The Genetics of Primary Dystonias and Related Disorders

Abstract & Commentary

Source: Nemeth AH. Brain. 2002;125:695-721.

A recent review in Brain affords Neurology Alert readers the opportunity to review a complicated area of movement disorders, the genetics of dystonia. Dystonias may be classified by their distribution (focal, segmental, multifocal, generalized), by age of onset, and by etiology. Primary dystonia refers to dystonia occurring without other neurologic findings, while "dystonia-plus" disorders include conditions in which dystonia is accompanied by myoclonus or parkinsonism. Secondary, or symptomatic dystonias, occur after stroke or drug exposure and are not considered further in this review. The final category, heredodegenerative dystonia, encompasses a wide variety of inherited neurodegenerative conditions where dystonia is accompanied by cognitive decline and pyramidal dysfunction. As a rule, primary dystonias are autosomal dominant while heredodegenerative dystonias are autosomal recessive.

Commentary

Primary dystonias, originally described as idiopathic, are now recognized to be genetic in origin. They are classified by their date of discovery, and movement disorder neurologists refer to them by the designation DYT followed by a number. DYT1 dystonia, also known as Opphenheim’s dystonia, is the most common genetic form; their symptoms typically begin in an arm or leg in childhood or early adulthood. DYT1 dystonia is 5-10 times more prevalent in the Ashkenazic Jewish population, and the penetrance is 30-40%. All cases of DYT1 dystonia arise from a single in-frame deletion of a GAG trinucleotide in the protein torsin A, a member of the heat-shock protein family. Torsin A is highly expressed in the substantia nigra and basal ganglia. Mutant torsin A forms inclusions around the cell nucleus suggesting that it may act as a chaperone in the folding of secreted proteins. Genetic testing for the DYT1 mutation is commercially available, and is most helpful in individuals with onset of dystonia in a limb before age 26. Other forms of primary dystonia include DYT6 and DYT7. DYT6 dystonia was described in 2 Menonite families, with autosomal dominant inheritance and incomplete penetrance. The clinical features of DYT6 are similar to DYT1, except that dystonia began in cranial or cervical regions in half the patients and symptoms typically began slightly later. DYT7 dystonia was described in a large German family with autosomal dominant adult-onset torticollis. DYT7 has been linked to chromosome 18, and DYT6 to chromosome 8.

The dystonia-plus syndromes include 3 major entities: dopa-responsive dystonia (DYT5), myoclonus-dystonia (DYT11), and rapid-onset dystonia-parkinsonism (DYT12). DYT5 is an autosomal dominant disorder that typically begins in the child’s first decade. Dystonia, parkinsonism (particularly affecting the legs), and diurnal worsening of symptoms are the rule, and the disorder is much more common in women. DYT5 may mimic atypical cerebral palsy. Since it is exquisitely responsive to levodopa or anticholinergics, all children presenting with a motor disorder not attributable to hypoxia should be given a trial of levodopa. DYT5 is linked to mutations in the gene encoding GTP cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor for the synthesis of tyrosine, levodopa, and serotonin. DYT11 is an autosomal dominant disorder with markedly reduced penetrance in offspring of affected females. Proximal myoclonus usually begins in the first or second decade, with or without dystonia. The condition is slowly progressive and is almost always alcohol responsive. Numerous families with myoclonus-dystonia have been linked to mutations in a gene encoding epsilon-sarcoglycan (chromosome 7), although other families are not linked to chromosome 7. DYT12 is a rare autosomal dominant disorder characterized by onset of dystonic spasms and generalized parkinsonism from hours to weeks. Symptoms may begin in childhood or adulthood and are typically resistant to treatment with levodopa. The disorder has been linked to chromosome 19 in 3 families.

The heredodegenerative dystonias are a group of disorders linked by their inheritance pattern (autosomal recessive) and the fact that dystonia occurs in the company of cognitive and pyramidal dysfunction. Included in this group are Fahr’s disease, pantothenate kinase-associated neurodegeneration, X-linked dystonia-parkinsonism (DYT3) and chorea-acanthocytosis. Fahr’s disease, idiopathic basal ganglia calcification, typically begins between ages 30 and 60 and presents with slowly progressive dystonia, parkinsonism, dysphagia, and psychiatric disturbances. Linkage to chromosome 14 has been reported in one family. Pantothenate kinase-associated neurodegeneration (previously known as Hallervorden-Spatz) is an autosomal recessive disorder typically presenting in childhood or adolescence with dystonia, parkinsonism, chorea, dementia, and pigmentary retinopathy. The "eye of the tiger sign" on MRI is a typical finding in childhood cases, due to deposition of iron in the medial pallidum and hyperintensity in the internal pallidum. The disorder is linked to a deficiency in pathothenate kinase, important in the synthesis of coenzyme A. DYT3 is limited to the Phillipine population where it is known as lubag. Symptoms begin in the fourth decade, usually with focal dystonia that generalizes within 5 years. Parkinsonism is also extremely common, and the illness usually progresses slowly and is unresponsive to levodopa. Chorea-acanthocytosis is an autosomal dominant disorder with onset in the 20s and 30s. Chorea, dystonia, parkinsonism, and dementia are common, as are mutilating orofacial dyskinesias. The responsible gene (chorein) is located on chromosome 9, and may be involved in the trans-Golgi network. —Steven Frucht

Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.