Chemistry Reference
In-Depth Information
3.
Huntington's disease
This is one of a family of diseases in which the expansion of CAG codon repeats resulting in extended poly-
glutamine (polyQ) tracts in the expressed protein. HD has a frequency of 4 in 10
5
among European populations
(less than 1 in 10
6
in Japanese and African populations), and is the most common of the polyQ diseases. It causes
movement disorders, cognitive deterioration, and psychiatric disturbances. Symptoms begin appearing insidi-
ously, typically between the ages of 35 to 50: the disease is progressive and fatal some 15
20 years after onset.
Motor disturbances include choreiform
1
involuntary movements of proximal and distal muscles and progressive
impairment of voluntary movements. In patients with juvenile onset HD, the symptoms include bradykinesia
(slowness of voluntary movements and of speech), rigidity, and dystonia (intense irregular muscle spasms); the
involuntary movements of the children often take the form of tremor, and they often suffer from epileptic seizures.
HD is characterised by a remarkable specificity of neuronal loss. The most sensitive region is the striatum, with the
caudate nucleus and the putamen particularly affected; in advanced cases, there is also loss of neurons in the
thalamus, substantia nigra, and the subthalamic nucleus. The age of onset of the disease as well as the severity of
the symptoms are a function of the length of the glutamine stretches
e
e
individuals with 35 CAG repeats or less do
not develop the disease; those with 35
39 have an increased risk; while repeats of 40 or over will always lead to
the disease in the course of a normal lifespan.
The gene for the protein involved, huntingtin of unknown function, consists of 67 exons, extending over 180 kb
of DNA and codes for a protein of 3144 residues (one of the longest polypeptide chains known). The polyQ
domain is close to the N-terminus, with the CAG repeat in the first exon. In common with other polyQ diseases,
huntingtin with its polyQ repeat is found within aggregates or inclusions within the nuclei of neurons
(
Figure 21.2
)
. These inclusions in several cases are formed by insoluble amyloid-like fibres, reminiscent of the
aggregated forms of proteins found in other neurological diseases. A conformational transition from random coil
to
e
-sheet, which shares most of the features typical of amyloids, takes place during the process of fibre formation.
Alterations in brain iron metabolism have been reported, resulting in increased iron accumulation in
Huntington's disease. This was particularly the case in basal ganglia from patients with HD compared to normal
controls. In studies in embryonic stem cells, huntingtin was found to be iron regulated, essential for the function of
normal nuclear and perinuclear organelles and to be involved in the regulation of iron homeostasis.
b
4.
Friedreich's ataxia
Friedreich's ataxia is the most common hereditary ataxia
2
and is the most prevalent cerebellar ataxia among
children and adults in Europe. It was first described in 1863 by Nikolaus Friedreich. His clinical observations
described the essential characteristics of the disease as an adolescent-onset ataxia, particularly associated with
clumsiness in walking, accompanied by sensory loss, lateral curvature of the spine, foot deformity, and heart
disease. Detailed neuropathological examination showed cerebrospinal degeneration. Friedreich's ataxia (FRDA)
is yet another of the fifteen neurological diseases in man which are known to be caused by the anomalous
expansion of unstable trinucleotide repeats. However, unlike Huntington's disease, the trinucleotide expansion
occurs in a non-coding region of the gene. The FRDA gene is composed of seven exons spread throughout 95kb of
DNA (
Figure 21.10
)
, and encodes for the 210 residue protein, frataxin. Frataxin protein levels are severely
decreased in FRDA patients, and most FRDA patients are homozygous for the GAA expansion in intron 1. Since
the mutation is in the noncoding intron, the consequence of the GAA expansion is to decrease the amount of
frataxin mRNA which is synthesised, thereby accounting for the decreased amount of protein. The characteristic
pathogenesis of FRDA includes abnormal iron accumulation in mitochondria, hypersensitivity to oxidative stress,
1. Choreiform movements are purposeless, involuntary movements such as flexing and extending of fingers, raising and lowering of shoulders
or grimacing.
2. Inability to coordinate voluntary bodily movements, particularly muscular movements.
