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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
Adult Onset Neurodegenerative Disorders:
CAG Triplet Repeat Expansion Mutations
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Molecular Genetic Testing in Mainstream Medicine Vol. 14: Spring, 1997 |
Adult Onset Neurodegenerative Disorders:
CAG Triplet Repeat Expansion Mutations
The ability to isolate, purify, and characterize genes has led to a remarkable increase in our knowledge of genetic disorders. Several novel molecular mechanisms leading to human disease have been described in the last decade. One of these mechanisms, termed "trinucleotide expansion" was described in association with fragile X syndrome in 1991. Since the publication of that paper, a set of disorders has been identified in which the responsible gene includes a run of three nucleotide bases (the "building blocks" of DNA) repeated in tandem many times. These triplet repeats are present throughout the human genome and have been found in many genes. Repeats below a certain length are stable in mitosis and meiosis for many generations. Above a certain threshold length, the repeated segments become unstable and expand, leading to the onset of disease. That this type of alteration of DNA could cause human disease was quite unexpected since a similar phenomenon had not been reported in other organisms. Eleven different genetic disorders have now been shown to be associated with trinucleotide repeat expansions. In some families the age of onset of symptoms may decrease and severity of symptoms may increase in successive generations, a genetic phenomenon known as "anticipation".
Several human genes have been identified that contain trinucleotide CAG (cytosine-adenine- guanine) repeats within the coding sequences. These repeats are translated as polyglutamine tracts in the protein product. Typically, the stable and nonpathological alleles have 10-30 repeats, while unstable pathological alleles have modest expansions, often in the range of 40-100 repeats. Transcription and translation of the genes are not affected by the expansion; a larger protein is made with the extra glutamines incorporated into the protein.
Several adult onset neurodegenerative disorders are now known to be associated with expansion of CAG repeats. These include Huntington disease (HD), spinocerebellar ataxia 1 (SCA 1), Machado-Joseph disease (MJD/SCA 3), Kennedy disease or spinal and bulbar muscular atrophy (SBMA), and dentatorubraopallidoluysian atrophy (DRPLA). HD, DRPLA, SCA 1 and MJD/SCA3 are inherited as autosomal dominant disorders, while Kennedy disease is inherited as an X-linked recessive disorder.
| Disorder | Chromosome | Normal Range | Affected Range |
| Huntington | 4p | 6-28 | 40-121 |
| SCA 1 | 16p | 6-39 | 41-81 |
| MJD/SCA 3 | 14q | 13-36 | 68-79 |
| Kennedy (SBMA) | Xq | 12-34 | 40-62 |
| DRPLA | 12p | 13-36 | 68-79 |
Clinical manifestations usually occur insidiously in middle adulthood and include uncontrolled choreiform movements, dementia and emotional and psychiatric disturbances. Death usually occurs within 15 years of diagnosis following a downhill course. The pathology involves generalized atrophy of the brain, especially in the corpus striatum and cerebral cortex.
The gene for HD is located on chromosome 4 at band p16.3 and its protein product is called huntingtin. Expansion of the triplet repeat can occur upon transmission by both sexes, but larger expansions are associated with paternal transmission. Individuals with 29-39 CAG repeats fall into a gray zone in which individuals may or may not manifest HD. Meiotic instability (i.e. expansion of the triplet repeat) has also been observed in this range of repeats.
Clinical manifestations usually occur in the second to fourth decade of life with gait and limb ataxia, dysarthria, ophthalmoplegia, and muscle wasting. The disorder is associated with neuronal degeneration in the cerebellar cortex, dentate nuclei and brainstem, and of the spinocerobellar tracts. Symptoms worsen over time, leading to death 10-20 years after onset of symptoms.
The gene for SCA 1 is located on chromosome 6 at band p23 and its protein product is called ataxin. There is correlation between the size of the CAG repeat and the age at onset and the duration of the disease, with larger repeats occurring in juvenile onset cases.
Clinical manifestations of MJD/SCA 3 are very similar to SCA 1. The disorder is probably more common than SCA 1. MJD was first reported in individuals of Azorean/Portuguese descent. MJD and SCA 3 were originally thought to be caused by mutations in different genes. However, molecular genetic studies have determined that both disorders are caused by expansion of a CAG repeat in the same gene.
