Characterized more than a century ago, Friedriech’s ataxia is a debilitating neurodegenerative disease, effecting gait (ability to walk), arm movement, and progressive muscular weakness. Symptoms usually are present before 25, but rarely begin before the onset of puberty.
The molecular mechanism was uncovered through familial studies in the 80s and a shared molecular event was identified in the 90s. A common mutation was identified, the change involved the expansion of a GAA nucleotide repeat in the first intron of the frataxin gene. Since the mutation is in an intron the individuals with this mutation can make the frataxin protein, but only at very reduced levels.
With lowered frataxin levels come abnormally high iron levels within neuronal mitochondria. These individuals have mitochondria that are drowning in iron while sometimes presenting in the clinic with iron deficiency by blood test.
From a toxicological point of view, a tough diagnosis.
Frataxin itself is not well understood. The protein is involved in iron storage and transport, but it does not appear to be a transporter. Under normal conditions there is little free iron in the mitochondria, but with reduced frataxin levels, mitochondrial function is severely compromised.
We have talked a bit in class about mutations that do occur within the coding region of genes and I have asked the toxicology students to describe how such a mutation as a repeat nucleotide expansion in an intron could lead to reduced protein levels. I have also asked them to suggest a genetic test for Friedriech’s ataxia, so if you want to know more, read on.
They will be using Schmucker and Puccio’s 2010 Human Molecular Genetics paper, “Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches” to develop their responses.
Gillespie Lab 
Friedriech’s ataxia is a “neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin’. The gene that causes FRDA was found to be on chromosome 9q13-q21.1. This gene codes for the protein frataxin. Frataxin is an important protein that plays certain roles related to cellular iron homeostasis. It is also crucial to embryonic development.The unfortunate thing about FDRA is that the brutality of the disease is determined by number of GAA triplet repeat expansions in the first intron of the frataxin gene. These GAA triplet repeat expansions are often mutations found as deletions or point mutations,that affect the usual function of frataxin. The frataxin mutation found in Frieddiech’s ataxia, a GAA repeat nucleotide expansion in an intron could lead to reduced frataxin protein levels by disturbing the protein’s folding or ‘affecting its functional residues”.
I think that the appropriate genetic test for Friedriech’s ataxia would be to perform PCR and then run it on a gel to see if the person has the frataxin mutation found in Frieddiech’s ataxia, a GAA repeat nucleotide. If the person the GAA repeat, then I believe they would be positive for Friedreich’s ataxia. After doing some research I found that not only genetic tests are used to diagnosis Friedreich’s ataxia. Nerve conduction studies, electrocardiograms, and blood tests are just some of the tests used in addition to genetic testing to diagnosis a patient with Friedreich’s ataxia.
Electromyogram can be used to examine the electric currents associated with muscular action from a graph.
I think your description of Friedreich ataxia was very similar to mine. This disease is definitely caused by reduced expression of the mitochondrial protein frataxin. I totally agree with you that FDRA is determined by the number of GAA triplet repeat expansions in the first intron of the frataxin gene. It’s very interesting what PCR can do and how it has been used for so many different things. I agree with you that we can perform a PCR to determine if someone has Friedreich ataxia. After performing a PCR, we can run the sample on a gel to see if the person has the frataxin mutation. I agree if GAA repeat is seen in the gel, then that person probably has Friedreich ataxia.
Great description, brief, informative and easy to understand.
Luis, i appreciate your positive feedback. I had a hard time with this post- I didnt really know how to explain all that I wanted to say, but im glad you felt it information and easy to understand.
Friedreich ataxia (FRDA) is an autosomal recessive disease primarily characterized by progressive neurological disability. It is caused by a homozygous GAA repeat expansion mutation within intron which leads to reduced expression of frataxin protein. A significant proportion of patients also present with a hypertrophic cardiomyopathy in some cases cause premature death. FRDA is caused by insufficient levels of the protein, frataxin, which is involved in mitochondrial iron metabolism. All patients carry at least one copy of an intronic GAA triplet repeat expansion that interferes with frataxin transcription. Normal chromosomes contain up to 35 to 40 GAA triplets in an Alu sequence localized in the first intron of the frataxin gene. FRDA chromosomes carry from approximately 70 to more than 1000 GAA triplets. Therefore, the molecular diagnosis of FRDA is based on the detection of this expansion, which is present in homozygosity in more than 95% of the cases. The remaining patients are heterozygous for the GAA expansion and carry a frataxin point mutation as the other pathogenic allele.
Polymerase chain reaction (PCR) can be used to directly detect the intronic GAA expression. PCR requires only a small amount of DNA, but high quality DNA is very important. Ambiguous results, particularly in heterozygote, can be resolved by subsequent hybridization of PCR products with an oligonucleotide probe containing GAA repeat. The expanded GAA triplet repeat may be detected by PCR amplification followed by agarose gel electrophoresis analysis. In a carefully performed PCR testing, if the fragment detection is enhanced by hybridization with a GAA oligonucleotide probe then it is as effective in identifying patients and carriers. I think it will even allow a more accurate sizing of the repeat. In the case of smaller expansions, the amplified fragment may be directly sequenced to identify very rare nonpathogenic variant repeats, such as GAAGGA. Sequence analysis of the five coding exons of the frataxin gene should be performed in clinically affected individuals who are heterozygous for an expanded GAA repeat to identify point mutations.
Your description of using PCR method is pretty clear. And I think PCC method is a good way to examine Friedreich ataxia from the lab experiment methods so far.
Your explanation of FDRA and its causes is so clear that even a person that has limited scientific knowledge would comprehend it. The test which you suggest that maybe conducted for diagnosing for FRDA is also clear in a way that it tells the reader the main idea and main steps of the test.
I liked your specific explanation of both the disease and the method to test for FRDA. PCR is one method that I would not have guessed would be a way to prove whether someone has the disease. However, it makes perfect sense that detecting the GAA repeat through amplification can help spot the disease.
I liked the way you defined what FRDA is and made it so informative. It gives a lot of insight to the person who is reading it. I also agree that PCR may be useful and I loved the way you explained why PCR may be helpful in detecting the intronic GAA expression.
Friedreich’s ataxia is a neurodegenerative disease (this means that the disease is caused primarly due to neurological malfunctions, leading to an increased difficulties in doing actions such as coordination of one’s body) , possibly caused by a protein called Frataxin. This protein is usually responsible for various functions dealing with cellular iron homeostasis, but Friedreich’s ataxia may be caused by iron overload. How severe this disease is based on the number of repeats of the GAA triplet in the intron. The normal range should be from 6 to 36 repeats, where as affected patients have from 70 to 1700 repeats. These repeats are made only of pyrimidines and purines. This may lead to a different way the protein folds compared to as how it is actually supposed to fold, leading to the wrong functions that protein was supposed to take.
