Normal caudate nuclei.
Normal caudate nuclei, small lateral ventricles.
HD. Atrophy of the caudate nuclei.
HD. Atrophy of the caudate nuclei and dilatation of the lateral ventricles.
GFAP immunostain, showing gliosis. Left: HD; right: normal caudate nucleus.
Caudate nucleus from Huntington's disease (left) and from normal brain (right). GFAP immunostain.
Huntington's Disease (HD) is a fatal autosomal dominant condition that begins usually in the4th to 5th decade of life and is characterized by behavioral changes, chorea, and dementia. In a small percentage of cases, symptoms begin before age 20. Gross examination of the brain reveals atrophy of the caudate nucleus and putamen and dilatation of the anterior horns of the lateral ventricles, which are obvious on MRI in advanced cases. Milder changes may be detected on neuroimaging years before the onset of symptoms. Degeneration begins in the caudal portions of the caudate and putamne and advances rostrally. Cortical atrophy is also present in advanced cases. Microscopically, there is loss of medium size spiny, enkephalin-containing internuncial neurons in the caudate nucleus and putamen, loss of cortical neurons, and gliosis. Proliferation of reactive astrocytes causes the affected nuclei to appear more cellular than normal. There are also neuronal intranuclear inclusions containing huntingtin, the protein encoded by HTT (see below).
molecular abnormality of HD is CAG
trinucleotide expansion of the HTT(HUNTINGTIN)
gene on chromosome 4p. This adds a polyglutamine
segment to huntingtin. This protein is widely expressed
throughout the brain. It is thought that the CAG-expanded
huntingtin has a toxic function. However, huntingtin
is a key cellular protein involved in cellular transport
and is important for cell viability. Therefore,
loss of huntingtin function may also contribute
to the pathogenesis of HD. The CAG triplet expansion
is probably due to malfunction of cellular processes
that repair strand breaks and remove mispaired bases
from DNA. The expanded huntingtin, conjugated with
ubiquitin, forms aggregates (inclusions) in the
nuclei cytoplasm and dendrites of affected neurons. These inclusions can
be detected by immunohistochemistry using antibodies
to huntingtin. These findings suggest that there
is an error in the proteolytic degradation of the
expanded huntingtin. Normally, this degradation
takes place in cellular chambers called proteasomes
and involves conjugation of huntingtin with ubiquitin.
Impairment of this process apparently causes huntingtin-ubiquitin
complexes to be translocated into the nuclei. Adult-onset patients have 40-50 repeats. A high number of repeats is associated with early onset and more rapidly progressing disease. The
expanded CAG repeat is unstable and may increase
in size in successive generations. This causes the
disease to appear at a younger age and more severe
form, a phenomenon known as anticipation.
Anticipation occurs more commonly if the mutated
allele is inherited from the father.
CAG repeats on other genes are also seen in spinobulbar muscular atrophy (Kennedy's disease), Machado-Joseph disease, an autosomal dominant ataxia seen mainly in Portugese of Azorean descent, and cerebellar degenerations. Paternally inherited HD shows the phenomenon of anticipation, i.e. the number of repeats increases in the offspring, resulting in earlier onset and more severe disease. Biochemical analysis of the striatum in HD shows loss of neurotransmitters, including GABA, acetylcholine and glutamate, which correlates with the loss of small neurons. Decrease of GABA and unbalanced dopamine activity result in chorea.
A rare form of chorea, beginning in adolescence or early adult life, is associated with an erythrocyte abnormality (chorea with acanthocytosis). Pathologically, this entity is similar to Huntington's disease but is caused by a different gene defect. Sydenham Chorea is a transient disorder in rheumatic fever caused by antibodies that react with neuronal antigens in the basal ganglia.
- Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol. 2005;40:622-33. PubMed