Friedreich’s Ataxia (FRDA)
Friedreich’s Ataxia (FRDA)
What is FRDA?
Friedreich’s ataxia (FRDA) is a rare inherited genetic disorder that progressively damages the nervous system and heart. Symptoms usually begin between 5 and 15 years, causing impaired coordination, slurred speech, swallowing difficulties, sensory loss, fatigue, hearing and vision problems and spinal curvature. There is currently no cure, and many patients eventually die from heart disease.
Why is it relevant to India?
FRDA is relatively rare but is diagnosed regularly at Nizam’s Institute of Medical Sciences, Hyderabad, with about one case per month. Many affected individuals come from consanguineous marriages, which increase the likelihood of inheriting two copies of a rare recessive disease-causing variant.
Why is FRDA geographically unusual?
FRDA has historically been reported mainly among populations of European, North African, West Asian and South Asian ancestry, while it has not been reported in comparable populations from sub-Saharan Africa, East Asia and parts of Southeast Asia. A 2026 study from the University of Oklahoma Health Sciences Center, published in Human Molecular Genetics, investigated the genetic basis of this uneven distribution.
How is FRDA caused?
FRDA results from mutations in the FXN gene, which produces frataxin, a protein essential for mitochondrial function. The most common disease-causing mutation is an abnormal expansion of repeated DNA sequences within an intron of the FXN gene. While normal alleles contain relatively few repeats, disease-associated alleles may contain 100–1,500 repeats. The expanded sequence reduces frataxin production, impairing mitochondrial energy generation and causing toxic by-product accumulation, ultimately damaging energy-demanding cells such as nerve and heart cells.
How is it inherited?
FRDA is autosomal recessive. An affected individual generally inherits an expanded FXN variant from both parents. A person carrying only one expanded variant is usually unaffected but can transmit it to their children.
What did the new study find?
Researchers found that about 95% of expanded variants could be traced to just two long-normal FXN variants. These variants appear to have undergone rare ancestral changes, termed “protomutations,” in Eurasia. They gradually developed into pre-mutations and subsequently underwent rapid repeat expansion that produced disease-causing variants.
What does ancient DNA reveal?
Analysis of ancient human remains showed that both protomutations were already present in Europe and Western Asia at least 9,000 years ago, but were absent in the analysed Neanderthal and Denisovan genomes. Their limited geographical origin and distribution may help explain the present-day concentration of FRDA in particular populations.
Significance:
Understanding how these ancestral variants evolved into disease-causing expansions could help researchers identify why some FXN variants become unstable and eventually develop into FRDA, potentially opening pathways to prevent or slow the genetic progression of the disease.