To find a genetic test for Friedreichs ataxia, we may be able to perform polymerase chain reaction (PCR) to test whether a person has the repeated GAA triplet by extracting a cell from that person. Just as we used PCR to find chromosome 16, PCR may also be affective in finding these repeats of the GAA triplet.
I thought an effective test would be PCR as well. I flelt PCR coupled with gel electrophoresis would be more practical however. Simply because runing the PCR sample on the cell allows us to visualize the results better. Also because the repeats of this mutation can become so large, if we saw concentrated bands toward the top of the gel closer to the wells, more than likely the mutaiton repeat is in the genome.
Friedriech’s ataxia, a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin, is an autosomal recessive disorder caused by a gene mutation at the centromeric region of chromosome 9q13-21.1, which is at the site of the gene coding for the 210- amino-acid protein frataxin. Frataxin, a monomeric mitochondrial protein, is involved in iron homeostasis through an unknown mechanism. Expression of frataxin is highest in tissue rich with mitochondria including liver, heart, and skeletal muscle. The mutation occurs when an excessive number of repeats homozygous GAA trinucleotide DNA sequence in the first intron of the frataxin gene coding. This expansion changes the gene expression by decreasing the synthesis of frataxin, and this expansion of GAA repeat results in frataxin deficiency by interfering with transcription of the gene by adopting an unstable helical structure. The age of disease onset, the severity, the rate of progression, and the extent of neurological involvement vary with the number of repetitive GAA sequence. The lager the GAA expansions, the earlier the age of the onset occurs.
From the lab experiment so far, the way which can be used to diagnose if the frataxin gene coding mutation presents is to perform the polymerase chain reaction (PCR). By running the sample into the gel, it can determine if the person has excessive number of repeats GAA trinucleotide. Additionally, to diagnose Friedriech’s ataxia, Electromyogram can be used to examine the electric currents associated with muscular action from a graph.
I think your explanation of Friedreich ataxia as a disease caused by reduced expression of the mitochondrial protein frataxin was very similar to mine. We all have similar description of Friedreich ataxia because its description is very precise. I totally agree with you that frataxin is a monomeric mitochondrial protein that is involved in iron homeostasis and I even had similar idea. PCR is such a widely used technique that when we think about a genetic test for Friedreich ataxia the first thing that comes to our mind is PCR. I agree with you that by running the sample into the gel we can determine if the person has frataxin gene coding mutation present in them by seeing the GAA repeat in the gel.
A lot of people are suggesting PCR as a test and then running it though a gel. I was wondering if there is a restriction enzyme that would cut the DNA so that there only the GAA repetition would be seen. Being that the GAA repetition can be repeated 10s to 100s or even 1000s of times, how can one actually find out if the band of DNA consist of GAA repetitions?
I agree with Ummea. We all have very similar answers because Friedreich ataxia is very specific. I like the way you described it because it was so organized and easy to understand.
Friedreich’s ataxia FRDA is an autosomal recessive disease caused by a mutation of a gene called frataxin, which is located on chromosome 9. We know that frataxin is found in the mitochondria of humans, but don’t know its function. It disturbs nervous system, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease and diabetes.
FRDA has been mapped to a gene on 9q13-q21 that affects production of the protein frataxin. In most cases, the mutant gene contains expanded GAA triplet repeats in the first intron; in a few pedigrees, point mutations have been detected. Because the defect is located on an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing; switching off a gene, through induction of a heterochromatin structure.
The very obvious molecular characterization of the FRDA triplet expansion requires the use of PCR protocols to amplify normal and mutated alleles combined with Southern blotting analysis to accurately size the expansion. This is to evaluate triplet repeat primed PCR (TP PCR) as a screening method for FRDA diagnosis in the diagnostic laboratory. The sample can then be run through the agarose gel electropherosis to determine the result of the GAA trinucleotide in the individual.
Brief, yet informative, you clearly communicated knowledge and understanding FA. We both discussed PCR in our analysis’, and so has several of our classmates. I wonder, however, if it”s because students truly believe PCR is an effective tool, or, is it because our repeated use of PCR in pharmacogenomics lab has caused us to think that the testing has more use and applicability than it acually does. You should also considery electromyography, which in this case can help understand the extent of FA related neuronal damage has affected the muscle fibres.
your description of FRDA was precise to the point. it gave me the information i needed to know and your proposal for PCR was good too. by using PCR we can test the positive or negative for each person.
Mutations in the genome are not as uncommon as many people think. Some mutations may not cause any problems in the body while some can cause diseases that are life threatening. One example of a genome mutation that causes disease is the neurodegenerative disease (disease that causes problems in the brain leading to other body internal problems), Friedreich’s ataxia (FRDA). This disease is associated with the chromosome 9q13-q21.1 which encodes a protein called fraxtin. This protein is vital for iron level control in the body and is found in high quantities in many vital organs of the body, especially those which need a high energy content such as liver, heart, and muscle.
The mutation is said to be found in the first intron of this sequence and has to do with a GAA codon repeat. In the normal genome, the number of repeats for this codon is 6 to 36 repeats where as in the mutated genome, it can range from 70 to 1700 repeats. This causes a transcription error and affects the synthesis of protein as well as creating an unstable protein structure. However this error is not created directly by the intron since introns are cut out of the mRNA. Instead, it silences another gene needed and creates problems with the protein. The higher the number of repeats, the more severe the disease is in a patient.
In order to see if a person has this specific repeat of GAA sequence, a PCR experiment seems the most appropriate. Only a small of DNA is needed which would be amplified. And because the sequence is known, primers can easily be made to target the desired sequence in the genome in order to see if the person has this mutation. Running it through a stained gel with a control group will allow a speedy and possibly an accurate assessment if a person has this specific mutation and through extensive experimentation, perhaps even find the severity of the mutation.
I didn’t even think about a silencing gene. Interesting. We had similar theories though. We both felt the mutaiton had to occur during the synthesis of the template because the introns are cut out. Somehow the introns had to effect the exons essentially.
The silencing is an interesting theory. I did not thing that by silencing another gene needed it can create problems with the protein.
I really liked how you started this off by saying that mutations are not as common as people think. You also organized this very well by telling us what FDRA is and talked about why PCR may be the most useful. I think it would be helpful next time to define what PCR is for people that may not know.
Friedriech’s ataxia, also known as FRDA, is a neurodegenerative disease mainly caused by gradual increase of neurological disability. It is an autosomal recessive illness. Examples of symptoms of FRDA are fatigue in muscles, loss of ability to move arms and legs and scoliosis. Its main cause is reduced expression of the mitochondrial protein called frataxin. FRDA’s diagnosis shows inadequate levels of frataxin which functions in mitochondrial iron metabolism. Normally, chromosomes contain from about 35 to 40 GAA triplets in an ALU sequence. These repeats are found in the introns in the frataxin gene. However, on the other hand, FRDA chromosomes carry from around 70 to more than 1000 GAA triplets.
