What is Huntington's Disease?

The human brain is an amazing organ. Encased in the protection of the skull and bathing in the cerebrospinal fluid, the spongy 1.5kg mass of brain tissue is the most complex organ in the human body. The brain is responsible for the unconscious control of the internal organs, sensory perception, movement, consciousness, thought and reasoning, memory and personality. The brain is integral in everything from our existence and normal functioning through to the creative and intellectual thought that enables humans to work and interact in such diverse and marvellous ways. 

However, when this incredible organ fails us, the consequences can be devastating. It is estimated that one in five New Zealanders will suffer from brain disease in their lifetime. Disorders such as stroke, epilepsy, Alzheimer’s, Parkinson’s, Huntington’s, motor neurone disease, multiple sclerosis and deafness affect thousands of New Zealanders every year. These are all neurological diseases and collectively are among the top five most common causes of death and long term disability in New Zealand. The cost of neurological disease to individuals, families and society is enormous.

Understanding Neurological Disease

Understanding the brain is the last frontier of medical research and one of the most challenging areas of medicine. In order to understand and potentially treat neurological diseases, scientists need to understand the structure and functioning of the healthy brain, and then explore what is happening in the brain of patients with neurological diseases. 

Professor Richard Faull is Director of Auckland University’s Centre for Brain Research where interdisciplinary teams from science, medicine and the community are working together to understand and find improved ways of treating neurological disease. While the Centre has teams looking into many different diseases, in this resource we will explore the work led by Professor Faull relating to Huntington’s disease, a neurological disorder caused by a gene mutation which has devastating consequences for the patient and their family.

Huntington’s disease (HD) is an example of a neurological disease caused by an autosomal dominant gene mutation on chromosome 4. Because the allele associated with the mutation is dominant, a person only needs to inherit one copy of the mutated allele to inherit the disease (Fig. 1). 

Huntington’s disease (HD) is an example of a neurological disease caused by an autosomal dominant gene mutation on chromosome 4. Because the allele associated with the mutation is dominant, a person only needs to inherit one copy of the mutated allele to inherit the disease (Fig. 1). 

The Phenotype 

People with HD are born carrying the mutation, and initially live with no ill effects. The mutation’s damaging effects accumulate in the brain over time. Symptoms usually begin around the age of 40. These are initially quite mild, but gradually become worse as the disease progresses. 

The disease progressively degenerates brain cells, reducing the person’s ability to walk, talk, reason, think and remember. Psychiatric and behavioural disturbances develop, including mood swings, irritability and depression. These eventually decline into dementia. Involuntary movements are also part of the disease, including chorea (twitching, jerking and writhing) and dystonia (muscle contractions that lead to twisting movements and abnormal postures). The symptoms eventually become so debilitating that sufferers rely totally on others for their care. The disease causes death usually about 20 years after onset. 

The disease puts an enormous strain on the affected person and their family, emotionally and financially, and on health services. At-risk individuals have a high risk of suicide and suicidal thoughts. They will often have watched a parent decline and die from the disease. Because symptoms usually appear after childbearing age, people have often potentially passed the disease to their children by the time their own symptoms appear.

The brain is a part of the central nervous system, connected to the rest of the body via the spinal cord which is in turn connected to all parts of the body via the peripheral nervous system (Fig. 4). Understanding the structure of the brain and how it functions is essential if scientists are to understand the effect of HD on the brain and work out how to reverse that effect. 

Brain tissue is made up of two types of cells; neurones or nerve cells, and glial cells. The glial cells have structural and support functions while the neurones are specialist cells that transmit information. With ten thousand million (1010) neurones or nerve cells inside the brain, and the potential for each of these nerve cells to be in contact with up to 1000 other cells, the communication potential is immense.

Neurones consist of dendrites, a cell body and an axon (Fig. 5) which transmit signals carried as electrical impulses throughout the body. The dendrites receive information and the axon is used to transmit information. Glial cells provide an insulating cover around each axon called a myelin sheath (a bit like the plastic insulation that you see on electrical wiring) which helps send the electrical impulses along the axons. Glial cells also provide nutritional and physical support for the neurones.

The brain is organised into different regions (Fig. 6). The cerebral cortex makes up the outer layer of the brain. It has special regions for processing information relating to the senses (vision, smell, hearing, touch and taste) movement, language, emotion, etc. It is divided into two hemispheres, each with different functions. The left hemisphere controls the right side of the body and speech. The right hemisphere controls the left side of the body and spatial perceptions.

Deep inside the brain is a structure called the basal ganglia. Understanding this structure is important to understanding HD as it has a role in organising motor (muscle movement) and mood functions of the brain.

The cerebellum sits at the back of the brain. The cerebellum controls balance and coordination and is where learned movements are stored.

How Do We Know All This? 

HD is named after George Huntington who published a paper in 1872 comprehensively describing the disease, including its pattern of inheritance. When Mendel’s work was rediscovered in 1900, people recognised that the disease was following a Mendelian dominant pattern of inheritance. 

Beginning in the 1960s, relatives of people with HD launched various organisations aimed at combating the disease. They fundraised and provided avenues for the co-operative exchange of materials and ideas between different groups of scientists. 

An intense effort to discover the at-fault gene began in the early 1980s. The researchers found large families with HD, each emanating from a single individual who had the disease, and established detailed pedigrees. Using their blood samples, gene mappers found its location – on chromosome 4 – surprisingly quickly, and it was the first genetic disease to be mapped to a chromosome without any prior knowledge of its location. 

