Dystonia is a neurological movement disorder characterized by sustained muscle contractions that often induce uncontrollable twisting or repetitive movements, and abnormal postures and positions. The disorder may affect the entire body or only a selected part of it, such as the eyes, neck, arms, or legs. Dystonia may also be associated with pain.¹ It tends to consistently affect the same groups of muscles, thus producing rather predictable movements over time. Initially, dystonia tends to be precipitated by specific movements or tasks, though later it can be activated by sustained movements, and in advanced stages can be present at rest.

Symptoms may arise as a result of dysfunction of the basal ganglia or thalamus, parts of the brain responsible for the modulation of movement. Because of the complexity of the condition, it may be misdiagnosed as other disorders, such as stress, stiff or "wry" neck, or a psychogenic disorder. In fact, dystonia is one of the most common movement disorders. According to the Dystonia Medical Research Foundation:

Dystonia is estimated to be six times more prevalent than Huntington's Disease, ALS, or Muscular Dystrophy . . . yet as few as five percent of the over 300,000 persons in North America estimated to be affected have been correctly diagnosed.²

Dystonia may be caused by a number of factors, but the most common identifiable cause has a genetic basis. The best example of inherited dystonia is that associated with the DYT1 gene. This gene is known to cause early-onset dystonia, but may present as many different phenotypes. Because the DYT1 mutation is transmitted in an autosomal dominant fashion, inheriting only one copy of the mutation represents a 50/50 chance of inheriting the gene abnormality.⁴ However, because there is only a 30-40% phenotypic penetrance, there may be many unaffected family members that have inherited the genetic mutation.⁴

Dystonias are usually categorized by age of onset, distribution of affected body regions, and the cause of the disease. While adult onset dystonia tends to start in the upper extremities, head or neck, and remain focal in distribution, childhood onset dystonia tends to progress from a focal to a generalized distribution, affecting most or all of the body. The causes of dystonia may be grouped into primary or secondary categories, though the specific pathophysiology of each is not fully understood:³

• Primary dystonia (previously called idiopathic dystonia or dystonia musculorum deformans) is often hereditary, although sporadic forms may occur. Early-onset primary torsion dystonia is an autosomal dominant disorder most commonly associated with the mutation of the DYT1 gene. Dystonia occurs as the sole disorder in these individuals and is not related to any other underlying neurological or medical condition.
• Secondary dystonia (symptomatic dystonia) may occur as the result of other neurological conditions. These conditions may include multiple sclerosis, Wilson's disease, perinatal ischemic injury, post-traumatic events (e.g., motor vehicle accident), or a side effect of medication.³ The most common form of secondary dystonia is tardive dystonia, which is caused by chronic use of neuroleptics, antiemetic drugs, or antipsychotic drugs.³ Other disease-causing factors include neurotransmitter abnormalities and basal ganglia dysfunction. Some ethnic groups, particularly Ashkenazi Jews, have also been shown to be inclined to certain forms of dystonia. Dystonia may be a feature of other movement disorders, such as Parkinson's disease or Huntington's disease. ⁴

Several types of dystonia have been classified according to the cause, age of onset, and body parts affected:

Early-onset dystonia (Generalized Dystonia or Primary Torsion Dystonia) usually begins in childhood or adolescence, typically around 12 years, although the age of onset can range from four to 44 years.¹⁰ Symptoms usually begin in an arm or leg and then spread to the other limbs within five years, gradually becoming more generalized in distribution.¹⁰ This causes the body to twist into abnormal positions.

Early-onset, primary torsion dystonia (PTD) is the most common and most severe form of hereditary dystonia.¹⁰ The most common mutation associated with PTD has been mapped to chromosome 9q34 in the DYT1 gene, which encodes a novel ATP-binding protein called "torsinA" whose function is not clear. The discoverers of the DYT1 gene hypothesize that:

The prominent expression of the DYT1 gene within the substantia nigra pars compacta, which provides dopaminergic innervation to the basal ganglia, implicates a disturbance of dopaminergic function in the pathophysiology of early-onset torsion dystonia.¹¹

A 3-base pair (GAG) deletion in the DYT1 gene causes the symptoms of early-onset dystonia. The disorder follows an autosomal dominant pattern of inheritance with 30-40% penetrance.¹⁰ This reduced penetrance means that 60-70% of the individuals who carry the gene will not develop the symptoms. PTD occurs in all ethnic groups, with the highest prevalence occurring in the Ashkenazi Jewish population.¹⁰ The assay for the GAG deletion in the DYT1 gene is the only genetic test commercially available for dystonia and can identify the mutation in symptomatic and asymptomatic individuals. Due to the many types of dystonia, the test cannot rule out other forms of the disease.⁴

Below is a PTD family pedigree showing the inheritance of the DYT1 gene.

According to the discoverers of the DYT1 gene,

[W]e suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early onset PTD [primary torsion dystonia].¹²

There are four main reasons an individual may want to be tested for the DYT1 "GAG" mutation:

1. A positive test result will help provide an answer for a symptomatic individual. This can help establish a prognosis and lead to appropriate patient management. Due to the reduced penetrance, not all individuals who have the DYT1 mutation develop the symptoms of dystonia.⁴ In the absence of a positive family history for the DYT1 mutation, a negative test result does not necessarily rule out another inherited form of dystonia.⁴
2. Other family members of the affected individual can obtain information as to whether or not they have the DYT1 mutation. This knowledge can help them, and their physicians, determine their risk for developing the symptoms associated with dystonia.
3. A positive test for the DYT1 mutation can allow for genetic counseling and family planning. Genetic counseling is important in helping individuals and family members understand what is involved in a genetic test, how to interpret the results, and what a positive result means.
4. Some medications may be contraindicated in patients with dystonia. Dopamine receptor blocking agents (DRBAs) are a class of drugs that can cause and/or aggravate existing dystonia.¹ Therefore, knowing that an individual may have dystonia will help them avoid the detrimental effects of DRBAs. This class of drugs includes many antipsychotic medications and medications for the treatment of nausea and vomiting. For a list of DRBAs visit www.wemove.org/dys_mdmc.html.

Dystonia is a neurological movement disorder that continues to be misunderstood. The clinical presentation of dystonia can be confusing since its symptoms can also be caused by other disorders. Because of the clinical complexity of the disease, genetic testing can be useful in diagnosing and establishing a prognosis for dystonia. Identifying the type of dystonia can help determine the appropriate therapy to use. Increasing awareness of the disorder and its clinical signs will improve patient management and help physicians to direct individuals to support groups and other resources.