The genetics of Huntington’s disease

This chapter describes the nature of the genetic mistake. The genetic code, or DNA molecule, is wound up onto structures called chromosomes. The gene for HD is located on chromosome 4. As we have two copies of our genes the chromosomes are in pairs. Only one copy of the HD has to be abnormal to cause the condition. This results in a pattern of inheritance called autosomal dominant and both males and females can be affected. Genes code for proteins; the protein encoded by the HD gene is called huntingtin. Proteins are made of building blocks called amino acids. The gene for HD has an expansion of the genetic code for glutamine. Therefore, abnormal huntingtin has an expansion of the number of glutamines. The genetic code for glutamine is CAG so the mistake in the gene is sometimes called a CAG repeat expansion disorder or in referring to the protein it is called a polyglutamine repeat expansion. The gene is in one part of the cell and the protein-making machinery is in another part of the cell so a chemical messenger is required which is called RNA. Explaining this is important for understanding some current clinical trials

Genetic counselling: a new diagnosis in the family

This chapter describes the process of genetic counselling in general but with an emphasis on Huntington’s disease. The chapter discusses issues for a new diagnosis in the family and describes the challenges of telling children that they are at risk. Medical doctors often lead genetic counselling teams as they are specially trained to give information about genetic disorders and explain the implications of genetic tests. The doctor or counsellor has to understand your particular circumstances and support you in a way that allows you to make your own decisions. A diagnosis of HD has implications for you and all your close relatives.

Changes in the brain

This chapter explains the change which can be seen in the structure of the brain of someone with Huntington’s disease (HD). There is a recognized pattern of damage which occurs. Several areas of the brain are affected but the brunt of the damage occurs in the basal ganglia especially the caudate and putamen nuclei, these are sometimes called the corpus striatum. There are complex connections between the areas of the brain: in the case of HD the direct and indirect pathways are important for understanding some of the physical features and why drugs which block the dopamine 2 receptors are used to treat chorea.

Genetic counselling for unaffected family members

This chapter focuses on aspects of genetic counselling for those at 50 per cent risk for Huntington’s disease (HD). There are various options including not being tested. Predictive testing for HD is described together with some perspectives from patients. There are four types of results from a predictive test: normal, intermediate allele, reduced penetrance, and abnormal. The implications of these are discussed. Options regarding testing in pregnancy are discussed which include: no testing and accepting a risk, invasive tests such as chorion villus sampling or amniocentesis and preimplantation genetic diagnosis. Finally, the issue of testing someone at 25 per cent risk is discussed.

Facts and figures about Huntington’s disease

This chapter gives a brief history of Huntington’s disease (HD) starting with the original description by George Huntington. The prevalence of HD is discussed together with data variations in different parts of the world. For example the incidence of HD in Europe and North America is approximately 1 person in 10,000. Apart from humans, no other animal naturally develops HD. The condition can start at almost any age but it is more frequent in midlife. The duration of the disease can be very variable but 20 years is often given as an approximate average.

The physical features of Huntington’s disease

This chapter focuses mainly on the movement disorder, speech, balance, weight loss, swallowing, and speech. Chorea or purposeless involuntary movement is most commonly associated with HD. A patient may have a mixture of movement problems such as dystonia (abnormal posture), and bradykinesia (slowness of movement). The pattern of movement disorder may vary between people but frequently the dystonia and bradykinesia become more prominent as the disease progresses. As this happens more professionals may become involved in the care. It is important for the carer(s) to also take care of themselves.

Laboratory testing

This chapter describes the way genetic testing is done. Essentially, the test measures the number of CAGs which are repeated in the first part of the gene. It is possible to measure the size of a section of the gene for Huntington’s disease (HD) so as to know how many CAG repeats are present in the gene. The results are classified as: normal (under 27 repeats) intermediate alleles (27–35 repeats), reduced penetrance alleles (36–39) and those which are unequivocally abnormal (40 and above). The chapter also describes the relationship between the CAG repeat length and age of onset as well as the new mutations.

Treatment of Huntington’s disease

Treatment of Huntington’s disease (HD) is currently symptomatic and supportive. This is sometimes expressed as saying that there is no treatment to alter the natural history of the condition. There is no specific drug treatment for HD but drugs which are commonly used are dopamine blockers or selective serotonin re-uptake inhibitors (SSRIs). Sometimes mood stabilizers are used. Non drug treatments are also very valuable and should not be overlooked. As important as the drug treatment is the input from other support services such as social services, physiotherapists, and speech therapists. This is not an exhaustive list.

Clinical research

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.

Behavioural and emotional aspects of Huntington’s disease

This chapter focuses on the behavioural and emotional aspects together with problems relating to thinking (cognitive defects). In many ways, these problems are often more difficult to manage for the families than the physical problems described in the previous chapter. Some of the issues discussed include: lack of perception of the needs of others; depression, apathy, and anxiety; difficulty planning ahead and changing plans in the light of new information; outbursts of temper; preoccupations or perseveration. There is a discussion of how a carer may have to change or adapt in order to avoid some of these problems. Some of the drugs used to help with the behavioural problems are the same as the ones used to treat the physical problems.