Hyperkinetic movement disorders

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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.

GENETICS AND BIOLOGY OF HUNTINGTON DISEASE (HD)

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).

30.1 Simplified structure of human huntingtin (HTT).
It is predominantly composed of HEAT (Huntingtin, Elongation factor 3, protein phosphatase 2A, TOR1) repeats, containing degenerate 38 amino acid motifs that normally appear in tandem arrays with each unit consisting of two helical domains separated by a non-helical region. A polyglutamine stretch (polyQ, encoded by CAG) is located in the N-terminal region. Proteolytic cleavage by caspase 6 and other proteases forms toxic N-terminal fragments.

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.

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.

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.

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:

Juvenile onset (4–19 years of age) accounts for 10% of cases and is particularly linked to paternal transmission.

Early onset (20–34 years of age).

Mid-life onset (35–49 years of age).

Late onset (over 49 years of age) accounts for 25% of cases and is particularly linked to maternal transmission.

PATHOLOGIC GRADING OF SEVERITY

The Vonsattel grading scheme for the severity of atrophy of the basal ganglia correlates with the clinical severity of disease (Fig. 30.2).

30.2 Grading of striatal atrophy in HD.
The system of grading proposed by Vonsattel defines four degrees of severity of involvement in HD.

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).

30.3 Cerebral atrophy in HD.
(a) Surface of frontal lobe showing mild gyral atrophy. (b) Coronal section showing mild gyral atrophy.

30.4 Striatal atrophy in HD.
(a) Characteristic atrophy of the caudate nucleus (C) and putamen (P) in HD. There is also generalized widening of the cerebral sulci. (b) Comparison of a normal cerebral hemisphere (left) with that from a patient with HD (right), illustrating the severe atrophy of the basal ganglia.

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.

30.5 (a) Rarefaction and gliosis of the putamen in HD of moderate severity. The smaller neurons are mostly lost, but some of the large neurons (arrow) are spared, as is usual until quite late in the disease. The smaller neurons normally outnumber the large neurons by 150–250-fold. (b) Loss of myelinated fibers (arrows).

The normal striatum has two neuronal compartments:

The patch (striosome) compartment. Most patch neurons have spiny dendrites, as revealed by Golgi impregnation (spiny neurons), and contain the neurotransmitters gamma-aminobutyric acid (GABA), enkephalin, dynorphin, and substance P.

The matrix compartment. Most matrix neurons have smooth dendrites (aspiny neurons), and contain acetylcholinesterase (large aspiny neurons), or the reduced form of nicotinamide–adenine dinucleotide phosphate (NADPH) diaphorase (NO synthase), somatostatin, neuropeptide Y, and cholecystokinin (small aspiny neurons).

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.

Table 30.1

Distribution and pattern range of 1C2 immunoreactivity in HD

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.

CLINICAL PRESENTATION OF HUNTINGTON DISEASE (HD)

CNS symptoms and signs

Hyperkinetic hd

This is the commoner variant of HD, and is the form of disease in almost all patients with mid-life or late-onset HD.

Choreiform movements are prominent.

Some patients, particularly those with late-onset disease, develop neuropsychiatric disease long before the onset of the movement disorder.

The mean duration of disease is 17 years, death usually occurring from cachexia and bronchopneumonia.

Akinetic-rigid hd

This is an uncommon form of HD, seen in some patients with juvenile or early-onset disease.

Rigidity and akinesia are prominent.

Progression of disease is relatively rapid.

Peripheral abnormalities

Peripheral features of HD, such as weight loss and skeletal muscle wasting, are probably unrelated to the neurological dysfunction or general sickness. Huntingtin is expressed in many tissues and organs.

Weight loss, beginning as minor loss in presymptomatic gene carriers and ending with profound cachexia in advanced disease. Correlates with CAG repeat number.

Skeletal-muscle wasting, possibly due to defects caused by mutated huntingtin in myocytes.

Cardiac failure. Leading cause of death in these patients. Autonomic nervous system involvement may contribute.

Impaired glucose tolerance: insulin production reduced, altered gene transcription in islet cells.

Leukocytes have altered gene transcription, and mitochondrial function. Adenosine A2A receptor function and monoamine oxidase activity are disrupted.

Osteoporosis: severity correlates with the number of CAG repeats.

Testicular atrophy. The highest levels of huntingtin expression are found in the brain and testes. men have reduced testosterone concentrations but fertility is unaffected.

(Adapted from van der Burg et al. 2009.)

DIFFERENTIAL DIAGNOSIS OF HUNTINGTON DISEASE

Approximately 1–2% of patients clinically diagnosed as having HD have been found to have CAG repeats in the normal range. These patients may represent either clinical misdiagnosis or HD phenocopies.

The akinetic–rigid form of HD overlaps clinically with Wilson’s disease, juvenile parkinsonism, neuroaxonal dystrophy, and some neurometabolic storage disorders.

The hyperkinetic form of HD overlaps clinically with chorea associated with SLE, drug-related movement disorders, neuroacanthocytosis and McLeod syndrome (see below), and hereditary ceruloplasmin deficiency (see Chapter 22).

Neurodegenerative disorders other than hd that cause atrophy of the basal ganglia

Multiple system atrophy (MSA, see Chapter 28), in which atrophy of the basal ganglia is associated with diagnostic inclusion bodies.

Corticobasal degeneration (CBD, see Chapter 28), in which basal ganglia disease is associated with swollen neurons and tau-related pathology in the cerebral cortex and the substantia nigra.

Frontotemporal lobar degeneration (FTLD) (see Chapter 31), especially FTLD-FUS.

NEUROACANTHOCYTOSIS

This term is applied to multisystem degenerative neurologic disorders, genetically heterogeneous, associated with acanthocytes in the blood. The two main neuroacanthocytosis syndromes are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. The latter is an X-linked disorder characterized by striatal degeneration and myopathy, occurring in association with the Kell blood group variant, in which the Kell blood group precursor protein, Kx, is lacking.

NEUROACANTHOCYTOSIS

The mean age of onset is 32 years (range 8–62 years).

Patients often present with chorea but may develop other movement disorders, including dystonia, tics, and parkinsonism.

Neuropsychiatric disturbances, cognitive impairment, bulbar signs, and seizures are common manifestations.

Acanthocytosis is not present in all affected patients.

The defective pathway that causes a red cell membrane abnormality and neurodegeneration remains obscure.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The main findings are atrophy, neuronal loss, and astrocytic gliosis in various brain regions (Fig. 30.7). Examination of a fresh blood film reveals acanthocytes. In some cases acanthocytes are not easy to find and repeat examination or scanning electron microscopy of blood may be necessary for diagnosis.