The gene for MJD/SCA 3 is located on chromosome 14 at band q23.1. There is little information known about its protein product.
Clinical manifestations of Kennedy disease/SBMA include progressive muscular weakness of upper and lower extremities in adult males. The clinical symptoms are secondary to the neural degeneration. Affected males have reduced fertility and excessive development of the male mammary glands (gynecomastia). Since Kennedy disease is inherited in an X-linked recessive manner, female carriers have few or no clinical symptoms.
The gene for Kennedy disease is located on the X-chromosome at band q21. The mutation is in the androgen receptor gene. Interestingly, point mutations in a different part of this gene have been found in phenotypic females with a male chromosome constitution (androgen insensitivity syndrome).
Clinical manifestations of DRPLA present in two different ways. Individuals with age of onset before age 21 exhibit progressive myoclonus epilepsy and intellectual decline followed by the appearance of ataxia and choreoathetosis. Individuals with age of onset after age 21 present with ataxia, choreoathetosis and psychiatric problems. Longer CAG repeats are associated with the early onset disorder and inheritance from affected fathers. This disorder is often misdiagnosed as HD.
DRPLA is documented predominantly among Japanese individuals. The gene for DRPLA is located on chromosome 12 at band 13.31. Little is known about the protein product or its function.
Patients with clinical symptoms mentioned in the previous section are candidates for direct testing of the CAG repeat in the relevant genes. This type of testing has been designated "diagnostic testing." A complete neurologic exam is required on each patient prior to acceptance for testing.
Predictive testing is available for Huntington disease to identify individuals with the mutation before onset of symptoms. This testing presents ethical and logistical challenges due to the late onset and severity of the disorder and limited treatment options. Many individuals have requested predictive testing to help make decisions concerning family planning, health and life insurance, and choice of employment.
The Huntington Disease Society of America has developed guidelines for centers offering predictive testing for HD. Predictive testing should be offered in conjunction with a clinical geneticist, neurologist, genetic counselor, psychiatrist/psychologist, DNA diagnostic laboratory director, and often an ethicist. The DNA test is not performed until all members of the team agree that the patient has the appropriate knowledge and psychosocial support to cope with the results of the test, whether positive or negative. The guidelines are voluntary and are not legally binding; however, families and professionals who participate in these programs find them extremely helpful.
The laboratory test for each of the five disorders described above is called a direct DNA test because the disease-causing mutation is analyzed directly. Direct DNA tests require a sample only from the patient. Additional family members do not usually need to be tested to make a molecular diagnosis on a particular patient.
Several different methods are used in the laboratory to determine the number of CAG repeats in the genes pertinent to each disorder. Results are given to the referring physician/geneticist as the number of CAG repeats with the normal and abnormal range of repeats provided. Patients with HD, SCA 1, and MJD/SCA 3 will have one normal size allele and one abnormal (expanded) allele since these are all autosomal dominant disorders. Male patients with Kennedy disease will have one abnormal (expanded) allele on their only X chromosome since this is inherited as an X-linked recessive disorder.
The benefit of direct DNA testing for the number of CAG repeats in HD, SCA 1, MJD/SCA 3, Kennedy disease and DRPLA is that patients with a variety of neurodegenerative symptoms can be given a specific diagnosis. Appropriate treatment and genetic counseling can then be provided for the patients and their families.
An 85 year-old woman was given a diagnosis of "senile chorea." Symptoms had been present for approximately 30 years. The family had been told that the patient could not have Huntington disease because no one else in the family was affected. Upon her death, blood was drawn at autopsy and sent the DNA diagnostic lab for testing for HD, SCA 1, and MJD/SCA 3. An expanded allele of 40 repeats was found in one of her Huntington genes, consistent with a clinical diagnosis of Huntington disease. The family was understandably unnerved by this test result.
There are several adult children and grandchildren in the family who are now deciding wheater or not to have predictive testing. Had direct DNA testing been available when this patient first became symptomatic, her family would have had a correct diagnosis sooner and this may have impacted their life choices.
Contributed by Elaine Spector, Ph.D. (CO)
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
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