Friedreich’s ataxia, or FRDA, is a genetic disorder that progressively damages the nerves and the heart.
The affected individuals typically begin to show symptoms between the ages of 5 and 15. They become unsteady and their coordination is impaired. Their speech slows down and slurs. Swallowing becomes difficult. Hearing and vision deteriorates. They feel fatigued, lose sensation, first in the arms and legs, then in the trunk and other parts of the body, and the spine curves to one side. Eventually, most patients die relatively young, of heart disease. There is no cure.
According to Ashwin Dalal, a medical geneticist at the Nizam’s Institute of Medical Sciences in Hyderabad, the institute diagnoses one case of FRDA every month on average — and almost all of these individuals come from consanguineous marriages. That is, marriages between relatives, such as uncles and nieces, or between cousins. Many Indian communities practice consanguinity — and it greatly increases the risk of genetic diseases that are otherwise rare. Friedreich’s ataxia is one such disease.
Curiously, so far, FRDA has not been reported in people from sub-Saharan Africa, North America, and China, Japan, and Southeast Asia. For a long time, scientists have only found it in individuals of European, North African, West Asian, and South Asian descent.
A new study from researchers at the University of Oklahoma Health Sciences Center in the U.S. has finally cracked the puzzle. Their findings were reported in June 9 in the journal Human Molecular Genetics.
Inefficient powerhouses
FRDA is caused when a gene called FXN becomes mutated.
The FXN gene codes for a protein called frataxin. Frataxin is essential for mitochondria, which are our cells’ powerhouses. The chemical ATP, which is the cell’s energy currency, is made mostly in the mitochondria. Nerve, spinal cord, brain, and heart muscle cells use a lot of energy. When their frataxin levels become abnormally low, the mitochondria produce ATP less effectively and also accumulate toxic by-products. This renders the cell dysfunctional, leading to the symptoms of FRDA.
Structure of the frataxin protein.
| Photo Credit:
Emw (CC BY-SA)
The most common disease-causing mutations occur in a part of the FXN gene called the intron. A mutation takes the form of modifying the number of times a particular sequence of bases is repeated in the intron. Normal variants of the FXN gene contain 5-11 or 12-33 repeats. They’re called the short normal and long normal variants. The short-normal variant is common in Europe and South Asia (85-90% of the population), sub-Saharan Africa (90%), and East Asia (over 99%). The long-normal variants are absent in East Asia and make up most of the rest in sub-Saharan Africa and in Europe and South Asia.
However, the DNA sequences of people with Friedreich’s ataxia revealed their FXN alleles variants had 100-1,500 repeats. The researchers called them expanded variants.
The short-normal and long-normal variants have an open structure in the chromosome that allows cells to make frataxin as needed. However, the expanded variants forced the chromosome to assume a closed shape that reduced frataxin expression.
Individuals who develop Friedreich’s ataxia carry two copies of the expanded variant, one from each parent. A person with only one copy is called a carrier. Even though they themselves won’t have the disease, carriers can pass their defective introns to their children.
Fortunately, genetic tests can find out if a person is a carrier and whether they passed their extended variant to their children.
From mutation to disease
The researchers also found that 95% of the expanded variants of the intron originally came from just two long-normal variants. Specifically, they reported that at two times in history, a long-normal variant mutated to an extended variant, both times in Eurasia. We don’t know why these events happened nor why only long-normal variants mutated this way. We also don’t know why this never happened in sub-Saharan Africa. On the other hand, the absence of long-normal variants in East Asian populations could explain why these problematic mutations didn’t arise there.
Scoliosis is a common complication of FRDA.
| Photo Credit:
Bricelyn H. Strauch/JHU
These originator mutations, which the researchers called protomutations, didn’t straightaway lead to Friedreich’s ataxia. Instead, they slowly but steadily changed into pre-mutations — where the number of repeats was abnormally high but not enough to significantly impair frataxin expression.
The non-disease-causing but still abnormal pre-mutations turned into an extended variant in a sudden burst of repeat expansion in a single or few parent-to-child transmissions.
Recall that people with Friedreich’s ataxia die earlier. So over time, the extended variants disappear from the population. People with protomutations and pre-mutations on the other hand did not present that risk. As a result, they acted as ‘reservoirs’ in the population that steadily replenished the depleting extended variants over time.
Taken together, the patchy distribution of protomutations can explain why Friedreich’s ataxia occurs only in some populations. The protomutations arose only a few times and only in populations with a sufficient number of the long-normal variants.
Ancient DNA
Finally, by analysing DNA from the skeletal remains of individuals who lived in ancient times, the researchers also found both the two protomutations were present in Europe and Western Asia at least 9,000 years ago. However, they were not seen in the Neanderthals and Denisovans.
In a statement, research team leader Sanjay Bidichandani credited “the longstanding tradition in the human genetics community of freely sharing DNA sequence data” to be “crucial to accurately track the presence of susceptibility to Friedreich’s ataxia from prehistoric humans to a wide variety of extant populations”.
These findings will help scientists understand what makes the two protomutations different from other long-normal variants that don’t turn into pre-mutations. This answer in turn will help find ways to prevent or at least slow down the genetic changes.
D.P. Kasbekar is a retired scientist.
Published – August 17, 2026 09:00 am IST
