Ataxia, a medical term originated from the Greek language meaning "without order," refers to disturbances in the control of body posture, motor coordination, speech control, and eye movements. Several brain areas, including the cerebellum and the spinocerebellar tracts, substantia nigra, pons, and cerebral cortex control these functions. Injuries in one or more of these areas or in the spinal cord may lead to some form of ataxia. Birth trauma, medication toxicity, drug abuse, infections, tumors, degenerative disorders, head injury, stroke , or aneurysm, as well as hereditary neurological disorders also may cause ataxia. Many different types of inherited ataxias are presently known. Examples include Machado-Joseph disease , ataxia-telangiectasia , and Friedreich ataxia .
Among children without inherited neurological disorders, important causes of ataxia are medication toxicity and post-infection inflammation of the brain. The later may happen as a complication of other viral diseases, such as measles, chicken pox, or influenza. While most people recover completely, some can have permanent neurological deficits.
Accidental ingestion of some drugs may cause ataxia, seizures , sensory neuropathies, or coma and death. The chronic administration of antihistamine medication and anticonvulsive drugs may cause ataxia in children, and should not be administered without instruction of a healthcare provider. Ingestion of seafood contaminated with high levels of methyl-mercury also causes ataxia, as does accidental ingestion of solvents. Some drugs used in treating certain types of tumors, such as those in colorectal cancer, are especially neurotoxic and can induce temporary, but usually reversible ataxia. Alcoholism, metabolic disorders, and vitamin deficiencies may also lead to ataxia.
Non-hereditary ataxia is known as sporadic or acquired ataxia. Approximately 150,000 people in the United States alone are presently affected by ataxia, either the acquired or hereditary form. Friedreich ataxia is the most common inherited ataxia, occurring in 1 out of 50,000 population.
Causes and symptoms
Ataxia may be a consequence of brain trauma, stroke, or aneurysm. Chronic and progressive ataxia is generally associated with either brain tumors or with one of the several types of inherited neurodegenerative disorders affecting one or more brain areas involved in movement and coordination control. Other neurodegenerative disorders, such as Parkinson's disease and multiple sclerosis , may present cerebellar and/or gait ataxia as one of the clinical signs. Another cause of either chronic or progressive ataxia is the congenital (present at birth) malformation of some structures of the central nervous system .
Hereditary ataxias are rare diseases, divided into two main categories according to the pattern of inheritance: autosomal dominant ataxias and autosomal recessive ataxias. Hereditary ataxias are additionally classified into types according to the affected structures and gene location of the defective chromosome. Autosomal dominant inheritance requires the presence of the mutation in only one of the two copies of a gene (maternal or paternal) to trigger the onset of the disease at some point in life, whereas autosomal recessive inheritance requires the inheritance of the mutation in both maternal and paternal genes. Other forms of hereditary ataxias are associated with metabolic disorders, such as the Maple Syrup Urine Disease, Adrenoleukodystrophy , and Refsum disease .
Autosomal Dominant Cerebellar Ataxias (ADCAs) are a group of ataxias divided into Types I, II, and III, according to the symptoms involved. Spinocerebellar ataxias (SCAs) Type 1, 2, 3, 4, 5, 6, 7, 10, and 11 belong to the ADCA group. Dominant Spinocerebellar Ataxias (SCAs) have several overlapping clinical signs, and a common feature to those belonging to the ADCA group is cerebellar ataxia, which manifests in difficulty walking and speaking. SCA1, 2, 3, and 4 may also involve partial paralysis of the eyes, slow eye movements, poor motor coordination, dementia , peripheral neuropathy (pain , numbness, or tingling sensation in the extremities of limbs and hands), optic neuropathy, and deafness. All of these symptoms are not necessarily present. SCA2 and SCA7 may also result in retinal damage, whereas those with SCA10 exhibit loss of muscle control and generalized seizures without other symptoms.
