus and spiny cells projecting to the internal pallidum being less affected. Earliest changes in the brain are seen in the striatum, 90% of which are medium spiny projection neurons (MSP), there is dominant death of MSP in the caudate nucleus. Death continues gradually in layers 3, 5 and 6 of the cortex, the CA1 region of the hippocampus and substantia nigra.

This loss of neurons leads to loss of important neurotransmitters such as GABA, GAD, glutamate and acetylcholine in the striatum. However there is an increase in serotonin levels in most striatal subdivisions. Excess metabolites of serotonin or serotonin itself facilitate striatal atrophy in HD. There is a reduction in postsynatptic dopamine receptors D1 and D2, also a reduction in dopamine transporter DAT in striatum might result in the cognitive impairments seen in HD.

The basal ganglia’s function is prominently affected in the early stages of Huntington’s and plays a key role in movement and behavioural control. The basal ganglia ordinarily inhibits a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in awkward initial movements; motions to be unintentionally initiated; movement to halted before its intended completion. Therefore damage to this area results in the characteristic involuntary movements associated with HD.

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