|MadSci Network: Genetics|
First, a little bit of background information:
Ataxia is the term for progressive disorders involving muscle coordination and muscle action. Friedreich ataxia is one particular ataxia, and it is inherited in an autosomal recessive manner (both parents of an affected child are "silent" carriers of the trait). Friedreich ataxia has an incidence of 1/100,000 births, and the age of onset is usually before 10 years of age. Loss of muscle coordination occurs gradually over about 20 years, and ends with complete loss of ambulation. There are also cardiac and endocrine symptoms associated with this particular ataxia. No cure is available, and so the only thing doctors can do is treat the symptoms.
Further information on other ataxias can be found here: Ataxia Classifications
Now, to the original questions: Has the gene responsible been found? and Can people be screened for the gene?
The answer to both questions is yes . . . well sort of, but the answers are still controversial. The gene was localized to chromosome 9 in 1988, but further progress was slow. By studying family trees and using molecular biology, it was further localized to a specific region of chromosome 9 which is designated 9q13-q21. Then in 1996 a group at the University of Valencia in Spain reported that they had found the gene and the mutations responsible for Friedreich ataxia. They called the gene X25. A few months later, a competing laboratory at the Imperial College School of Medicine at St. Mary's in London, UK published a report that the X25 gene was really just a fragment of a gene that they had already discovered and named STM7. A flurry of heated editorials and rebuttals appeared in scientific journals in the following months, and as far as I can tell, the controversy still has not been completely settled. Settling this dispute will be important for deciding what the specific protein coded for by this gene is used for, and for trying to develop effective treatments.
But in terms of screening for carriers of the mutation, or performing a genetic test to diagnose, in this case knowing exactly what the gene is is not important. Point mutations have been found in the location of the putative genes in affected individuals, so sequencing the region is a relatively simple way to determine whether a mutant gene is present. And there is no dispute regarding what seems to be the most common type of mutation: a trinucleotide repeat.
Trinucleotide repeat mutations are responsible for lots of different human diseases, including (among others) Huntington's disease, fragile X syndrome, and spinocerebellar ataxia type 1. In Friedreich ataxia, the nucleotide sequence GAA in a particular part of the gene is unstable. A non-carrier typically has fewer than 66 repeats, and a carrier has a much higher number, with the largest frequency in the 201 to 1,200 repeat range. The severity of the disease seems to correlate with the size of the repeat. The repeat is called unstable because it can be increased in size from generation to generation. For example, a woman with a repeat number of 38 had two affected children, and her gene had expanded to greater than 400 repeats when it was passed on to her children. However, this is an extreme example of the type of instability that can be seen. In most cases, a person will only be affected if they inherited a large repeat from each of their parents, who were unaffected carriers.
It is easy to use PCR (polymerase chain reaction) to screen for repeat length, so this can be used to determine is someone is a carrier of an expanded allele. However, as with all recessively inherited diseases, if both members of a couple wishing to have children are carriers, their chance of having an affected child is only going to be 1 in 4. Thus screening for the gene can alert a couple to their chances of having an affected child, but certainly does not mean that they cannot have unaffected children. This is one of the paradoxes of genetic screening; often we obtain information which is informative, but does not necessarily suggest solutions or treatments.
Further information on the genetics of specific human diseases can be found on the Online Mendelian Inheritance in Man Medical Database site. This site is searchable, and while it tends to be pretty technical, it does offer some more basic information.
Hope that answers your questions!
: ) Carolyn Pettibone
Possibly useful references:
Publication that asserted that X25 is the Friedreich ataxia gene: Campuzano, V. et al (1996) Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 (5254): 1423-1427. Competing group asserting that STM7 is the actual gene: Carvajal, JJ et al. (1996) The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4-phosphate 5-kinase. Nature Genetics 14 (2): 157-162 Epplen, C. et al (1997) Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene. Human Genetics 99 (6): 834-836. Filla, A et al (1996) The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. American Journal of Human Genetics 59 (3): 554-560. Timchenko, LT and Caskey CT (1996) Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. FASEB Journal 10 (14): 1589-1597.
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