SCA1 is caused by an abnormal gene expression located on chromosome 6. Genes consist of several different protein sequences, each coding (providing instructions) for one specific amino acid. A sequence error or abnormal repetition of a nucleotide (a building block of DNA and RNA) in a given gene impairs adequate protein synthesis or results in a wrong protein. In SCA1, abnormal amounts of the nucleotide CAG lead to symptoms such as eye-muscle dysfunction and increased tendon reflexes. The onset of symptoms usually occurs around the age of 30, or during the fourth decade of life. Increased amounts of CAG occur in each new generation, resulting in symptoms that usually appear earlier in life. SCA1 is also known as Spinocerebellar Atrophy I, Olivopontocerebellar atrophy I, and Menzel Type ataxia.
SCA2 is associated with abnormal gene expression on chromosome 12. Major symptoms include Parkisonism (tremors and spasticity ), myoclonus (muscle spasms), Pons atrophy, and slowing of eye movement. SCA2 is subdivided in Episodic Ataxia Type 1 or EA1 (also named Paroxysmal and Myokymia syndrome) and Episodic Ataxia Type 2 or EA2. The onset of EA1 occurs in general around the five to six years of age, with muscles quickly becoming flaccid or rigid, tremors in the head or in the limbs, blurred vision, and/or vertigo. The severity of these episodes varies, and episodes usually last for about ten minutes, although in some cases they may last for as long as six hours. These episodes are generally triggered by stressful situations, anxiety, and abrupt movements, and also occur spontaneously due to a metabolic dysfunction. EA2 symptoms usually begin during school years or adolescence. The crisis starts with vertigo and ataxia, and is often associated with involuntary eye movements. This condition is treatable with daily administration of acetozolamide. When untreated, crisis may occur a few times per month, lasting from 1 to 24 hours. However, most affected individuals will experience a decrease in intensity and number of crises as they mature.
SCA3 ataxia is also known as Machado-Joseph disease and the gene affected is on chromosome 14. Dystonia (spasticity or involuntary and repetitive movements) or gait ataxia is usually the initial symptom in children. Gait ataxia is characterized by unstable walk and standing, which slowly progresses with the appearance of some of the other symptoms, such as abnormal hand movements, involuntary eye movements (i.e., nystagmus), muscular wasting of hands, and loss of muscle tone in the face. SCA3 symptoms greatly vary among affected individuals as does the age of onset. Higher numbers of the CAG nucleotide repeats is associated with earlier onset and more severe symptoms. In addition, the number of CAG repeats tends to increase in each new generation, causing earlier onset and increased severity. There is no cure for Machado-Joseph disease.
SCA4 ataxia's genetic defect is located on chromosome 16, and results in major symptoms of cerebellar ataxia and sensory abnormalities. SCA4 may occur in two different forms, type I or type III. Both forms present symptoms 5–7 years earlier per generation. Symptoms usually become evident in type 1 from ages 19 to 59 years; from 45 to 72 years in type III. Difficulty walking, loss of muscle control, loss of fine-movement coordination of hands, and absence of tendon reflexes are the main symptoms observed in this progressive and crippling condition.
SCA5 ataxia is an extremely rare disorder linked to a defect on chromosome 11. Symptoms include mild ataxia and speech disorders. SCA5 ataxia was identified in one family descending from the paternal grandparents of Abraham Lincoln.
SCA6 ataxia is caused by a mutation on at chromosome 19. Clinical signs are varied, with some patients having limb and gait ataxia along with episodic headaches or nausea, and others having gait ataxia, speech difficulty, and abnormal eye movements. Initially, most patients only sense a momentary imbalance and mild vertigo when they make a quick movement or turn. After months or years, balance problems become more pronounced. The disease progresses over 20–30 years and eventually leads to severe disability. The age of onset ranges from 6 to 86 years. Periodic episodes of paralysis occur on one side of the body and last for days. Episodes may be triggered by head injuries and emotional stress. Some persons with SCA6 ataxia experience a more rapid progression and require wheelchair for support and mobility approximately 5 years after onset.
