Dystonia as a symptom was discussed in Chaps. 3 and 4. Here we are concerned with a disease or diseases of which dystonia is the major manifestation. The broad category of primary dystonias and what has been termed “dystonia-plus,” meaning the addition of features such as parkinsonism or tremor, are now denominated by “DYT” followed by a number. It is more practical to know the gene correlate of each clinical disorder. The most important of these is DYT1, or dystonia musculorum deformans.
Historical aspects Schwalbe’s account, in 1908, of 3 siblings of a Jewish family who were afflicted with progressive involuntary movements of trunk and limbs probably represents the first description of a disease in which severe and progressive dystonia was the sole manifestation. In 1911, Oppenheim contributed other cases and coined the term dystonia musculorum deformans in the mistaken belief that the disorder was primarily one of muscle and always associated with deformity. Flatau and Sterling, in the same year, first suggested that the disease might have a hereditary basis and gave it the more accurate name torsion dystonia of childhood. At first, the condition was considered by some to be a manifestation of hysteria; only later was it recognized as a neurologic entity with a predilection for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood, is progressive over a few years, and is restricted to Jewish patients. The dominant form begins later, usually in late childhood and adolescence, progresses more slowly, and is not limited to any ethnic group.
As indicated in Chap. 4, most instances of idiopathic (primary) dystonias that come to our attention, particularly the segmental or restricted types, do not conform to the typical hereditary disorder as defined above, although some may represent limited variants of the inherited form of disease. In general, the more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to involve an axial or a distal region alone. Only the paravertebral, cervical, or cranial muscles may be involved (focal dystonia including torticollis and writer’s cramp), with little change from year to year. The clinical classification of the predominantly adult-onset dystonias is made more complex by the fact that both the restricted and generalized forms may be sporadic or genetic.
Genetic aspects Molecular genetic studies, although still incomplete, hold the promise of clarifying the classification of the heritable dystonias. Six genes have been identified as causing primary dystonias and a number of others cause what might called “dystonia-plus” as they encompass tremor, parkinsonism or myoclonus. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common mutation in DYT1 is a deletion of a single glutamate from the torsin A peptide and accounts for most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.
The function of torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Walker and Shashidharan).