Although physical tests don’t provide substantial accuracy to diagnosing a disease due to the fact that many diseases have some common symptoms, it can give an idea on what kinds of disease the patient may have if the test is thorough. Some symptoms of FDRA include walking unsteadily, having trouble keeping balance, falling down frequently, muscles feeling weak, little to no reflexes in legs and jerky eye movements. By performing an electromyogram (EMG), which is a test that measures the level of electrical activity in the muscle cells, the results may show abnormalities in the heart. By extracting some blood, using genetic testing or polymerase chain reaction, it is possible to identify if one has the disease according to the number of GAA repeats.
I really like how simply you explained it! And i especially found the EMG method of diagnosing the disease really interesting. I didn’t think of it that way myself. I thought of the very common PCR method but your method would help verify results in a different testing manner.
Although we did not use EMG is the lab, it is a great method to use. I like how you gave several options and paths that one canuse to genetically test for the GAA repeats.
When a gene is processed it goes through several stages before it can be translated into a protein. First it has to be transcribed into mRNA which codes for proteins. mRNA is transcribed from DNA in a series of steps. Some of these steps include: cutting out the introns with spliceosomes and leaving them within the nucleus, attaching the A-tail which determines how long the mRNA will live, and attaching a methyl cap. Friedriech’s ataxia occurs on the first intron of the frataxin gene. The introns are cut out of the DNA while the exons are being sent into the cytoplasm for transcription and ultimately translation into a protein. One might ask how introns that are left behind within the nucleus can affect the production of a protein in the cytoplasm. The mutation more than likely occurs during the transcription of DNA into mRNA. Polymerase is an enzyme that travels along template strands of DNA and attaches the complementary base pairs to each nucleotide. If there is an error on the template strand then polymerase will code that error. This could cause the entire strand to be misaligned by the number of repeat base pairs. If there is an error in transcribed mRNA there will be an error on the translational level which would cause a reduction in the number of synthesized proteins. Theoretically, if there was a marker we could place on a template with a repeat nucleotide mutation polymerase could avoid it and not code that transcribe that gene. However practically, we could extract the DNA from mitochondria test it for the mutation and by using PCR and gel electrophoresis.
Extracting mitochondria DNA is also very interesting instead of using the general genome. I don’t know if the mitochondria DNA would work but to try and see if the mutation can be found that way is very unique. If it did work then the possibilities of diagnosing other genome mutations in this manner can increase and even become easier.
I liked that you explored a different aspect of this mutation in detail than the previous comments. It was very refreshing to see something different. I wonder if the Mitochondrial Test would actually work?
Friedreich’s Ataxia (FA) is an inherited recessive neurodegenerative disorder caused by the partial reduction in levels of the mitochondrial protein frataxin. The disease is characterized by a progressive, unrelenting sensory neuropathy due to death of primary sensory neurons of the dorsal root ganglia while other neurological symptoms present variably. FA is caused by mutations in the FXN gene encoding a mitochondrial protein, frataxin. Mutations in this gene lead to a reduced expression of frataxin, which causes the clinical manifestations of the disease. Approximately 98% of individuals with FA have a homozygous expansion of the GAA trinucleotide repeat in intron 1 of the FXN gene. The remaining 2% of FA patients have the trinucleotide expansion on 1 allele and a point mutation or deletion on the second allele. Friedreich’s ataxia has a defect in a gene located on chromosome 9. Because of the inherited abnormal code, a particular sequence of bases (GAA) is repeated too many times. Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich’s ataxia it can be repeated hundreds or even over a thousand times. I think PCR is the best way to find out if person has Friedreich ataxia. It is easy to use PCR to screen for repeat length of GAA sequence. After performing a PCR, we can run the sample on a gel with control sample to see if the person has the frataxin mutation. It will show us if GAA repeat is seen in the gel, then it means that person probably has Friedreich ataxia.
I think that PCR would be a very good way to test for Fredreich’s ataxia because this test is simple and relatively quick. In addition to that, the test can be used for genetic finger-printing. Just like how to used PCR to identify the ALU sequence in non-coding region of the DNA.
PCR is a fast and easy method to analyze DNA. It can quickly test the many GAA repeats because they contribute to the high molecular weight of the molecule. In the agarose gel, the heavier molecules tend to move less.
I agree that PCR is a good way to test the results for a huge number of reasons. Mainly because of its ability to amplify a target DNA sequence. and also because you get back results relatively fast (about 5 minutes depending on the gel used)
Very good description-detailed, informative, and to the point.
Fredreich’s ataxia is a disease that causes damage to the nervous system that can cause problems with gait and heart. This occurs when there is a mutation in a gene that codes for frataxin. The protein has a role in the function of the mitochondria. In the absence of frataxin, the iron builds up and can cause free radical damage. Problems deriving from the mitochondria would lead to nerve and muscle problems.
The mutant gene contains an extended GAA triplet that repeats over and over again. As the repetition increases, fredreich’s ataxia worsens. Since the mutation is located on an intron, the mutation does not result in the production of abnormal frataxin proteins. This is because the introns stay in the nucleus while the exon exits the nucleus into the cytoplasm to get translated. Since the mutation is found on the intron, the mutation causes gene silencing. The long GAA repeat decreases the expression of the heterochomatin-sensitive transgene which decreases the promoter accessibility. This decreases transcription of the frataxin gene.
A cost effective test that could be used to test for fredriech’s ataxia would be a test that would test their gait such as can you walk on your toes, your heel, and heel to toe in the early stages. Then they can get an electromyogram, which would measure the electrical activity of the muscle cells. As for a genetic test, the parents could be tested to see if they have the recessive allele for the defective fredriech gene. Since it is known that this gene is found on chromosome 9, scientist can amplify and sequence the chromosome to see if there is a GAA repetition.
Your suggestion on how to detect FRDA is cost effective when it come to “walk on your toes, your heel, and heel to toe in the early stages” and the fact that you stated that we know where this gene is we can just concentrate on that specific location and not waste money and time searching for it.
Good point, if scientists searched for the GAA repetition in a parents sequence, they would know exactly who are carries the gene. Helping to prevent the gene from going to another generation.
I liked that you explored a cost effective test that is simpler than PCR. I wonder how the electromyogram test would compare to PCR in regards to cost. It is very interesting that there are so many ways to diagnose this fatal condition, if only a feasible cure could be discovered from all this research… Hopefully one Day!
