Search Results

This chapter describes some of the work which has been undertaken to understand the cause of the selective nerve cell death which occurs in Huntington’s disease (HD). It has long been recognized that the change in the gene results in the protein product doing something which it should not: this is called a gain of function mutation. Despite the identification of the gene nearly 30 years ago a coherent story of the cause of the neurodegeneration has not been established. The chapter describes some of the animal models which have been developed and also the neuronal inclusions or aggregates which develop in cells.

This chapter explains some of the research activities which are currently in place. It describes the global research platform called ENROLL-HD. It also describes the process of undertaking a clinical trial. The current clinical trials are focusing on lowering the amount of huntingtin in the cells of the brain especially the caudate and putamen nuclei. The plan is to interfere with the chemical message between the gene and the protein-making machinery of the cell. These drugs are called anti-sense oligonucleotides (ASOs). It is not known if these treatments will result in an alteration of the natural history of Huntington’s disease (HD) but there is hope because the treatment does not rely upon an understanding of the abnormal function of the abnormal huntingtin protein. Currently, the treatments are developed by spinal injections but a future development will be to have drugs which do not have have to be given by spinal injection. This work is contrasted with ideas of gene editing. Brief mention is made to understand genetic factors other than the length of the CAG repeat which influence the age of onset because such an understanding can lead to new avenues for drug treatments.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by the triad of a movement disorder, dementia, and various psychiatric disturbances. HD is caused by the abnormal expansion of a trinucleotide (CAG) repeat in the huntingtin gene of chromosome 4—a mutation that is inherited as an autosomal dominant. When the number of CAG repeats exceeds 39, the individual harboring it goes on to develop HD. The most common time of onset is in the fourth or fifth decade, but the age of onset is inversely correlated with the size of the triplet repeat expansion. In rare instances, persons with very large expansions may have onset in childhood, and those with expansions only just into the abnormal range may have onset late in life. Children of affected fathers, if they receive the abnormal allele, tend to inherit an allele that is even further expanded, and thus usually experience the onset of symptoms at a younger age than their fathers; this phenomenon is known as paternal anticipation. The progression of HD is inexorable and usually leads to death within 15 to 20 years of symptom onset; patients in the final stages have severe dementia and are unable to speak, eat, or purposefully move. Death typically results from the consequences of immobility such as pneumonia or malnutrition. The movement disorder of HD has two major manifestations: involuntary movements (eg, chorea, dystonia) and impairments of voluntary movement (eg, clumsiness, dysarthria, swallowing difficulties, falls, bradykinesia, rigidity). Chorea generally predominates early in the course and is gradually eclipsed by motor impairment as the disease becomes more advanced. In the end stages, patients are rigid and immobile. A variety of medications are used to suppress chorea in HD, including neuroleptics, benzodiazepines, and dopamine-depleting agents such as tetrabenazine, but it remains controversial whether these agents convey functional, as opposed to cosmetic, benefits. HD, like many other neurodegenerative disorders, is associated with a variety of psychiatric problems. Some of these problems such as insomnia or demoralization may be thought of as nonspecific. They have a variety of causes and are associated with many different medical conditions.