Neurodegenerative Diseases: Huntington Disease

Abstract

Huntington disease (HD) is an autosomal dominant disorder with full penetrance and rare de novo mutations. Early changes include mild motor decline with clumsiness and slowed gait, progressive changes include dystonia and chorea, parkinsonian symptoms, slow and stiff gait, dysphagia, tremor, and depression and suicidal ideation. In the late stages, rigidity, severe bradykinesia, dysphagia, inability to swallow, seizures, and inability to walk or speak predominate.

On MR imaging, atrophy of the striatum (especially caudate nucleus), cortical gray matter, globus pallidus and thalamus are the predominant features.

Loss of medium-sized spiny GABA-substance P- or GABA-enkephalin-positive neurons which project to the globus pallidus and pars reticulata of the substantia nigra is noticed in the caudate nucleus. Small spiny neuropeptide Y, somatostatin and NADPH-diaphorase-positive interneurons as well as large non-spiny cholinergic interneurons are not involved. Other affected regions include the globus pallidus, ventrolateral thalamus, and subthalamic nuclei. In the cerebral cortex, slight loss of pyramidal neurons in layers III, V and VI of the frontal lobe, CA1 region of the hippocampus and concomitant reactive astrogliosis might be seen.

HD is characterized by an expansion of the CAG repeat in exon 1 in the huntingtin gene (HTT) mapped to short arm of chromosome 4q16.3 which encodes the protein huntingtin. Huntingtin plays several roles in regulating the dynamics of autophagy, is expressed in innate immune cells and plays as wild-type huntingtin a role in the intracellular transport of vesicles and organelles.

The number of repeats can increase from one generation to the next one (normal alleles: 26 or fewer repeats; intermediate alleles: 27–35 repeats; individual not at risk to develop the disease, risk of having an affected child). HD-causing alleles: 36 or more repeats (reduced penetrance: 36–39 repeats; full penetrance: 40 or more repeats). Environmental factors, genetic modifiers, and other factors determine the development of the disease over time. Maternal or paternal transmission is possible, whereby the paternal transmission is associated with higher number of repeats.

Treatment consists in managing rigidity (baclofen and diltiazem), chorea (haloperidol or atypical antipsychotics), and myoclonus (valproate). HD is a progressive disorder with a mean duration of disease of 17 years (2–45 years).