Two ancient Eurasian mutations explain why Friedreich's ataxia spares East Asia and Africa

Friedreich's ataxia, an incurable genetic disorder that progressively damages the nerves and the heart, occurs in people of European, North African, West Asian and South Asian descent but has not been reported from sub-Saharan Africa, North America, China, Japan or Southeast Asia. A new study from the University of Oklahoma Health Sciences Center, published June 9 in Human Molecular Genetics, explains why.

Symptoms begin between the ages of 5 and 15: patients grow unsteady, speech slurs, swallowing becomes difficult, hearing and vision fade, and most die relatively young of heart disease. The Nizam's Institute of Medical Sciences in Hyderabad diagnoses one case a month — almost all in people born of consanguineous marriages, marriages between relatives, which raise the risk of rare diseases, says geneticist Ashwin Dalal.

The cause is a mutated FXN gene, which codes for frataxin, a protein essential for mitochondria, the cell's energy-producing structures. Normal variants carry a short DNA sequence repeated 5-11 times ('short normal') or 12-33 times ('long normal'); in patients the count balloons to 100-1,500. Expanded variants force the chromosome into a closed shape that cuts frataxin production, crippling energy-hungry nerve and heart cells. The disease needs an expanded copy from both parents.

The study found 95% of the expanded variants descend from just two long-normal variants that mutated — twice in history, both in Eurasia. These 'protomutations' first became pre-mutations, with high but not yet disease-causing repeat counts, before expanding fully within one or a few parent-to-child transmissions. Because patients die early, disease variants keep vanishing; symptomless pre-mutation carriers act as reservoirs that replenish them. East Asian populations lack long-normal variants, possibly why the mutations never arose there.

Ancient DNA showed both protomutations existed in Europe and Western Asia at least 9,000 years ago, but not in Neanderthals or Denisovans. Team leader Sanjay Bidichandani credited the tradition of freely sharing DNA data as crucial to tracking susceptibility from prehistoric humans to present-day populations.