SCA7 ataxia is also known as olivopontocerebellar atrophy III, and results from a defect on chromosome 3. Symptoms of SCA7 ataxia occur earlier with each generation, and earlier onsets are associated with more severe symptoms. The onset of symptoms occurs in younger ages when the mutated copy of the gene is inherited from the paternal side. Ataxia, severe eye problems (retinal and macular degeneration), and early blue-yellow color blindness are typical clinical signs of the disease. Decreased vision occurs in over 80% of individuals with SCA7 ataxia, and almost one third of these persons eventually become blind. Hearing loss is also associated with SCA7 ataxia, and may slowly progress over decades. In more severe cases, usually associated with paternal inheritance of the defective gene, heart failure, liver disorders, muscle loss, and developmental delays can all occur. The degree of severity of SCA7 ataxia, the age of onset, and the rate of progression greatly vary both within and among families.
SCA10 ataxia is caused by an unstable protein repeat on chromosome 22. The main characteristics of SCA10 are generalized motor seizures, irregular eye movements, gait and limb ataxia, and speech difficulties. The age of onset ranges from 10 to 40 years. SCA11 ataxia is a very rare disease, mapped to chromosome 15. SCA11 progresses slowly over decades, with onset between adolescence and young adulthood. All individuals develop gait disorders, increased reflex action, eye disturbances and irregular movements, and speech difficulties.
Some inherited metabolic disorders cause progressive nerve degeneration with ataxia as one of its symptoms, as is the case with the group of diseases known as leukodistrophies. One famous example is Adrenoleukodystrophy (ALD), a rare autosomal dominant disease that causes progressive loss of the myelin sheath that covers the nerve fibers, along with progressive adrenal gland degeneration. ADL has two forms: the X-linked ADL (or X-ADL) and the non X-linked ADL (or ADL). The X-ADL is the more devastating form of the disease, with the onset of symptoms occurring between four and ten years of age. ADL (non X-linked) disease usually begins during adulthood, between 21 and 35 years of age and progresses slowly. In both forms of ADL, the loss of myelin by nerve fibers is due to an abnormal accumulation of saturated long fatty acid chains in the brain, because of a metabolic error involving a protein that transports fatty acids. The gene responsible for X-ADL was identified in 1993. The disorder was presented in the film Lorenzo's Oil, based on the story of Lorenzo Odone and his parents' quest to find a cure for the disease. Other X-ADL symptoms are seizures, speech and swallowing difficulties, gait and coordination ataxia, visual loss, progressive dementia, and loss of hearing that ends in deafness. As the mutation is inherited in the X chromosome, ADL is more severe in boys than in girls, because females have two X chromosomes, and the normal copy (or allele) of the affected gene will compensate for the dysfunctional one. Treatment with adrenal hormones can save the child's life and Lorenzo's oil, a mixture of oleic and euric acids, reduces or delays the onset of symptoms in carriers of the mutation without manifested symptoms. Oral intake of DHA (docosahexanoic acid) is prescribed for children and infants with X-ADL. As the neurological degeneration is progressive, prognosis is usually poor with patients dying within 10 years from the onset of symptoms.
Another metabolic disorder causing ataxia is the maple syrup urine disease or MSUD, an inherited disease caused by a metabolic disorder involving the breakdown of certain amino acids by enzymes. MSUD may occur in three different forms: neonatal convulsive crisis (classical form); progressive mental retardation (intermediary form); or recurrent ataxia and encephalopathy (intermittent form). The disease was first discovered in the Mennonite Community of Lancaster, PA, where MSUD affects 1 out of 176 individuals, although it is rare in other populations. MSUD onset may occur between five months of age and the second year of life. During crisis, the urine presents an odor similar to maple syrup and the blood shows high levels of branched amino acids and ketoacids. Between crises, such concentrations are normal both in urine and blood. Severe crises with high concentrations of ketoacids may be life threatening, requiring dialysis. The standard treatment is protein restriction in the diet; but some patients who respond to the administration of thiamine during crises may benefit from the intake of thiamine on a daily basis.
Refsum disease is caused by a dysfunction in the metabolism of lipids that leads to high concentrations of phytanic acid in tissues and blood plasma. Phytanic acid is a component of chlorophyll, obtained through the diet. The enzyme phytanic acid hydrolase normally helps eliminate phytanic acid from the body. The inheritance is autosomal recessive, and the onset may occur between the first and the third decade of life. One of the first symptoms is night blindness, but the pace of progression varies among affected individuals. Other main symptoms are irregularities in the retina of the eye, bone and skin changes, and the abnormal gait, speech patterns, and muscle movements associated with cerebellar ataxia. Treatment involves dietary restrictions and blood transfusion exchanges aimed at halting the progression of the disease and resolving symptoms.
