Dystonias Caused by DYT1 Gene Mutation

Most cases of early-onset primary dystonias, which may become symptomatic during childhood or early adulthood, are due to mutations of a gene known as DYT1. This gene has been mapped to the long arm of chromosome 9 at 9q34.1. This form of primary dystonia is also known as Dystonia musculorum deformans (DMD). Other forms of DYT1 dystonia include...

• Early-onset primary dystonia
• Idiopathic torsion dystonia (ITD)
• Primary torsion dystonia
• Primary generalized dystonia

To avoid confusion with other primary dystonias, researchers suggest that this form of the disorder should be referred to as DYT1 dystonia or Oppenheim dystonia, after the researcher who first identified the disease.

The mean age of onset of DYT1 dystonia is approximately 12 years. Symptoms rarely begin after the age of 29 years. In approximately 90 to 95 percent of cases, symptoms begin in a leg or an arm, and then spread to other regions of the body. Patients whose symptoms initially involve a leg tend to have an earlier age of onset than those whose symptoms initially affect an arm. Symptom onset involving a leg is also associated with an increased likelihood that the condition will evolve to generalized dystonia. The rate of progression to generalized dystonia typically occurs more quickly in patients with leg onset compared to those with initial arm involvement. Although the rate of progression is extremely variable from patient to patient, it usually is more rapid within the first 5 to 10 years following symptom onset.

For patients with initial arm involvement, dystonic spasms first appear when performing specific activities, such as writing or playing a musical instrument. As the disease progresses, dystonic symptoms occur with other unrelated activities of the arm and be provoked by the actions of other body parts. This phenomenon is known as overflow. In some affected individuals, walking causes the arm to move backward behind the body. Eventually, dystonia may be present even when the arm is at rest, potentially leading to a sustained, twisted position or posture. For those with symptom onset in the arm, dystonia tends to progress to the other arm or nearby areas of the upper body and neck. There is about a 50 percent chance of progression to generalized dystonia.

In contrast, for patients with initial leg involvement, there is an approximate 90 percent chance of progression to generalized dystonia. Those with leg onset develop distinctive gait abnormalities, such as unusual twisting or swinging of the leg as it is moved forward; however, these symptoms may not occur with other activities, such as dancing, running, or walking backward. The hip may also be extended or abducted in an outward position. The foot may swing and elevation or extension of the knee may be present. In some patient, inward turning of the heel and upward bending of the sole of the foot (equinovarus deformity) is associated with difficulty positioning the heel on the ground. In addition, severe flexion of the trunk may result in a "bent over" posture with extension of the neck. As the disease progresses, dystonic spasms occur with less specific activities of the leg and are triggered by actions of other parts of the body (overflow). Eventually, symptoms are present even when the leg is at rest, resulting in abnormal, sustained positions or postures.

As DYT1 dystonia progresses, symptoms may spread to involve other areas of the body, particularly in those patient with initial leg involvement. The dystonia may eventually become segmental and then generalized in nature, with distortion of affected regions. In such cases, associated findings may include...

• Involvement of the neck (cervical dystonia or CD), including jerky head movements. The head may become temporarily tilted or twisted (torticollis) in a sideways, forward, or backward position. These episodes may become more sustained as the disease progresses.
• Twisting movements or abnormal posturing of the upper body and severe bending of this area. This posturing may result in a fixed sideways curvature of the spine, known as scoliosis. In addition, there may be pronounced inward spinal curvature of the lower back, known as lordosis as well as twisting of the pelvis.
• Difficulty walking or eventually the inability to walk, in some cases.

In rare cases, difficulties in speech or dysarthria may develop along with facial grimacing. However, the throat (pharynx), vocal cords, face, and tongue, tend to remain unaffected.

The DYTI gene
DYT1 dystonia is an autosomal dominant disorder, meaning that it may be manifested in some individuals who have a single copy of the mutated DYT1 gene. However, the disorder has reduced penetrance. In other words, not all individuals who carry the gene mutation will develop DYT1 dystonia. Evidence suggests that 30 to 40 percent of those with the mutated DYT1 gene have symptoms of the disorder; thus, most people with the mutated gene do not develop symptoms of dystonia.

