Diseases with Abnormal Involuntary Movements Huntingtons Disease

Huntington's disease (HD), a disorder of trinucleotide repeat expansion, is inherited in an autosomal dominant trait. The HD gene on chromosome 4 encodes the protein huntingtin, which is widely expressed in the central nervous system. The gene contains a CAG-trinucleotide repeat that normally expands up to 26. In HD patients, the repeat length expands to over 36. A repeat length of over 100 is associated with juvenile-onset disease and is usually transmitted by the father.

Clinical Features

The disease presents in the third and fourth decades of life; successive generations have an earlier onset (anticipation phenomenon). The prevalence is 5 to 10 per 100,000 population. Choreic movements, psychiatric features, and dementia characterize the clinical picture. The choreic movements—abrupt, brief, asymmetric, and jerky—involve the face, tongue, and extremities. They occur spontaneously and during voluntary activities, eventually leading to severe impairment of gait, speech, and swallowing. The juvenile variant presents with akinetic rigidity, dystonia, and seizures, and has a shorter clinical course.

The psychiatric symptoms are manifold, including behavioral and personality changes, distractibility, mood and affective disorders, mainly depression, and psychosis often resembling schizophrenia. These symptoms are combined with a cognitive decline that slowly progresses to dementia. Alcoholism and suicide have a high incidence among HD patients. The clinical course averages from 10 to 15 years.

CT scan and MRI show variable cortical atrophy, mostly of the frontal lobes; enlargement of the anterior horns; and atrophy of the caudates. Subsequently, the

FIGURE 5.30

Huntington's disease. This 50-year-old man had a family history of Huntington's disease. He was diagnosed with the disease at age 37 years and died 13 years later. Transverse section shows (A.) moderate convolutional atrophy, severe atrophy of the caudates and putamens, and flattening of the walls of the enlarged anterior horns as compared with (B.) normal control. C. CT scan of the head from a different patient with Huntington's disease shows flattening of the lateral ventricular walls.

FIGURE 5.30

Huntington's disease. This 50-year-old man had a family history of Huntington's disease. He was diagnosed with the disease at age 37 years and died 13 years later. Transverse section shows (A.) moderate convolutional atrophy, severe atrophy of the caudates and putamens, and flattening of the walls of the enlarged anterior horns as compared with (B.) normal control. C. CT scan of the head from a different patient with Huntington's disease shows flattening of the lateral ventricular walls.

Juvenile Huntington Disease Cat Scan

FIGURE 5.3 1

A and B. The putamen and the caudate show marked atrophy and myelin losses (LFB-CV), (C) neuronal losses (HE), and (D) dense astrogliosis (Holzer stain).

lateral walls of the anterior horns lose their normal curvature and become straight or concave (Fig. 5.30).

Pathology

Grossly, the cerebral cortex is atrophic, the white matter is diminished in volume, and the lateral ventricles are enlarged. The distinctive pathology is confined to the striatum; the caudate and putamen are severely atrophic (see Fig. 5.30).

The histology is characterized by severe neuronal degeneration in the striatum, particularly of the medium-

sized GABAergic spiny neuron. The neuronal losses are accompanied by a reduction of myelinated fibers and astrogliosis (Fig. 5.31). The cerebral cortex shows variable neuronal losses. The presence of ubiquitin-immunoreactive nuclear inclusions in remnant spiny neurons and ubiquitinated neurites in the affected regions is characteristic.

The chemical pathology is characterized by a deficiency of the inhibitory neurotransmitter y-aminobutyric acid (GABA) and of the enzyme glutamate decarboxylase.

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