Hyperkinetic movement disorders

Published on 19/03/2015 by admin

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Last modified 19/03/2015

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Hyperkinetic movement disorders

Several clinical conditions are characterized by the presence of excessive uncontrolled movements and are grouped as hyperkinetic movement disorders. These are chorea and ballismus, myoclonus, and dystonia. Tics can also be classed as hyperkinetic disorders, though pathologic studies of the commonest type (Gilles de la Tourette syndrome) have not yet revealed significant histopathologic abnormalities.

CHOREA

Chorea is characterized by the presence of non-rhythmic rapid involuntary movements and can be divided into hereditary and sporadic groups.

image GENETICS AND BIOLOGY OF HUNTINGTON DISEASE (HD)

image HTT, the gene for HD, is subtelomeric on the short arm of chromosome 4 and codes for the protein huntingtin (HTT), which is widely expressed in fetal and adult tissues, but of unknown function. HTT includes a CAG repeat sequence in its N-terminal region. The normal gene contains 9–37 CAG repeats (each encoding glutamine); in HD the number of repeats ranges from 37 to 100 or more. Huntingtin is a very large protein predicted to consist mainly of repeated units of about 50 amino acids, termed HEAT repeats. These repeats are composed of two antiparallel α-helices with a helical hairpin configuration, which assemble into a superhelical structure with a continuous hydrophobic core (Fig. 30.1).

image The polyglutamine resulting from transcription of the CAG repeat has been shown to bind several other proteins. Proposed mechanisms contributing to pathology include loss of huntingtin function, and toxic gain of novel function(s). Nuclear aggregation has been proposed to cause transcriptional dysregulation, impair proteolysis, and stimulate apoptosis. The cellular functions of huntingtin are still not completely understood. The protein is mostly cytoplasmic, with membrane attachment via palmitoylation at cysteine. A putative nuclear export signal is present near the C-terminus but a clear nuclear localization signal has not been identified. HTT shuttles into the nucleus, has a role in vesicle transport, and can regulate gene transcription. It may also regulate RNA trafficking.

image Longer CAG repeats predict earlier onset and more rapid neurologic decline. However, there is up to 50–70% of variance in age of onset, due to modifying genes and the environment.

image HD, along with several other inherited neurological disorders caused by expansion of a CAG repeat, is classed as a polyglutamine disorder. Prevalence of HD is 4–10 per 100 000 in the western world, with many more people at risk of the disease. Mean age of onset is 40 years, death occurring 15–20 years from onset.

image The disease shows anticipation: later generations are affected at an earlier age and more severely than earlier generations in the same family. This phenomenon is associated with a progressive increase in the length of CAG repeat sequences as the disease is transmitted through successive generations. Very rare sporadic cases of HD are usually due to expansion of a 34–37 CAG repeat (intermediate allele) in an unaffected male patient.

HUNTINGTON DISEASE (HD)

HD causes chorea, rigidity, and cognitive decline leading to dementia. The incidence of this disease is 4–7/100 000 in most populations. It is an autosomal dominant condition with a variable age of onset:

MACROSCOPIC APPEARANCES

Cerebral atrophy is usually present (Fig. 30.3) with a reduction in brain weight of approximately 30%. This is associated with a 21–29% loss of volume of the cerebral cortex and a 29–34% loss of white matter. The most characteristic macroscopic abnormality is atrophy of the caudate nucleus, putamen, and globus pallidus (Fig. 30.4).

MICROSCOPIC APPEARANCES

The most marked histologic changes are seen in the basal ganglia where loss of neurons is associated with astrocytic gliosis in affected areas of the striatum (Fig. 30.5). In general, morphometric studies are required to show loss of large pyramidal neurons in the neocortex and hippocampus, which occurs in the absence of astrocytosis. Neuronal loss may also be found in the hypothalamus, substantia nigra, and cerebellar cortex, particularly in severe early-onset cases. The neuronal loss from the striatum preferentially affects certain neuronal subtypes.

The normal striatum has two neuronal compartments:

Spiny neurons are severely depleted in HD. Loss of aspiny neurons is much less marked and occurs in late stages of the disease.

Immunohistochemical staining for ubiquitin or huntingtin reveals pathological accumulation of huntingtin protein within intranuclear inclusion bodies or in neurites. Abnormal neurites have been shown to be widely distributed throughout the cortex in HD by immunostaining for ubiquitin. Intranuclear inclusions are found in cortical neurons (Fig. 30.6 and Table 30.1). However, inclusions tend to be numerous only in cases with a long expansion repeat and hence a younger age of onset. In late-onset cases associated with a short expansion nuclear inclusions may be sparse.

image

30.6 Patterns of huntingtin accumulation, revealed by labeling of polyglutamine repeats with the antibody 1 C2. The labeling may be diffuse, or aggregated into granules or discrete inclusions. Combinations of nuclear and cytoplasmic inclusions are occasionally seen.
The types of inclusions vary between different brain regions (see Table 30.1). (a) Diffuse nuclear, (b) aggregated nuclear (the aggregate is not in the nucleolus), (c) diffuse nuclear and cytoplasmic, and (d) granular, cytoplasmic-only inclusions. (e) Cytoplasmic inclusions in the cortex, (f) small aggregates in the neuropil, and (g) aggregates in oligodendrocytes of the subcortical white matter.

image CLINICAL PRESENTATION OF HUNTINGTON DISEASE (HD)

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