Although most individuals with DYT1 dystonia are affected by early limb-onset dystonia, disease severity may vary greatly from patient to patient. In other words, the DYT1 gene has variable expressivity, meaning that the symptoms vary in range and severity.

Some individuals with DYT1 dystonia have no apparent family history of the disorder. This may be explained by low penetrance of the gene in other family members who are carriers or by the variable expression of the condition. Therefore, the disease may remain undiagnosed in mildly affected family members. Other evidence suggests that the disorder results from a new genetic mutation that occurs randomly for unknown reasons (sporadically).

The underlying cause or causes of the gene's low penetrance and variable expressivity remain unknown. Various mechanisms may play some role. These include the interaction of other genes that modify or change the activity of other genes, genetic anticipation, or other genetic factors. Environmental influences may also play a role, including trauma, such as injuries to the arms, legs, or head. Symptoms may begin or worsen in a previously injured part of the body. Peripheral injury may influence functioning of the basal ganglia and its pathways and play some role in "triggering" symptom onset in certain individuals who have a mutated DYT1 gene.

The mutation responsible for DYT1 dystonia is deletion of one of a pair of certain basic chemical "building blocks" of DNA known as guanine, adenine, and guanine (GAG trinucleotides) in the DYT1 gene's coded instructions. The DYT1 gene regulates or "encodes" production of a protein known as torsinA. Although the protein's specific function is unknown, it appears to be related to a class of proteins (heat-shock proteins) that enable cells to recover from injury or stress. TorsinA is found in neurons throughout the brain.

Most ethnic populations are affected by DYT1 dystonia. However, the disorder is most common among individuals of European Ashkenazi Jewish descent. (For further information, please see the section entitled "Epidemiology.") The DYT1 gene mutation is responsible for most cases of early limb-onset primary dystonia in Jewish families (kindreds). Genetic analysis of affected Ashkenazi kindreds has shown that these families share a common set of genes (known as a haplotype) that are closely linked to the DYT1 gene (on chromosome 9q) and typically inherited with it as a unit. (Such sharing of a specific haplotype more commonly than normally expected by chance is known as "linkage disequilibrium.") Experts indicate that the association of the linked genes with DYT1 suggests that the disorder is largely due to a single mutation event in the past (founder mutation). It has been calculated that the original or founder mutation was introduced into the Ashkenazi Jewish population approximately 350 years ago in Lithuania. Genetic analysis has revealed that the DYT1 disease gene also appears to be responsible for most cases of early limb-onset primary dystonia in non-Jewish kindreds. However, such investigation has not revealed a common set of closely linked genes (i.e., linkage disequilibrium) to suggest a single founder mutation in these non-Jewish families.

In a study of 174 Ashkenazi individuals with early- or late-onset primary dystonia, more than 90 percent of those with isolated or familial early limb-onset dystonia carried the chromosome 9q haplotype. Most of these patients had progression to multifocal or generalized dystonia. In contrast, those who did not carry the haplotype comprised the majority of patients who had late-onset dystonia with initial involvement of head or neck (cervical) muscles rather than limb muscles. In almost all of these patients, the dystonia remained focal or segmental. Thus, such evidence suggests that a single mutation event is responsible for most cases of early limb-onset dystonia in individuals of Ashkenazi descent, yet is not the cause of primary adult-onset cervical dystonia. Rather, researchers indicate that the latter may result from either DYT1 mutations, other dystonia genes, and/or other factors. In at least some families, evidence suggests that late-onset and cervical- or cranial-onset primary dystonia–or, more rarely, late-onset dystonia that also involves the legs or trunk–is due to mutation of other dystonia genes.

Accordingly, following is a description of primary dystonias that have been mapped to genes other than the DYT1 gene (or simply excluded from the DYT1 gene) in certain families.

	DYT6 Dystonia