Mutations are actually pretty common. They can lie dormant in the body for long periods of time going unnoticed as they covertly plan their attack on the normal DNA sequence. It only takes one change in the normal strand to completely alter everything from what is spliced within the nucleus to gene expression. A good example of a mutation that leads to harmful conclusion is Friendrich’s Ataxia (FRDA). FRDA is an autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia, dysarthria, lower limb areflexia, decreased vibration sense, muscular weakness of the legs and positive extensor plantar response. This disease is associated with chromosome 9q13-q21.1. There this disease encodes a small mitochondrial protein called frataxin. This protein is vital for controlling the amount of iron within the body, more importantly within the muscles, kidney, and heart.
The mutation itself takes place in the intron and is believed to be an expansion of the GAA codon sequence. The normal number of repeats ranges from 6 to 36 repeats, whereas in FRDA patients, the number of repeats ranges from 70 to 1700 repeats, most commonly 600 to 900 GAA. These codon repeat sequences are abnormally high and that’s a problem because too many of these sequences will lead to transcription errors. Suppose the useful data to maintain the body’s iron levels were the parts of the sequence that were being left as introns, and lets also assume that those introns were being replaced with GAA sequence. This would affect the mRNA that is supposed to become the protein that does this job. If this happens a lot, you will end up with many unstable proteins making this disease that much more prominent.
An ideal way to track these sequences is a PCR experiment. In the experiment, you already have the expectation because of the control. All that’s left now is to watch the set primers react to the patient’s DNA and see through the gels if these strands of genes come up. If they do, then you could also postulate how severe the disease is . One more thing you can do, is take a blood sample and you could check the severity iron levels through a western blot. This way you could also check and see if the protein bands in relation to the disease are in the individual. And if that works, you can also see what effects the levels of iron have on the individual’s immunity system. IF the person has Friedreich ataxia, expect to see very stable consistency!
With the use of a western blot one can measure the relative amounts of the protein present in a given sample. This could be beneficial in comparing the amount of frataxin protein present in a normal person vs FRDA patient.
I like how you speculated what might happen if PCR works to identify the disease. Not only did you speculate a diagnose but the next step after a person is diagnoe which is something I did not think of doing.
Friedreich ataxia is an incurable condition that affects the nervous system causing movement problems that exacerbate with time. The disease can also lead to heart conditions, diabetes, impaired vision, hearing loss, or an abnormal curvature of the spine (scoliosis). Friedreich ataxia caused by a gene mutation on chromosome 9 at the site of the gene that encodes for a protein named frataxin. The mutation results in an excessive repeat of GAA (guanine adenine adenine) trinucleotide DNA. The GAA sequence is repeated at least 200 times to 1000 times more than normal.
One way to detect this mutation is through an experimental kit which was designed to identify Triple Repeat disorders (in this case the GAA) in a DNA sample. This kit uses a common method known as Polymerase Chain Reaction which we routinely use in our lab class. The kit comes with the complete PCR “cocktail” and the primers are specially formulated to identify the GAA repeat sequence.
Once the PCR is run and a replicated clean sample is obtained, the presence of the GAA can be identified through another method we discussed in class which is known as Southern Blotting. Southern blotting is a process that starts with Restriction Endonucleases that cut up the DNA sample into fragments. Then they are separated on a gel and classified by size. The DNA is transferred from the gel to a nylon membrane, and this membrane is immersed in a solution that contains a radioactive single stranded labeling probe. The membrane is cleaned to eliminate the extra-unattached probes and then dried. An X-ray is then taken of the membrane and the labeled probe will help reveal hybridization band and the presence of the disease.
This kit for discovering the presence of the disease was developed through extensive scientific research. As it pertains to this class, this method appears to be a relevant manner to detect this disease among the other existing methods.
I enjoyed that you looked into on your own about the kits for the disease. It was interesting to read about a kit that has been made to detect this gene, especially to find out that the kit involves a technique that we frequently use.
Friedreich ataxia or FDRA is an autosomal recessive disease that results from a mutation of a gene locus on chromosome 9. The disease was first described in 1863 by Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany. FDRA is said to be the earliest of the inherited ataxias to be distinguished from other locomotor ataxias. Friedreich ataxia is the most common of the autosomal recessive ataxias. The disease accounts for at least 50% of cases of hereditary ataxias. Some symptoms include progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs, and extensor plantar responses.
The gene associated with the FDRA is known to be mapped to chromosome 9. It encodes a small mitochondrial protein known as frataxin. The common mutation is a GAA triplet-repeat expansion within the first intron of the frataxin gene. In most healthy patients, the number of repeats ranges from 6 to 36 repeats. In a FRDA patients, the number of repeats ranges from 70 to 1700 repeats. The harshness of the disease is associated with the number of repeats that are present. Most patients carry two expanded GAA alleles which can lead to strongly reduced frataxin expression in all tissues. These mutations are small deletions or point mutations which can disturb the normal function of frataxin. It can either affect protein folding or the functional residues.
A test that we can perform would be a PCR. We can amplify the gene on chromosome 9 to get a better picture of what is actually occurring & check for the repeated GAA sequence. If there is abundant amount of the sequence which we will observe on the electrophoresis, we can confidently confirm that the sample is affected by FDRA.
Marvin, you did a great job in describing what FDRA is. You included all crucial background knowledge as well as its importance to reduced protein levels. I also agree that PCR is a good method to use.
Friedriech’s ataxia is an inherited disease that causes nervous system damage and caused movement irregularities. The disease is caused by a mutation within the first intron of a frataxin gene. There is an excessive number of GAA repeats in FRDA patients compared to healthy individuals. Healthy individuals have six to thirty-six repeats of GAA, whereas FRDA patients have 10 to 300times more repeats. Moreover, there is a correlation between the number of repeats and the seriousness of the disease. Nonetheless, the frataxin mutation found in Friedriech’s ataxia could lead to reduced frataxin protein levels. This is because the majority of patients bear two expanded GAA alleles which causes significantly reduced frataxin expression in every tissue. A GAA repeat nucleotide expansion in an intron stimulates limited transcriptional inhibition, which leads to reduced frataxin protein levels.
We have conducted lab experiments that involve genetic testing. The procedure known as the Polymerase Chain reaction (PCR) can be used to amplify a small sequence of an individual’s DNA in a test tube. This genetic test can be used for Friedriech’s ataxia. GAA repeats can form intramolecular triple-helix structures because they contain purines on one strand and pyrimidines on the other strand. PCR produces a large amount of DNA in a test tube from a trace amount. This generates thousands to millions copies of a particular DNA sequence. PCR involves a DNA template, sequence-specific primers, nucleotides, magnesium ions, a buffer containing salt, and Taq polymerase. There are three main steps involved in PCR amplification. The steps include a denaturing step, annealing step and an extension step. The denaturing step involves heating (94°C) in order to separate the double-stranded DNA template into two single stranded molecules. During the annealing step, the oligonucleotide primers anneal to find their complimentary sequences on the two single-stranded template strands of DNA. During the extension step, the Taq DNA polymerase adds nucleotides one at a time to create a complimentary copy of the DNA template. These three steps are repeated 40 times. Running it through a stained gel will identify if there is a GAA repeat nucleotide expansion.
