Muscular dystrophy and multiple sclerosis are probably the two most well-known movement disorders. As a result, they have received a lot of research funding, enabling medicine to move closer to finding effective treatments and cures. There is a movement disorder, however, that is just as serious, but often neglected. Ataxia is a movement disorder that makes patients’ lives extremely difficult, yet is unheard of by many people. As a result, research into treatments is significantly far behind. Awareness of ataxia must be increased in order to drive the research that will improve the lives of its sufferers.
The word ataxia comes from the Greek “a taxis,” meaning “without order” (1). Ataxia is a disease in which a person’s movement is uncoordinated. The severity varies from case to case, but all forms of ataxia are characterized by difficulty in controlling balance and movement. The most obvious symptom of ataxia is an unbalanced gait that often gives people the appearance of being intoxicated. People with the condition often walk with their feet further apart than is typical in what is clinically called a “broadened base” (2) to compensate for poor balance. Ataxia may also affect the coordination of the hands and fingers, resulting in poor fine motor skills such as writing. Speech may be slurred and eye movements may be slower than normal, leading many people to believe that people with ataxia are mentally retarded. More sever forms of ataxia may cause serious swallowing and respiratory problems (1).
Ataxia may be caused by infections, injuries, or genetic factors that cause degenerative changes in the central nervous system. Those forms caused by disease or injury are known as sporadic ataxia and are not very common. The more usual forms of ataxia are hereditary and may be either dominant or recessive. The relevant genes are located on autosomal chromosomes and so affect males and females equally. Dominantly inherited ataxias are usually less severe, and most people do not show symptoms until their twenties or thirties, or even as late as their sixties. Recessively inherited ataxias, such as Friedreich’s Ataxia (FA), are more serious and usually begin during childhood. They are more degenerative than dominant and sporadic ataxias and are more likely to lead to death. FA in particular is associated with serious cardiac problems (1).
All forms of ataxia affect the cerebellum, the part of the brain controlling balance and coordination. Ataxias that are pure cerebellar only affect balance and coordination. Some forms may also affect the basal ganglia and the spinal cord. These forms are referred to as cerebellar plus ataxia or spinocerebellar ataxia and may cause neuropathy (dysfunction of the peripheral nervous system), dementia, weakness, rigidity, and spasticity (1).
Until fairly recently, ataxia was thought to be strictly a movement disorder. Further studies have shown that more advanced cases may have cognitive and emotional effects. The cerebellum, once thought to deal solely with movement, is now understood to be involved in many processes within the brain. It contains more neurons than the rest of the brain combined, and processes information faster than any other part of the brain. It is connected to the cerebral cortex by an estimated forty million nerve fibers, receiving information from sensory, motor, cognitive, language, and emotional areas (3). In addition to motor functions, the cerebellum helps control skilled mental performance, sensory acquisition, discrimination and categorization, tracking, prediction, and task sequences (4). As a result, any damage to the cerebellum may result in impaired memory of newly learned information and procedures, and problems with “executive functions” such as planning and keeping thoughts in the proper order. Patients may also experience an increase in irritability, anxiety, and depression (2).
The part of the cerebellum most affected by ataxia is the layer of Purkinje cells. Each fold or “folium” of the cerebellum can be separated into three layers, the middle of which is made up of large, flat neurons called Purkinje cells. These cells are essential for relaying information within the cerebellum. They have highly branched dendrites that receive hundreds of thousands of inhibitory and excitatory impulses to process. Their myelinated axons extend through the white matter to synapse with the central nuclei of the cerebellum, the only cortical neurons to do so. They are responsible for processing efferent impulses from the motor cortex (5). It is when these cells die or become damaged that the cerebellum is unable to function properly.
Drug treatments do exist for ataxia, but they have been largely unsuccessful so far. A few forms of ataxia are linked to deficiencies of vitamin E and coenzyme Q10. Drug treatments have proven effective for these types, but such ataxias are very rare and less serious than the more prevalent ones (2). Amantadine has been shown to slow the progress of ataxia in some people and to increase energy levels, though the results do not appear to apply to the entire ataxia population (2). In addition, GABAergic agents may reduce cerebellar tremors, but are not effective for treating ataxia symptoms as a whole (2).