In 1993 the mutation was identified and the gene was cloned. This has opened up new options for people from HD families. Previously they had to wait until after death for a diagnosis: now they can be tested to find out whether they carried the mutation before they become ill.

Strict conditions surround genetic testing. In New Zealand only people over 18 years of age are eligible, and they must be counselled before and after the test. Less than five percent of potential carriers elect to be tested, mostly because there is no cure. 

Pre-implantation genetic diagnosis – where embryos created by IVF can be tested before a genetic disease before being implanted, is also available, but in New Zealand it is publicly funded only in a limited way, and usually if the at-risk parent has been tested first. Fetuses can also be tested, giving parents the option to terminate the pregnancy if the baby is found to be a carrier.

Genetic Fitness 

HD is found in about 5–7 individuals per 100,000, although there are rare areas with a much higher prevalence. Amongst Asian and African peoples the prevalence is much lower; in Japan, for example, it is only 0.5 per 100,000. 

There is no evidence for the HD mutation conferring any fitness on carriers: in other words, on average they have the same number of children as non-carriers. A mutated IT15 gene does nothing helpful. However, because its deleterious effects generally appear after carriers have had their children, it survives. Mutations whose effects take hold after child-bearing age have quite different patterns of allele survival to mutations whose effects appear earlier in life. 

Some gene mutations have no effect at all on which amino acid is transcribed, so are silent, having no observable effect on the phenotype. Some mutations, however, do offer a selective advantage to their carriers. Sickle cell anaemia is one example of this. People who are heterozygous for the gene that makes their red blood cells sickle-shaped are more resistant to the effects of malaria. The sickle cell mutation is therefore relatively common in tropical countries. This selective advantage increases the likelihood of the allele surviving in the population. No such selective advantage can be identified for the Huntingtin allele. 

Apart from racial heritage, the only factor that is identifiable in the patterns of Huntingtin alleles in different populations is that of founder effect. Where a population has established from a small gene pool in which the mutated gene was present, it is found in higher numbers in that population. One such population is found in Tasmania.

One Gene Mutation, but a Variable Disease 

Once, it was hoped that the clear single-gene nature of HD would mean that a cure would be reasonably achievable, and that the knowledge gained would help combat other diseases. However, it is not as simple as it once seemed: although it is a single gene mutation, variation is present in both the genotype and the phenotype of HD. Understanding this variation is an important part of the process of finding answers in the HD puzzle. 

In some cases, variation in the phenotype can be linked to variation in the genotype. This forms predictable patterns. In other cases, variation in the phenotype bears no relationship to variation in the genotype. When this happens scientists need to look for alternative reasons for this variation.

Phenotype Variation Caused by Genotype Variation 

People with HD do not all have the same number of CAG repeats in their gene. The differing number of repeats is linked to two types of variation that are seen in the disease symptoms (the phenotype): the onset of disease and how quickly it progresses. 

One aspect of phenotype variation that can be partially explained by genotype variation is the age of onset of the disease. Figure 8 shows that the longer the length of the chain of CAG repeats in the gene, the earlier the age of disease onset. When the chain is long enough, the disease manifests in children as young as one year of age. (In children the disease has different features: lack of movement, a rigid body and seizures). Sixty percent of the variability in age of onset is explained by length of CAG repeat, with other unknown factors contributing to the remaining 40%. 

The age of onset of the disease can decrease with each successive generation. This can be accounted for by known instability of the IT15 gene in the testicles (where sperm are formed). In cases of 28 CAG repeats or more, the number of repeats is prone to increase during sperm formation. In this way, when genes are passed through the generations by males, chain length tends to increase. Therefore, in successive generations, the age of onset becomes increasingly younger. This is known as genetic anticipation. 

This instability of the gene in the testicles also accounts for the rare spontaneous mutations. After some testicular hot housing, a previously normal but borderline number of 35 repeats can increase sufficiently to cause HD. People from white European races have higher frequency of huntingtin alleles with 28–35 repeats, and are therefore more vulnerable to instability during spermatogenesis. If the mutation occurs during spermatogenesis, it is a new or de novo mutation.

Phenotype Variation That Cannot be Explained by Genotype Variation

Although brain cell death in HD follows a reasonably typical path, it shows significant phenotypic variability. Some people experience major motor (movement) symptoms, and yet their mental faculties survive remarkably well. Others have the opposite experience. 

In 2010, a research team, primarily from The University of Auckland, published a study using brains from the human brain bank. They took sections from 12 HD brains, about a third of whom had mainly motor symptoms and a third of whom had mainly mood symptoms, as defined by a psychologist after interviewing the families of the subjects. They also took sections from 15 normal, or control brains. 

The team looked at the brains’ cerebral cortex, which has strong anatomical connections with the previously-mentioned striatum of the basal ganglia. They found that people with mainly motor symptoms had more damaged and lost cells in the primary motor cortex, which is the part of cerebral cortex responsible for movement. Those with mainly mood and cognitive symptoms had more cell loss in their anterior cingulate cortex, which plays an important role in mood and cognitive impairment (Fig. 9). 

The researchers looked for a genetic cause for this difference by checking whether there was an association with CAG repeat, but none was found. They concluded that the variability in symptoms is caused by the extent of cell loss in the corresponding functional regions of the cerebral cortex.