Huntington disease (HD) derives its eponymous title from Dr George Huntington, who described multiple affected individuals in a large North American kindred in 1872. His paper, published in the Philadelphia journal The Medical and Surgical Reporter, gave a graphic description of the progressive neurological disability that has endowed HD with the unenviable reputation of being one of the most feared and unpleasant hereditary disorders in man. The natural history is characterized by slowly progressive selective cell death in the central nervous system, and there is no effective treatment or cure. The prevalence in most parts of the world is approximately 1 : 10,000, although higher in some areas, such as Tasmania and the Lake Maracaibo region of Venezuela. The onset is mostly between 30 and 50 years, but it can start at virtually any age, including a rare juvenile form with different clinical features. The variable age of onset has been explained, at least in part, by the discovery of the underlying molecular defect.
The usual pattern of disease is characterized by a slowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance and eventual dementia. The mean duration of the illness is approximately 15 to 20 years and chorea is the most common movement abnormality. This takes the form of subtle involuntary movements such as facial grimacing, twitching of the face and limbs, folding of the arms, and crossing of the legs. As the disease progresses the gait becomes very unsteady and speech unclear.
Intellectual changes in the early stages of HD include memory impairment and poor concentration span. Anxiety and panic attacks, mood changes and depression, aggressive behavior, paranoia, irrationality, increased libido, and alcohol abuse can also occur. There is a gradual deterioration in intellectual function, leading eventually to total incapacitation and dementia.
Up to 5% of HD cases present before the age of 20 years and instead of chorea there is rigidity, with slowing of voluntary movement and clumsiness. A decline in school performance heralds the onset of a severe progressive dementia, often in association with epileptic seizures. The average duration of the illness is 10 to 15 years.
Traditionally HD has been said to show autosomal dominant inheritance with a variable age of onset, close to complete penetrance, and a very low mutation rate. In addition, it has been noted that the disorder often shows anticipation, whereby the onset is at a younger age in succeeding generations, particularly when transmitted by a male. The discovery of the HD gene in 1993 provided an explanation for some of these observations.
Mapping and Isolation of the HD Gene
HD was one of the first disorders to be mapped by linkage analysis using polymorphic DNA markers when, in 1983, the disorder was found to show close linkage with a probe known as G8 on the short arm of chromosome 4, greatly aided by collection of blood samples from the huge pedigree containing over 100 affected subjects living on the shores of Lake Maracaibo in Venezuela. As well as providing the first means of predictive testing for HD, this work also revealed that HD homozygotes are no more severely affected than heterozygotes. This is in contrast to many other autosomal dominant disorders. When the gene itself was isolated in 1993, it was found to contain a highly polymorphic CAG (polyglutamine) repeat sequence located in the 5′ region. The messenger RNA (mRNA) codes for a protein of approximately 350 kDa, known as huntingtin (also IT15). Huntingtin is expressed in many different cells throughout the central nervous system, as well as other tissues, although its function remains unclear.
The Mutation in HD
Almost all individuals with HD possess an expansion of a CAG polyglutamine (triplet) repeat sequence located in the 5′ region of the HD gene, a mutational mechanism first identified in humans in contrast to almost all other types of mutation that were first reported in other species such as Drosophila and mice. A joint working party of the American College of Medical Genetics and the American Society of Human Genetics recommended that HD genes should be categorized under four headings on the basis of CAG repeat length.
|Huntington Disease||Myotonic Dystrophy|
|Inheritance||Autosomal dominant||Autosomal dominant|
|Trinucleotide repeat||CAG in 5′ translated region||CTG in 3′ untranslated region|
|Repeat sizes||Normal ≤26||Normal <37|
|Reduced penetrance||Full mutation|
|Fully penetrant ≥40|
|Protein product||Huntingtin||MD protein kinase (DMPK)|
|Usually paternally transmitted||Usually maternally transmitted|
Alleles containing 26 or fewer CAG repeats are not associated with disease manifestations and are stable in meiosis.
Allele sizes of 27 to 35 CAG repeats do not cause disease but may show meiotic instability with a potential to increase or decrease in size. These ‘mutable’ alleles thus constitute a reservoir for new mutations. When an affected individual presents with what appears to be a new mutation, it usually emerges that the father carries a mutable allele. Furthermore, there is evidence that mutable alleles that expand are associated with a particular haplotype, as identified by intragenic and flanking DNA markers. This implies that certain haplotypes are more mutable than others.
Reduced Penetrance Alleles
This third category consists of alleles containing 36 to 39 CAG repeats. These are associated with either late-onset disease or complete absence of disease expression (i.e., non-penetrance).
The final group of HD genes contains 40 or more CAG repeats. These are invariably associated with disease, although sometimes this may not develop until the seventh or eighth decade. There is a direct relationship between length of repeat and disease expression, with the average age of onset for repeat sizes of 40, 45, and 50 being 57, 37, and 26 years, respectively. Most affected adults have repeat sizes of between 36 and 50, whereas juvenile cases often have an expansion greater than 55 repeats.
Parent of Origin Effect in Disease Transmission
The risk to offspring is 50% regardless of whether the affected parent is male or female, according to autosomal dominant inheritance. However, for reasons that are not clear, meiotic instability is greater in spermatogenesis than oogenesis. This is reflected in anticipation, occurring mainly when the mutant allele is transmitted by a male. Juveniles with the rigid form of HD have almost always inherited the mutant allele from their more mildly affected father.
Explanations for this include the possibility that expansion is caused by slippage of DNA polymerase, simply reflecting the number of mitoses undergone during gametogenesis. An alternative possibility is based on the observation that huntingtin is expressed in oocytes, so that there could be selection against oocytes with large expansions as a consequence of preferential apoptosis.
Clinical Applications and Future Prospects
Predictive genetic testing is part of routine clinical genetic practice, but there is universal agreement that this should be offered only as part of a careful counseling package. Experience to date indicates that more women than men come forward for this, and the psychological disturbance in those given positive results is low. Some 60% of candidates test negative (i.e., they receive good news), and the reasons for this departure from the expected 50% are not clear.
Prenatal diagnosis is possible for those couples who find this acceptable, although only about 25 such tests are performed in the United Kingdom annually. Obviously there are considerable emotional and ethical issues associated with termination of pregnancy; the condition is late in onset and the couple must consider the possibility of effective therapy being available in the foreseeable future. One appealing therapeutic approach is based on the observation that large CAG repeats result in intracellular accumulation of huntingtin‘aggregates’, which are cleaved by a protease known as caspase to form a toxic product that causes cell death (apoptosis). Caspase inhibitors have been shown to have a beneficial effect in a HD mouse model. Another therapeutic approach under consideration is fetal neuronal cell transfer into regions of the brain, such as the caudate nucleus and putamen, which become atrophic in the early stages of the disease. This approach carries ethical considerations that will be difficult for some couples.