Genetic studies have brought further insight into the causes of hereditary ataxia, but are still a long way from developing treatments. In 1993, the first gene, Spinocerebellar Ataxia Type 1, or SCA-1, was identified by researchers at the University of Minnesota and Baylor College of Medicine. This gene is linked to certain dominant forms of ataxia. Located on chromosome six, this particular gene appears to cause ataxia when repetitions of the CAG codon are above forty (6). More repetitions are linked to earlier onset. Genes through SCA-28 have been found since then, suggesting that it may take the combined influence of several genes to trigger the onset of ataxia (1). Fewer genes have been discovered for recessive ataxia, though one has been found that suggests treatment possibilities for FA.
In one study, a number of proteins linked to ataxia were tagged. Many of these proteins revealed cellular pathways that may lead to Purkinje cell death if misfolded due to genetic mutations (7). Another study successfully reactivated the frataxin gene in a cell culture, a gene that is often deactivated in patients with FA (8). Though this is still a long way from a cure, this achievement suggests that it may be possible to use a virus vector in stem cells or to develop a pill that will reactivate the frataxin gene in people with FA.
The area of research that currently holds the most promise is the controversial idea of stem cells. If it were possible to grow new cerebellar neurons, particularly Purkinje cells, it would be possible to treat all forms of ataxia. Unfortunately, viable neurons have not been successful grown from adult stem cells. Embryonic stem cells have to ability to differentiate into any type of cell, but adult stem cells have more limited capabilities. Ethical concerns hold back much of the research on embryonic stem cells, so more focus is on adult stem cells. Stem cells do exist within the adult hippocampus which, given the proper chemical signal, can differentiate into different types of neurons, however the chemical signal for Purkinje cells in not currently known. Purkinje cells develop when the embryo is roughly ten days old and do not typically develop any more after that, making it very difficult to force adult stem cells to differentiate into them (1).
Another problem is that stem cells must be genetically similar to the host to prevent rejection. One solution is to use cells from a sibling, specifically cord blood from an infant, which is full of stem cells, but there is only a one in four chance that the major immune determinant genes will be the same (9). The better, though more controversial, method is therapeutic cloning. In this procedure, the patient’s DNA is transferred to one of her own egg cells (or his or her mother’s). This egg is then grown as a “synthetic embryo” and harvested for stem cells (9). The problem is that the cells would still have the original mutation, and, with the exception of the frataxin gene, it is not yet known how to correct these mutations. This is an area that must be further explored before a cure can be created.
Stem cell research has given way to a still experimental treatment for one type of ataxia. In 2005, Angie McDonald, a sufferer of FA, underwent the first stem cell treatment for ataxia (10). The treatment consisted of injecting stem cells from umbilical cords into the bloodstream and the base of the skull. Though the procedure did not eliminate her symptoms, it did decrease their severity and gave her more energy. In an interview with BBC news a year later, she said the effects were wearing off, but she planned to receive another treatment (11). Though this is still very new and by no means a cure, it may be possible in the coming years that more forms of ataxia will at least be treatable by this method.
Research on ataxia is highly under-funded as most governments place it low on the priority list. Very few people have even heard of the disease, including many medical professionals. Though the disease in uncommon (approximately 15,000 Americans have it (1)), it is much more prevalent than was once believed. Many people have been misdiagnosed by their physicians, because it is so often forgotten as a possibility. Because of the ignorance of the public, many people with ataxia suffer prejudice. The unbalanced gait of ataxia gives people the appearance of being drunk. Police officers often do not accept ataxia as a valid reason for failing motor control tests, because so few have heard of it. Many people with ataxia must wear medical alert tags to prove that they actually have a medical condition (12). Children in particular suffer from the stigmas of ataxia. Since it so often goes undiagnosed in children, they may be scolded for sloppy handwriting and clumsiness mistaken for carelessness.
In order to educate the public about ataxia and the importance of research, International Ataxia Awareness Day (13) was created. This day, September 25th, is intended to teach people about ataxia and to encourage them to donate to ataxia research. Nearly all research done on ataxia so far has been funded by volunteers, because governments give so little support. Volunteers are also needed to donate money for specialized computers, communications and mobility aids, and home adaptations.
Ataxia needs to be recognized for the serious disease it is. More effort should be made to educate the public about this condition. Emphasis on this disease will help encourage donations to support research on an often neglected illness that is, nevertheless, still a serious problem for many people. As stem cell research progresses, more ways are found to use adult stem cells, rather than embryonic stem cells. This research must continue so that safe, ethical treatments and cures can be developed for this debilitating disease.