| Laboratory of Neurogenetics |
| Genetics of Dystonia |
| The gene responsible for some forms of early-onset dystonia, DYT 1 on chromosome 9, has been identified. In fact, virtually all cases of early-onset dystonia are attributed to a mutation (rare, abnormal change) in DYT 1 consisting of a three letter deletion in the genetic code that distinguishes the sequence of amino acids in a protein. |
| DYT 1 has been found to code for a protein known as Torsin A. Torsin A has similarities to the heat shock proteins and proteases (proteins that break down other proteins) that help cells recover from stresses, including heat, traumatic injury, and chemical poisoning. Early-onset dystonia affects 50,000 people in North America and is the only human disease found associated with these proteins. |
| In patients with early-onset dystonia, the DYT 1 mutation results in the loss of an amino acid, glutamic acid (shown as E above), in the Torsin A protein. Although most patients with Early-onset ITD have the DYT-1 deletion mutation, not all persons having the mutation become vulnerable to the disease. Susceptibility to early-onset dystonia disappears after age 28 and people over this age with the mutation are virtually free from the risk of developing symptoms. Therefore, other genetic or environmental factors may play a role in triggering symptoms in humans with a genetic predisposition to the disease. Early-onset dystonia, associated with the DYT 1 gene, is only one of the genetic forms of dystonia. Other genetic forms include late-onset dystonia, dopa-responsive dystonia, dystonia-parkinsonism, myoclonic dystonia, and rapid-onset dystonia-parkinsonsim. |
| There are numerous loci (chromosomal positions) associated with various forms of dystonia. |
| Designation | Mode of Inheritance | Chromosomal Location | Gene Product |
| DYT1; Early-onset Idiopathic Torsion Dystonia (ITD) | Autosomal Dominant | 9q34 | ATP binding Protein |
| DYT2; Autosomal Recessive Dystonia | Autosomal Recessive | - | - |
| DYT3; X-Linked Recessive Dystonia Parkinsonism Syndrome (XDP) | X-Linked Recessive | Xq13.1 | - |
| DYT4; Torsion Dystonia 4 | Autosomal Dominant | NA | NA |
| DYT5; Dopa Responsive Dystonia (DRD); Hereditary Progressive Dytsonia with Marked Diurnal Fluctuation | Autosomal Dominant | 14q22.1-22.2 | GTP Cyclohydrolase I |
| DYT5; Dopa Responsive Dystonia (DRD); Hereditary Progressive Dytsonia with Marked Diurnal Fluctuation | Autosomal Recessive | 11p15.5 | Tyrosine Hydroxylase |
| DYT6; Adult-onset ITD of mixed type | Autosomal Dominant | 8p21-22 | - |
| DYT7; Focal Adult-onset ITD (Idiopathic Focal Dystonia) | Autosomal Dominant | 18p | - |
| DYT8, DYT9; Paroxysmal Dystonic Choreathetosis | Autosomal Dominant | 2q33-25 1p21-13.3 | - |
| DYT10; Paroxysmal Dystonia; Kinesigenic Choreathetosis | Autosomal Dominant | - | - |
| DYT11; Myoclonic Dystonia; Alcohol Responsive Dystonia | Autosomal Dominant | 11q23 7q21-q31 | ?DRD2 |
| DYT12; Rapid-onset Dystonia Parkinsonism | Autosomal Dominant | 19q13 | - |
| X-linked Sensorineural Deafness, Dystonia, Mental Retardation (DFN1) | X-Linked Recessive | Xq22 | DDP |
| The numbers refer to the chromosomal location of each "loci". For example Xq13.1 refers to a loci on the 13.1 segment of the long arm (q) of chromosome X. |
| One of the forms of dystonia that we are particularly interested in is X-linked dystonia parkinsonism (XDP) also known as Lubag. This disorder appears to occur exclusively in the Filipino population and is characterized by adult onset, parkinsonian features with progression to severe generalized dystonia within 7 years of onset. |
| Lubag is believed to originate ancestrally from the Filipino island of Panay, where approximately 1/4000 males are affected. In the local Illongo dialect, "Lubag" describes the twisting motion seen in many affected individuals. The average age of onset of symptoms in Lubag is 35 years, with cases reported from the age of 12-48 years of age. Symptoms include blepharospasm, toricollis, other focal dystonias and dystonic tremor. Common features include abnormal gait, leg dystonia, oromandibular dystonia, neck dystonia and truncal dystonia. Additionally, 4 out of every 10 people with XDP also show symptoms of Parkinsonism. |
