First described by Nikolaus Friedreich in 1863, Friedreich ataxia (FA) is a rare, progressive neurogenetic condition found in approximately 1 in 40,000 people worldwide. While it is relatively rare, it is the most common form of inherited ataxia. It is sometimes confused with spinocerebellar ataxia, a different group of inherited ataxias.
FA affects the function of the cerebellum, the part of the brain that helps plan and coordinate movements. When a person decides to move his or her arm, nerve cells in the brain send an electrical signal to the spinal cord, and the peripheral nerves pass the signal on to the arm muscles. As the arm moves, the person feels it moving because nerve cells there send an electrical signal back through your peripheral nerves, up to the brain. In FA, this flow of sensory information through the peripheral nerves and the spinal cord is most severely affected. Combined, these problems lead to the progressive losses of balance, coordination and muscle strength that characterize FA.
The first presenting feature of FA is typically ataxia, manifesting as a general unsteadiness when walking with increased tripping, especially in dark conditions. Over time, speech may change so it becomes more slurred (known as dysarthria), handwriting becomes less clear, and fine movements with hands and feet become harder to execute. Affected individuals become unable to stand without losing their balance, requiring assistive devices to remain mobile. Some people with FA experience stiffness and cramping in their legs, and muscles may weaken over time. Reflexes are often absent.
Other non-neurological features of the condition include hypertrophic cardiomyopathy (an increase in size of the walls of the heart, often of the left ventricle), heart arrhythmias, scoliosis, hearing loss, optic atrophy, urinary urgency, increased insulin sensitivity, and a higher tendency to develop diabetes over time.
One notable feature of FA is that it does not affect the part of the brain involved in cognition and learning. Since FA does not affect the ability to think and learn, people with FA lead active, rewarding lives. They go to college, hold careers, get married, and start families. A retrospective study of women with FA conducted at CHOP also found that they were no more likely to have a serious pregnancy complication than other women and are able to successfully carry a pregnancy to term.
We now know that while FA most commonly begins during childhood, it can present later in life, even well into adulthood. This situation, termed late-onset FA, can cause somewhat different symptoms and requires slightly different medical management.
Although there is no cure specifically for FA right now, some prescription medications and over-the-counter supplements can help manage some of the symptoms of the condition. In addition, physical therapy and regular exercise can maximize function and prolong walking. CHOP is part of a network of centers around the world devoted to clinical FA research, and many new therapeutic approaches to FA are in various stages of development. For more information on the latest research in the field, please see www.curefa.org. Also see Friedreich's Ataxia Research at The Children's Hospital of Philadelphia»
FA is caused by alterations, or mutations, in the frataxin (FXN) gene located on the long arm of chromosome 9. Genes are specific instructions for making proteins, which in turn provide structure to cells and drive the chemical reactions inside them. In the vast majority of FA cases (>95%), this alteration is a larger than normal number of DNA bases (known as the “GAA trinucleotide repeat”) in a specific region at the beginning of the gene. This series of repeats in turn acts like a roadblock to the proper reading of the gene, and prevents frataxin from being made and assembled as it should. In other cases (<5%), a change in a single DNA base can cause an error in the genetic instructions themselves, so the frataxin protein made from these instructions is not normal. In either case, individuals with FA have two altered copies of the frataxin gene, so they are unable to make the normal amount or type of frataxin. Individuals with only one altered copy of the gene are called “carriers,” and have no features of the condition whatsoever. Approximately 1 in every 120 people of Western European descent is a carrier for FA.
Scientists believe the frataxin protein regulates the levels of iron inside mitochondria, the tiny cellular powerhouses that use oxygen to convert the food we eat into energy the cell can use to function. Iron is essential for this process, but an imbalance inside the mitochondria contributes to oxidative stress, the buildup of harmful oxygen-based free radicals that damage the mitochondria and impair their working.
One theory proposes that frataxin acts like a storage depot for iron, releasing it only when needed. When frataxin is missing or defective, free iron accumulates in mitochondria and triggers this damaging oxidative stress.
Since mitochondria are needed in nearly all of the cells in the body, their damage from oxidative stress likely explains why FA affects cells of the nervous system (mostly the spinal cord and the peripheral nerves that connect the spinal cord to the body's muscles and sensory organs), heart and other tissues.
Reviewed by: David Lynch, MD, PhD
Date: March 2011