Trinucleotide Repeat Disorders
Part 9: Non-Polyglutamine Diseases

Descriptions of other diseases that involve codon repeat expansions.

Non-Polyglutamine Diseases

As noted in the introduction to this chapter, polyglutamine diseases are only a subset of the trinucleotide repeat disorders. As of this writing (summer 2001), researchers have identified six non-polyglutamine diseases that also fall under the category of trinucleotide repeat disorders. Because each disease involves a unique repeated codon, the six non-polyglutamine diseases show relatively little resemblance to one another. More importantly, none of them appear to have any strong similarity to Huntington’s Disease or the other polyglutamine diseases. For this reason, we provide only brief descriptions of these non-polyglutamine disorders. The descriptions follow below.

Fragile X Syndrome

Fragile X Syndrome (often abbreviated “FRAXA”) is a disorder involving the CGG codon (contrast this with the CAG codon involved in the polyglutamine diseases). The affected gene is called FMR1 and it lies on the X chromosome (hence the name “Fragile X Syndrome”). In asymptomatic individuals, the FMR1 allele has between 6 and 53 CGG repeats. In people with the disorder, the FMR1 allele has over 230 repeats. At present, not enough data exist to fully understand the effect that alleles with between 53 and 230 copies of CGG will have on individuals. Common symptoms of FRAXA include mental retardation, long and prominent ears and jaws, stereotypic hand movements (like flapping and biting one’s hands), hyperactivity, and others. The disease typically affects males.

Fragile XE Mental Retardation

Fragile XE Mental Retardation (often abbreviated “FRAXE”) is a disorder involving the GCC codon. The affected gene is called FMR2 and, like the gene causing Fragile X Syndrome, FMR2 lies on the X chromosome. In asymptomatic individuals, the FMR2 allele has between 6 and 35 copies of GCC. In people with the disorder, however, the allele has over 200 copies of GCC. At present, not enough data exist to fully understand the effect that alleles with between 35 and 200 copies of GCC will have on individuals. Common symptoms of FRAXE include mild mental retardation, learning deficits, and possible developmental delays.

Friedreich’s Ataxia

Friedreich’s Ataxia (often abbreviated “FRDA”) is a disorder involving the GAA codon. The affected gene is called X25 (also known as “frataxin”). In asymptomatic individuals, the frataxin allele has between 7 and 34 GAA repeats. In people with the disorder, the allele has 100 or more repeats. At present, not enough data exist to fully understand the effect that alleles with between 34 and 100 copies of GAA will have on individuals. There are many common symptoms of FRDA, some of which include slurred speech, heart disease, and diminished reflexes of the tendons. The name “ataxia” describes a loss of coordination, and this is typical in the limbs and trunk of those who have FRDA. The typical age of onset for this disorder is early childhood.

Myotonic Dystrophy

Myotonic Dystrophy (often abbreviated “DM”, not “MD”) is a disorder involving the CTG codon. The affected gene is called DMPK. In asymptomatic individuals, the DMPK allele has between 5 and 37 CTG repeats. In people with the disorder, the allele has at least 50 repeats in adult-onset cases, and can go up to several thousand in congenital cases. At present, not enough data exist to fully understand the effect that alleles with between 37 and 50 copies of CTG will have on individuals. Common symptoms of adult-onset DM include muscle weakness and degeneration, while such symptoms as kidney failure, facial dysmorphology, heart problems, premature balding, cataracts, and, in males, atrophy of the testicles are less common. The congenital form of DM is the most severe and its symptoms include diminished muscle tone, problems with respiration at birth, and developmental abnormalities. The term “myotonic” comes from “myotonia”—a condition characterized by frequent muscle spasms. Obviously, myotonia is quite common in DM.

Spinocerebellar Ataxia Type 8

Like Myotonic Dystrophy, SCA8 (Spinocerebellar Ataxia Type 8) is a disorder involving the CTG codon. The affected gene is also called SCA8. Asymptomatic individuals possess between 16 and 37 repeats of CTG in the SCA8 allele, while people with the disorder have between 110 and 250 repeats. At present, not enough data exist to fully understand the effect that alleles with between 37 and 110 copies of CTG will have on individuals. SCA8 is a slowly progressive disorder and its symptoms include decreased sense of vibration, sharp reflexes, and atrophy of the cerebellum, which has a large amount of control over the body’s learned movements. (For a more detailed description of the cerebellum, click here.)

Spinocerebellar Ataxia Type 12

Much like the polyglutamine diseases discussed above, SCA12 (Spinocerebellar Ataxia Type 12) is a disorder involving the CAG codon. But unlike the polyglutamine diseases, which have CAG repeats that occur in what is known as the “translated region” of DNA, the CAG repeats in SCA12 occur in what is called an “untranslated region” of DNA. In what basically amounts to an exception to the normal rule, the chemical information of an untranslated region of DNA is not used as instructions for making proteins. None of the codons in the untranslated region of DNA produce any amino acids at all (a realization that has prompted some scientists to refer to the untranslated region as “junk DNA”). This exception means that the CAG codons of SCA12 actually do not produce the amino acid called glutamine. Because of this fact, SCA12 is not considered a polyglutamine disorder.

The affected gene in SCA12 is also called SCA12. Asymptomatic individuals possess between 7 and 28 repeats of CAG in the SCA12 allele, while people with the disorder have between 66 and 78 repeats. At present, not enough data exist to fully understand the effect that alleles with between 28 and 66 copies of CAG will have on individuals. SCA12 is the most recent addition to the group of spinocerebellar ataxias. Since there are relatively few cases to date, the full effects of the disorder are not yet fully known. Given that it is a spinocerebellar ataxia, however, it is likely that some of the general symptoms include slurred speech and loss of coordination of some parts of the body.

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For further reading:

1. Cummings, C. J. and Zoghbi, H.Y. "Trinucleotide Repeats: Mechanisms and Pathophysiology." Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328.
   A fairly technical paper explaining the symptoms of each trinucleotide repeat disorder, as well as a breakdown of the codon involved and the amount of repeats in people with and without the disease (as of the publishing, however, updated and slightly different data regarding the numbers are available; see next entry in bibliography). Also discussed are theories regarding the function of the altered proteins.
2. GeneClinics. Online.
   An in-depth site with very recent information about all of the SCAs (and DRPLA). A wonderful resource to find out more about each disorder. (Look up the any of the SCA's by using the search feature.)
3. Online Mendelian Inheritance in Man (OMIM). Online.
   A compilation of abstracts from a multitude of different studies on HD. From case studies regarding inheritance to new methods of diagnosing HD, this is an excellent site for all the various types of HD research going on today. (Look up any of the trinucleotide repeat disorders using the search feature.)
4. Silverthorn, Dee Unglaub. "Human Physiology." Upper Saddle River, NJ: Prentice Hall, 2001. pp. 256-263, 396.
   Written for college students, this textbook has excellent explanations of all aspects of human physiology, as well as wonderful pictures to increase one’s understanding. The pages noted are excellent in teaching the functions of various parts of the nervous system.
5. Thompson, Richard F. "The Brain." New York: Worth Publishers, 2000. pp. 11-16, 296-303, 308-309, 451.
   An introduction to neuroscience. Very clearly explains the functions of the various parts of the nervous system. Also gives insight into current research going on in neuroscience.

Last Modified: 9-18-02

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