I like how you explained Friedriech’s Ataxia with detail as well as the PCR process. Although, I have seen many other people suggest PCR as a way to detect Friedriech’s ataxia, I do not think that it is the only way possible. There may be other diseases that also involve a GAA repeat. You said that normally people have around six to thirty six GAA repeats and FRDA patients have ten to three hundred times that amount. What happens if the test comes out to be only five times or four hundred times that amount? Does it have to be Friedriech’s ataxia or can it be some other condition?
Hereditary Ataxias are an inherited, or genetic, disorder. That means that it is caused by an abnormality of a single gene. To understand how the disease is passed on, it is important to know about genes and cells. This genetic pattern is called autosomal recessive inheritance, which means that the disease is hereditary, a double dose of the altered or non functioning gene is required to cause symptoms, the disease can strike males and females with equal likelihood, and that it is possible to carry the altered gene without having symptoms of the disease.
The most common mutation in the frataxin gene that leads to FRDA is known as a triplet repeat of GAA .In this type of mutation, a section of DNA is repeated over and over again, from as many as 100 to more than 1,000 times. The presence of this extra bit of genetic material interferes with the normal production of frataxin protein. A second type of gene flaw, called a point mutation, is much less common. In this type of mutation, a very small amount of DNA is altered. FRDA occurs when a person inherits two triplet repeats or a point mutation and a triplet repeat. Due to the fact that FRDA is a mutation that causes repetition of DNA I believe that PCR is the best way to find out if one has this mutation because we can do a simple experiment like the ones in our lab to see if there is a repeated GAA.
I enjoy the fact that you mentioned the triple repeats for the mutation and how you went about explaining how PCR would have been the most solid response in finding out if a person had the disease.
The effects of FRDA are that some of the cells in the nervous system degenerate over time. The cells most affected are those that transmit sensory and movement signals via long fibers. The fibers run between the central nervous system and the rest of the body. Cells in the heart and pancreas are also affected in this disorder. Some of these cells probably die because of the direct effects of the loss of frataxin others may die because of secondary effects.
Friedreich’s Ataxia is known for being a neurodegenerative disease (causes the loss of structure/function of neurons) and a autosomal recessive disease . The disease is caused by a gene mutation located on the centromeric region of chromosome 9 (the site that codes the protein Frataxin, 9q13-21.1), and is known for the excessive repetition of GAA trinucleotide (guanine, adenine, adenine). FRDA is the only disease within the category of neurodegnerative diseases that contains the specific coding sequence. The result of the coding sequence is that it alters the expression of the gene by forcing it to gain a unstable helical structure, which causes a reduction in frataxin expression. Frataxin is a protein that is associated with cellular iron homeostasis within the body, and is also encoded by th FXN gene that is located in the mitochondrion; which is used in th assembly of iron-sulfur clusters. A deficency of frataxin can cause severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation and an increased sensitivity to oxidative stress.
After analyzing my notes, I believe the most efficient way to go about testing for the disease would be to use a combination of PCR and Gel Electrophoresis. The apolymerase chain reaction would allow for the production of large amounts of the DNA, specfically the DNA found within chromosome 9’s 9q13-21.1 region. By following the proper procedures for PCR, we would be able to run a gel afterwards and attempt to locate the GAA repetition.
Your description about Friedreich’s Ataxia was very detailed and on point, i also agree with you that PCR might be one of the most reliable and effective way of detecting this mutation because the experiment can be run more than once to see if any error was made and if we can run the gels multiple times within hours it really adds to the efficiency of the process.
Source:
PMID: 20413654
Friedreich’s ataxia (FRDA) is a hereditary disorder that is most common in the Caucasian population. It is responsible for muscle weakness in the legs and tendons. People with this disease are more likely to develop diabetes and muscle degradation in the limbs of our body. Symptoms become more prevalent as adolescents reach the age of 25 and life expectancy is close to the 40‘s and 50’s. The mutation on the mitochondrial frataxin gene is responsible for FRDA. The mutation is the result of too many GAA codon repeats. Patients with normal repeats range from 6- 36 repeats and those with the mutant allele have repeats of 600- 900 GAA codon repeats. The number of repeats is proportional to the severity of the disease. Patients with greater amounts of codon repeats have a more severe case of FRDA. However patients do need some of the frataxin protein for survival. Frataxin is essential in embryonic growth and complete fraxatin deletion could result in lethality as experimented in mice. GAA expansion however induces transcriptional inhibition and is fact responsible for gene silencing and change in the conformation in protein shape. GAA repeats present a three helical structure.
The genetic test that can be used is to for Friedreichs ataxia would be to run it using PCR on agrose gel considering that the GAA repeats is a three helical structure the conformation using the gel would look “unusual.” By running it on the gel the agrose gel would be able to tell you whether the individual has the mutant gene or not.
After reading your response i noticed how you mentioned the use of PCR as a valid method to diagnose this mutation. As i also mentioned in my comment, the use of PCR would be a great method to use, becuase we would be able to identify the mutated GAA codon
Friedreich’s ataxia is a neurodegenerative disease, which consists of a disease lead by neurological deformities and malfunctions which cause the lack of functionality in certain body parts such as the lower limbs. This disease is primarily caused by the protein frataxin. Frataxin is a monomeric mitochondrial protein which responsible for various functions dealing with cellular iron homeostasis. This disease is induced when the mutation of the GAA trinucleotide replication is not controlled in the first intron of the protein being coded, which is frataxin. This results in the lack of frataxin production. The way in which this disease can be found is by the polymerase chain reaction ,PCR. If we run the gel in the PCR, we will be able to identify the mutation due to the GAA repeats found in the gel. The shape of the gel will help us identify weather the sample contains the mutant gene or not.
I agree with your genetic test for the disease. Your use of big and fancy words added to the detail of your writing. I like that you were brief and to the point with your description of FRDA.
I also agree with your use of PCR to identify this disease. It is the experiment I used in my post as well. I think it would be a very functional way to test the DNA to see if the mutation is present or not.
Friedreich’s ataxia is an autosomal recessive neurodegenerative disease that affects the muscle. It is caused by a defect in the frataxin gene located on chromosome 9. Frataxin is a protein involved in iron homeostasis. A defect in this gene causes the body to produce too much of the DNA trinucleotide repeat GAA. This leads to lower levels of frataxin protein and abnormally high iron levels within neuronal mitochondria. The human genome usually contains 8-30 repeats of GAA, however people with Friedreich’s ataxia can have up to 1000 copies of the gene. The amount of GAA repeats present in the body may indicate how bad the disease will be. Symptoms include abnormal speech, loss of coordination, muscle weakness, and change in gait to name a few. Scoliosis and heart disease are usual outcomes of the disease. There are tests such as Electrocardiogram and Electromyography that can be done to diagnose the disease.