Friedreich ataxia is the most common form of hereditary ataxia, affecting 1 out of 50,000 individuals. Friedreich ataxia is a progressive disorder affecting the arms and legs, with progressive weakness, loss of deep tendon reflexes, and sensory loss. Diabetes and/or some forms of heart disease may also be present in people with Friedreich ataxia. Onset of symptoms usually occurs before 20 years of age. As symptoms of Friedreich ataxia are similar to those found in other juvenile ataxias, diagnosis requires genetic testing to conform.
Genetic forms of ataxia must be distinguished from the acquired (non-genetic) ataxias. Diagnosis of inherited ataxias begins with the analysis of the clinical family history, physical examination, and neuro-imaging techniques such as CT or MRI scans. As similar symptoms are described in many different types of ataxia, genetic screening is the most reliable tool for diagnosis. Genetic tests for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17, episodic ataxia type 1, episodic ataxia type 2, DRPLA, Friedreich ataxia (FRDA), and Charlevoix-Saguenay ataxia are available.
Neurologists and geneticists are the front line treatment team for people with ataxia, along with specialized nurses and therapists. Both neurologists and geneticists usually participate in the diagnosis of the particular form of ataxia. Neurologists and other physicians provide treatment for the resulting symptoms. Genetic counseling and risk assessment of individuals without symptoms, but with a family history of the disease, is the task of the geneticist.
Except for some acquired and reversible forms of ataxia as initially described, there is no cure or preventive treatment for the progressive forms of the disease, or for those ataxias resulting from accidental lesions of motor brain areas and/or the spinal cord. Antispasmodic and/or anticonvulsive medications, and analgesics for some painful neuropathies, may control and relieve the respective symptoms in some ataxia subtypes. Wheelchair, walking devices, and speech aids may be required in different stages of the progressive forms of ataxia.
Recovery and rehabilitation
Whether the ataxia is an acute condition that is likely to improve, or a progressive disease, therapy is aimed at maintaining the highest practical level of muscle function and coordination. Physical therapists provide strengthening exercises where muscle tissue integrity is likely to return or plateau, and range of motion exercises where muscle movement is limited. Gait training is also an important part of rehabilitation for persons with ataxia, as physical therapists help persons adapt to abnormal muscle movements, while safely maintaining posture and walking. As the disease progresses, the goals of therapy adapt to the person's changing abilities. Speech therapists help assess difficulties with speaking and eating, and offer strategies to compensate for them. Occupational therapists also make positional devices available to help maintain posture and comfort.
Further basic research is needed before clinical trials become a possibility for this group of neurodegenerative diseases. Ongoing genetic and molecular research on the mechanisms involved in the disease will eventually yield enough data for the development of further diagnostic markers and, hopefully, allow the design of experimental gene therapies to treat many of the inherited ataxias.
The prognosis for a person with ataxia depends upon the type and nature of the disease. Ataxia as a result of trauma or infection may be a temporary condition, or leave some degree of permanent disability. Hereditary ataxias are usually progressive syndromes, with symptoms becoming more disabling over varying periods of time.
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National Organization for Rare Disorders (NORD). P.O. Box 1968 (55 Kenosia Avenue), Danbury, CT 06813-1968. (203) 744-0100 or (800) 999-NORD (6673); Fax: (203) 798-2291. [email protected] <http://www.rarediseases.org>.
Worldwide Education & Awareness for Movement Disorders (WE MOVE). 204 West 84th Street, New York, NY. (212) 875-8312 or (800) 437-MOV2 (6682). Fax: (212) 875-8389. [email protected] <http://www.wemove.org>.
a·tax·i·a / əˈtaksēə/ (also a·tax·y / əˈtaksē/ ) • n. Med. the loss of full control of bodily movements. DERIVATIVES: a·tax·ic / -sik/ adj.