The discovery of the gene has led to new insights about HD. Not all patients or family members will want or need genetic testing, but all should be offered genetic counseling. This can be provided by the physician or by referral to a genetic counselor. Here are some of the issues that may be explained:

Basic genetics - inheritance pattern

Huntington's disease is an autosomal dominant disease, which means it affects males and females with equal likelihood. Each child of an affected individual has the same 50 percent chance of inheriting the abnormal huntingtin gene, and therefore developing the disease one day. Inheriting a normal huntingtin gene from the unaffected parent does not prevent or counteract the disease-causing effects of the abnormal gene.

The huntingtin (IT-15) gene and the huntingtin protein

The huntingtin gene directs the cell to make the huntingtin protein, whose function is unknown. Huntingtin protein contains a sequence in which the amino acid glutamine is repeated a number of times. These glutamine residues are encoded in the gene by the DNA trinucleotide "CAG." The number of times that "CAG" is repeated (the CAG repeat number) determines the number of consecutive glutamines in that segment of the huntingtin protein. The huntingtin protein is made in normal amounts, whether it has a normal or excess number of glutamines, but it appears to be processed differently when it has an excess number of glutamines, so that the protein accumulates in the neuron. The details of this process and how it relates to the development of neurologic disease are currently being studied.

CAG repeats in the huntingtin gene

The normal and abnormal CAG repeat number ranges have been determined only by clinical experience, which includes that of about 10,000 affected and unaffected individuals worldwide. Normal huntingtin genes contain 10-35 "CAG repeats." Repeat sizes of 27-35 are at the upper end of the normal range, and will not result in Huntington's disease, but sometimes increase into the abnormal range in the next generation, particularly if passed on by a male. The risk for this event has not been quantified. 36-39 repeats are at the low end of the abnormal range, but may not result in Huntington's disease in the course of a normal life span. People with 40 or more repeats will develop Huntington's disease if they live a normal life span.

CAG repeat number and age of onset

There is a rough inverse correlation between the CAG repeat number and the age of onset of Huntington's disease symptoms. However, the CAG repeat number accounts for only about half of the variation in age of onset. Therefore, although it may be possible to give an age range in which symptoms are most likely to occur, the age of onset cannot be accurately predicted from CAG number alone. The CAG number also does not accurately predict what symptoms an individual will have, or how severe or rapid the course of the disease will be.

Instability of the CAG repeat number

The number of CAG repeats in somatic cells does not change during an individual's life, and genes with normal repeat sizes are almost always transmitted stably to the next generation. In contrast, genes with expanded CAG repeat sizes are prone to expand further as they are passed on to a child, particularly in the case of paternal transmission, although expansions can occur in maternal transmission as well. Thus, children who inherit the abnormal gene often have a larger repeat number than the affected parent, and may consequently tend to develop symptoms at a younger age. The earlier onset of symptoms in a child than a parent is called anticipation. In extreme cases, symptoms may be evident in the child while the father is still asymptomatic.

Absent family history of Huntington's disease

Some individuals develop Huntington's disease without ever knowing they were at risk, because they have no known family members with the disease. This occurs in two-to-five percent of all cases. Sometimes this can be explained by early death of a parent who carried the gene, but did not live long enough to manifest the symptoms, by adoption, or by mistaken paternity. Others represent "new mutations," caused by rare expansions of parental genes with a high-normal CAG repeat number (27-35 repeats) into the affected range in the child. Individuals with high normal CAG repeat sizes are not themselves at risk for developing Huntington's disease. Our understanding of the significance for their offspring is likely to improve, and they may be best referred to someone with specialized knowledge, such as a genetic counselor.

Genetic Testing

With the discovery of the gene a simple and accurate genetic test became available. The Huntington's disease gene test usually requires a blood sample, but can be performed on other tissues, such as skin, amniocytes or chorionic villus cells, or autopsy material. The test requires special molecular diagnostic facilities, but at least two dozen university and commercial laboratories in North America perform gene tests for Huntington's disease. The cost in most laboratories is around $400.

Genetic testing for Huntington's disease is potentially useful in three clinical situations: diagnostic, or confirmatory testing; predictive, or presymptomatic testing; and prenatal testing.

Diagnostic testing

Diagnostic genetic testing refers to the use of a gene test in a patient who has symptoms suggestive of Huntington's disease, with or without a family history. If the clinical suspicion is strong, this may be the only diagnostic test needed. It is important to remember that the presence of the huntingtin gene with an increased repeat number does not mean that a patient's current symptoms are caused by Huntington's disease, as the gene is present throughout life. Particularly in children, who have the most to lose by premature genetic diagnosis, the gene test should be used sparingly, and only when the neurologic symptoms strongly suggest the onset and progression of Huntington's disease.

Confirmatory testing should be performed in a patient who appears to have Huntington's disease if no other affected family members have previously had a gene test, to be sure that the "family disease" is really Huntington's disease and not some other condition. Diagnostic genetic testing is also very useful in the evaluation of an individual who appears to have Huntington's disease but who has a negative or absent family history.

A special note should be made about the effects of an individual's gene test on the individual's family. The presence of an expanded Huntington's disease gene in one individual has direct implications for that person's children, siblings, and perhaps his parents and collateral relatives. Any physician who diagnoses Huntington's disease in a patient must be prepared to face questions from and about these additional family members. Consultation with a genetic counselor may help to make this difficult situation easier.

Predictive testing

Predictive testing refers to the use of an Huntington's disease gene test in a person who has no symptoms but wants to know whether or not he carries the expanded gene. Predictive testing of healthy individuals requires a different clinical approach than the one to which physicians and patients are most accustomed. There are no direct medical indications for or benefits from a predictive test. There are also potential psychosocial risks to predictive testing, including adverse effects on the individual's mood, on relationships with friends and family and on insurability and employability. Predictive testing should be reserved for competent adults who have participated in a careful discussion of their genetic risks and the potential risks and benefits of the test itself.

The World Federation of Neurology, the International Huntington Association, and the Huntington's disease Society of America have published guidelines regarding the genetic and psychological counseling and support that should surround predictive testing. In keeping with these guidelines, Huntington's disease predictive testing centers have been established in various states. Referral of interested patients to a predictive test center is highly recommended. A referral list of facilities offering predictive genetic testing for Huntington's disease may be found in Appendix 2.

Prenatal testing

Prenatal testing for Huntington's disease is possible, and should be performed in conjunction with detailed genetic counseling. Affected or at-risk individuals or couples should be informed of all of their reproductive options (shown in table 1), with the understanding that different options are appropriate or desirable for different people.

For those who desire prenatal testing, the best time to make arrangements is prior to the pregnancy. Chorionic villus sampling can be performed very early, at 8-10 weeks, and a non-disclosing prenatal test, which determines only whether the fetus received a chromosome from the affected grandparent or the unaffected grandparent, without determining whether the fetus or at-risk parent actually carries the Huntington's disease gene, requires samples from several individuals.