I agree that using PCR may be a helpful way to genetically diagnose the disease but since the protein is normally present in the human body I don’t see how the test would be helpful because to my understanding PCR doesn’t tell you the amount of a target sequence present, only if the sequence is present itself.
I think a better test would be one that let’s us identify the amount of repeat GAA sequences present in the genome. High amounts of the sequence will indicate the presence of the disease.
I really like your post and felt it was well written. I felt you mentioned all that needed to stated to get the point across. I feel that anyone reading this will understand what is being stated in the post. I also agree with you with the and it being the best solution.
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease; it is an inherited disease that causes damages to the nervous system due to the reduced expression of the mitochondrial protein frataxin. The genes that encoded this small mitochondrial protein called frataxin are mapped to chromosome 9q13-21.1. There is a mutation that is an expansion of a GAA triplet-repeat within the first intron (non translated DNA region) of the frataxin gene. Usually in a normal health patient, the number of the repeated sequences is about 6-36 times; however, in a FRDA patient, the number of the repeated sequences can range from 70 to 1700 but majority of the patients are 600-900. The increase in the number of that repeated sequences will increase the severity of the FRDA in patients. The mutation can be deletions or point mutation and both can changes the frataxin function by changing the protein folding. Through many researches, scientists found out that histone deacetylase inhibitors (HDACi) can target the GAA repeated expansion to restore the frataxin level. HSACi inhibits the histones deacetylations thus the heterochromatin reverts back to an active open conformation that increases the gene expression. Another molecule that can increase the frataxin level is the recombinant human erythropoietin (rhuEPO). One of the genetic testing for Friedreich’s ataxia is polymerase chain reaction (PCR) because this technique can be used to amplify the small sequence and then it can be analyzed through the result from gel electrophoresis. PCR can be used to detect if the patient have the repeated sequences in their genes. Another genetic testing for Friedreich’s ataxia is Southern blot analysis, this technique can be used to detect the specific sequence of DNA from the samples.
I agree with you Hoi in your reference to PCR, as I mentioned in my blog post, PCR has many valuable uses as it is both efficient and does not waste materials and/or resources. I would also encourage you to consider the techniques of electromyograms, which, in this case would be very useful as you can test the excitability of muscle cells, which are the primary targets of FA, which functions to degenerate muscle tissue, by it’s mutations.
A neurodegenerative disease, Friedrich’s ataxia, is an inherited, rare condition that impairs nervous system function and motor function. Friedrich’s ataxia is triggered by a defect in FXN, a gene. A recessive disorder, FA only occurs in individuals that inherit two mutated alleles of a gene, one from each parent. The mutant gene is unique as it contains a repetitive GAA triplet code. There is a linear association of frequency of GAA repetition and severity of FA. The mutation occurs inside the cell (intronic), because of this, the mutation causes gene silencing. Typically manifesting its effects in childhood, FA, as it’s also known, can result in poor muscle coordination over time. The distinctive effects of FA result by degeneration of the spinal cord and peripheral nerves important in controlling and maintaining many of the body’s functions and processes. In addition to the damage to the spinal cord and the peripheral nervous system, FA also degenerates, to a lesser extent, the cerebellum, an area of the brain that controls motor function. Symptoms of FA include gait ataxia, which is difficulty in walking. Progressively, the ataxia can deteriorate the body’s systems and slowly spreads to the trunk and extremities.
A genetic test to test for Friedrich’s ataxia would be a polymerase chain reaction. With a polymerase chain reaction, we can directly detect the GAA expression inside the cell’s nucleus. This would be ideal as the PCR doesn’t require large amounts of genetic material to yield effective results. Running a sample in the gel, we’ll be able to discover any excess GAA repeats. Gel electrophoresis would be another similarly effective examination tool. Finally an electromyogram would be favorable as it can test the excitability and ability of muscle cells, which are primarily effected by FA.
You post was very informative and hit all the major points of FDRA. It was well written and straight to the point w/o any extra unneeded information. Your post had a lot of detail which helped visualized the mechanisms of the disease so clearly. I also agree with the PCR procedure, it being the best solution for a genetic test to test for Friedrich’s ataxia.
Your post was well written and structured. I liked the way you explain the history of Friedriech’s ataxia as well as what it does to the body. I like how you mentioned that the mutation in the FXN gene causes gene silencing, a factor which many other people forgot to add. However, I feel that you could have expanded a little more on explaining what an electromyogram does and how it relates to the disease. It tests for faults in one’s heart beat but some people may not see the relation between the disease and the test itself.
There are many diseases of the nervous system and brain that affect many people. Freidreich’s Ataxia (FRDA) is an autosomal recessive neurodegenerative disease that causes both gait and muscle impairment. Even though the disease is quite rare affecting around 1 in 50,000 people, the disease begins in early childhood, where patients develop weakened muscle coordination. With the passage of time his degeneration of muscles increases. The spinal cord and peripheral nerves deteriorate, becoming thinner. The neurological symptoms that are observed are caused by the disintegration “of the large sensory neurons of dorsal root ganglia and spinocerebellar tracts”. The damage that results from this relapse causes uncoordinated and uneven movements, as well as impaired sensory function. This disorder also causes problems with the heart and sometimes induces diabetes in patients.
Most of the times, there are genes that code for certain diseases. The gene that is associated with FRDA is mapped on chromosome 9 and encodes for the protein frataxin, found in the mitochondria of cells. Interestingly enough, scientists have discovered that without a normal level of frataxin, certain cells in the body cannot effectively produce energy to function. The most common mutation that occurs on this chromosome is a GAA triple repeat expansion within the first intron of the gene. . In healthy patients, between 6 to 36 GAA repeats exist. However, in patients affected by the disease, several more repeats occur, between 70 to 1700. The severity of the disease is correlated with the number of repeats. Since this disease is autosomal recessive, a person will only have the disease if they receive two copies of the mutated gene. Most patients that carry both copies express reduced frataxin in all tissues. Nevertheless, there are patients that carry only copy of the gene, but they have some other type of error with the other copy, moreover a point mutation or deletion. Whether the other copy of the gene has undergone a point mutation or deletion, they cause a disturbance that changes the function of frataxin either by affecting the folding of the protein or the functional remainders.
A genetic test that can help determine if a patient has the disease could be nerve conduction studies and electromyogram. Nerve conduction studies measure how fast and how well the nerves can transmit electrical signals, while an electromyogram measures the electrical activity of muscles at rest and during contraction. Nerves control muscles through impulses and muscles respond in very specific ways. Both nerve and muscle disorders can be detected because they cause the muscles to react in an abnormal function. Both are usually done together in order to give a more complete analysis of a condition. Electromyopathy is used to find the cause of weakness, paralysis, or muscle twitching and since this method cannot show brain or spinal cord diseases, nerve conduction studies are used. During this method information is gathered from the nerves that lead away from the brain and spinal cord.
very well written, would have liked to see a list of sources
Friedriech’s ataxia (FRDA) is an autosomal recessive disease that is inherited through a faulty gene that both parents carried. Scientists discovered the gene involved with the disease has been mapped to chromosome 9q13-q21.1. This gene codes for the production of frataxin protein, this protein is essential in regulating cellular iron homeostasis.
“The most common mutation is a GAA triplet-repeat expansion within the first intron of the frataxin gene.” Normally, people have the GAA repeat ranging from 6 to 36 but in FDRA patients, the amount GAA repeats was mostly between 600 and 900. With this triplet repeat expansion occurring, it disturbs the normal production of frataxin in the mitochondria. This is a big problem because specific cells in the body can no longer efficiently produce energy or function properly without normal levels of frataxin.
In order to see the whether the multiple GAA repetition is present, I would perform a PCR to amplify the DNA sequence. PCR is often used as a medical diagnostic tool to detect specific mutations that could possibly cause a genetic disease.
Mutations occur often in our genome. Some of these mutations can move through generations, and some can cause disease, where some others wont. An example of a mutation that will cause disease is neurodegenerative disease. This disease is a genetic mutation which overtime causes the body
this comment posted too early before i was finished. full comment is below..
Mutations occur often in our genome. Some of these mutations can move through generations, and some can cause disease, where some others wont. An example of a mutation that will cause disease is neurodegenerative disease. This disease is a genetic mutation which overtime causes the body to lose the function of neurons, it can result in the death of neurons.
Freidreich’s Ataxia (FRDA), is a rare inherited disease which is characterized by loss of voluntary muscle function or coordination and heart enlargement. This disease is an autosomal recessive, affecting both males and females. This mutation for this disease is the gene frataxin, which is located on chromosome 9. Frataxin is a protein that plays certain roles related to cellular iron homeostasis. This mutation means that the trinucleotide GAA DNA sequence is repeating too often on the chromosome. An FRDA patient will have this repeating sequence more than the normal individual, normally an individual has 8 to 30 copies of GAA, a FRDA patient can have as many as 1000. The larger the number of copies the early of an onset this disease will have.
The experiment I would suggest that we have done in our toxicology lab is to run a PCR gel on a sample of DNA. Through the PCR test we could determine if the tested DNA has the mutation with the GAA repeated sequence or if it does not. The test could prove or disprove if a person is positive or negative for FRDA.
Friedreich’s ataxia is an inherited autosomal recessive disease that causes damage to the nervous system resulting in symptoms such as muscle weakness, speech problems, and heart disease. Ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The ataxia gradually worsens and slowly spreads to the arms and then the trunk. Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich’s ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. Doctors diagnose Friedreich’s ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Several tests may be performed, including electromyogram (EMG) and genetic testing. A genetic test that I would perform on a patient to diagnose Friedreich’s ataxia would be a polymerase chain reaction (PCR) to amplify the DNA sequence GAA that is repeated.
Friedrich’s ataxia is a rare autosomal recessive disease that causes nervous system damage and movement problems. Because it is an autosomal recessive disease, both parents must pass on a recessive defective gene called the FXN gene. The FXN gene can be detected in chromosome 9. The normal sequence of this gene consists of 7 to 22 “GAA” repeats. However, in the defective FXN gene, this “GAA” repeats hundreds and even thousands of times.
The largely repeated “GAA” sequence greatly disrupts the production of a protein called frataxin. Without frataxin, certain cells, especially the peripheral nerves, spinal cord, brain, and heart muscle cells, are unable to produce the energy needed. Lack of frataxin can also lead to excessive iron buildup in the mitochondria, which may become toxic to the cell.
To detect this rare autosomal recessive gene, one can conduct a electrocardiogram (ECG). Fredreich’s ataxia is known to cause heart problems such as cardiac failure, heart rhythm abnormalities, and impaired conduction of cardiac impulses. If a patient has these symptoms, a electrocardiogram can easily map out the electrical impulses or beat of the heart. Having these symptoms would lead to an increase possibility of having Fredreich’s ataxia. After an ECG is conducted, one can also run nerve conduction tests to test the speed of nerve transmission. Fredreich’s ataxia also affects the peripheral and central nervous systems. Running nerve conduction tests would further help us determine if one has the disease.
Sources:
“Friedreich’s Ataxia Fact Sheet,” NINDS. Publication date September 2010.
NIH Publication No. 10-87
http://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm
“Friedreich’s ataxia.” Johnston MV. Movement disorders. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 597.
http://www.nlm.nih.gov/medlineplus/ency/article/001411.htm
Friedreich’s ataxia is caused by a defect in the Frataxin gene (FXN) which can be found in chromosome 9. The average human produces about 8-30 copies of the nucleotide repeat “GAA” but those with Fredreich’s ataxia produce too much of the DNA repeat. Sometimes the “GAA” nucleotide sequence is repeated thousands of times which interferes with the production of the Frataxin protein. Frataxin is localized to the mitochondria and without this protein, iron is improperly stored in the mitochondria which may lead to an unhealthy buildup of iron.
This condition is autosomal recessive meaning an individual must get two defective genes in order to display the trait. This disease can affect the areas of the brain and spine which control movements, coordination and sensory functions. Peripheral nerves begin to degenerate and the body has difficulty controlling and coordinating motions.
I believe that the most effective test to determine Friedreich’s ataxia would be to conduct a PCR which would be able to determine an excess amount of repeat sequences in the genome. Other suggested tests are an electromyogram which would measure electrical activity within the muscle cells. An electrocardiogram would also be able to measure irregularities of the heart, though, it would not be an effective test to diagnose the disease like a PCR would be.
Friedriech’s ataxia or FRDA is an inherited autosomal recessive disease that causes damage to the nervous system in the spinal cord and causes problems such as speech imariment and heart disease. It is discovered that the FRDA is mapped to chromosome 9q13-q21.1. this protein functional for the mitochondria, the removal of iron from the cytoplasm surrounding the mitochondria. In FRDA the most common mutation is a GAA triplet-repeat expansion, meaning the GAA triplet is repeating itself way too often and the larger the copy the more likely the person will have the disease. There is one solution, Idebenone is a treatment that is approved in Canada. I would propose that do a PCR gel on a sample of DNA. By running a PCR test we can see if the tested DNA has the mutation with GAA triplet. By doing so we can determine if the person has positive or negative for this disease.
Friedreich’s ataxia is a disease that is inherited and causes damage to the nervous system ultimately affecting the muscular system and the body’s movement. The effects of Friedreich’s ataxia are degenerations in nerve tissue of the spinal cord affecting the muscle sensory neurons directing arm and leg movement. The nerve degeneration results in gait abnormalities , to speech problems to heart disease. The Spinal cord thins out and the nerve axons loose some of their coating which causes a delayed reaction to a stimulus.
Friedreich’s ataxia is an autosomal recessive gene caused by a mutation in the FXN gene. The FXN gene codes the production of frataxin which is essential for the prober function ability of the cells mitochondria regulating the iron transportation. This mutation is caused by extra GAA repeats that cause the gene to be silenced rather than deformed.
I believe that there can be several ways to test for this gene abnormality. A PCR can be done by obtaining a small amount of the persons Dna, replicating it and then running a gel alongside a control to see if the person has the disease. Another way would be to get a Microarray slide that is specifically made for annealing to this mutation and scanning that. Other ways are to look for some of the early symptoms. Iron problems in the body usually lead to eye and liver problems, so if a person shows some of the possible symptoms that would be reason for further testing.
sources:
“Friedreich’s Ataxia.” Wikipedia, the Free Encyclopedia. Web. 06 Apr. 2011. .
Friedreich’s Ataxia, abbreviated FRDA, is a hereditary neurodegenerative disease. Studies have shown that the main cause of this disease pertains to a mutation in the “mitochondrial protein frataxin”. FRDA is caused by a repeat in the genetic sequence of the gene for the frataxin protein. Some mutations are very common, whereas others are extremely rare. ” The GAA triplet repeat expansion within the first intron of frataxin is the most common mutation known to cause FRDA”. As the genetic sequence repeats, the disease becomes much more fatal. FRDA directly attacks an individual’s nervous system; affecting his/her ability to walk and their control over everyday muscle movements. Any severe side effects from this disease can and will have detrimental affects on any human being.
In order to test someone for the presence of Friedreich’s Ataxia i believe that PCR, Polymerase Chain Reaction, would be the best choice. Doctors can take a blood sample from a person and concentrate and amplify it. They can then make copies of the DNA and run these copies on an Agarose gel. If positive controls for FRDA are next to the individuals DNA then it should be easy to tell if this person has FRDA.
Friedreich’s ataxia is an inherited autosomal recessive disease that causes great damages to the nervous system, which further leads to significant dysfunctions of the muscular system. Movement of the body is impaired due to the deterioration of the spinal cord and peripheral nerves. Further damages can be seen within the heart such as enlargement of the heart, myocardial fibrosis and cardiac failure, which result in symptoms such as chest pain, heart palpitations and fast heart rate. Symptoms can begin to be seen as early as 5 years of age. Both female and males can inherit this rare disease that results from a mutation of a gene locus on chromosome 9. Frataxin is a protein found in the mitochondria and is important for the use of cellular iron homeostasis and is produced by the FXN gene. When the gene is defective, there is a repeated occurrence of the DNA sequence labeled “GAA” that never stops unlike in a normal regulated FXN gene that is repeated between 7- 22 times. Some early symptoms include gait ataxia, which in time can get progressively worse and patients can develop scoliosis and loss of tendon reflexes in the knees and ankles.
There are several tests that can be taken to consideration to test for this genetic disease. Some of the tests performed include ECG, Electrophysiological studies, EMG (electromyography), Genetic testing for the frataxin gene, and Nerve conduction tests. But I feel that the best results can be conducted from a PCR, which can be used to amplify the desired sequence and identify if there is a GAA repeat nucleotide expansion.
sources:
PMID: 20413654
http://emedicine.medscape.com/article/1150420-overviewhttp://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm
Mutations are quite common in DNA replication and protein production that can ultimately lead to the development of certain diseases or malfunctions in the body. One known disease is the Friedreich ataxia which occurs in the Frataxin gene on chromosome 9. Friedreich ataxia causes muscular weakness and problems in movement. A person can inherit this disease if both parents have the gene for Friedreich ataxia. Having this disease means that the Frataxin gene has produced too many copies of the DNA trinucleotide, the repetitive GAA sequence in the intron. Since the issue is within the intron, there is an abundance of iron levels that are generated in the mitochondria. Normally, a person has 8 to 30 copies of this gene, but a person with Friedreich ataxia can receive up to 1000. People with this disease can suffer from symptoms such as muscle weakness, abnormal speech, problems with arm and feet movement, as well as poor vision and hearing loss.
Repeats of nucleotides in the intron region can lead to reduced protein levels and mutations. Changes in the intron regions can lead to duplication of certain genes, creating more than enough which will alter the protein sequence. Some amino acids may be replaced with another, also known as a missense change. Also excess amount of introns may not be spliced, allowing them to stick to mRNA, and destroying them in the end. Repeats of sequences will alter the proteins that are to be made, thus producing less when the body needs more. Friedreich ataxia results from decreased amount of proteins and large repetitions of the GAA sequence. To test whether a person has Friedreich ataxia, he or she can get an x-ray, ECG, EMG, or perform a genetic testing for the Frataxin gene using ELISA or PCR. With PCR (polymerase chain reaction), a specific DNA sequence is amplified and duplicated to see whether it has similar bands to those of the Frataxin gene. ELISA (enzyme linked immunosorbent assay) on the other hand tests for the types of proteins present in the DNA.
Sources:
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002384/
The paper we have been asked to write about is called “Understanding the molecular mechanisms of Friedreich’s ataxia to develop therapeutic approaches”. Friedreich’s ataxia is a neurodegenerative disease that effects the ability to walk, arm movement, and causes all muscles to weaken. This is disease is one of the toughest to diagnose, symptoms come about sometime between puberty and twenty-five years old. The disease is caused by the mutation of frataxin, a mitochondrial protein. The mutation causes a lower amount of frataxin to be produced in the infected and an increase in iron levels. The problem is that the majorly increased iron levels come up in a blood test as iron deficiency. While it is a tough disease to diagnosis an easy test I think is PCR. I think that the ability to test part of someone’s genes can easily show Friedreich’s ataxia in a person. The amplification of the genes would make it easy to find the disease in people and can help fight it. Maybe even in the future it could allow infected genes to be tested for a cure without the possibility of harming the person.
Friedreich ataxia or FRDA is a neurodegenerative disease, a disease that can cause problems in the brain and lead to other problems throughout the body. It is an autosomal disease that is caused by a mutation on the gene. Frataxin protein is essential to the body as it is used in iron homostasis. Little is known about Frataxin but it can be found in the mitochondria. FRDA is linked to a gene on 9q13-q21. This affects the production of the frataxin. In the mutation the GAA triplet repeats in the first intron. Since it is on the intron it causes gene silencing. On a mutated gene the GAA triplet is repeated many more times than on regular RNA. The more repeats a patient might have the more sick they could become. A way to see if a patient has the GAA repeat sequence is to run a polymerase chain reaction or PCR. This will amplify the portion of DNA needed to find out how severe the disease is. Then you would perform a gel to see exactly what it is you are dealing with.