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Dopa-responsive Dystonia

Also known as Segawa syndrome, dopa-responsive dystonia (DRD) is a genetic disorder that typically becomes apparent from approximately age 6 to 16. Girls are affected about 2 to 4 times more frequently than boys. Evidence suggests that approximately 10 percent of patients with childhood-onset dystonia are affected by DRD.

In many patients, onset is characterized by an abnormal, "stiff-legged" manner of walking (gait), with upward bending of the sole of the foot (plantar flexion) or turning of the foot outward at the ankle (eversion) and a tendency to walk on the toes. Dystonia may also extend to involve muscles of the arms, trunk, and, less frequently, the neck. In addition, DRD is typically characterized by signs of parkinsonism that may be relatively subtle. Such signs may include slowness of movement (bradykinesia), stiffness and resistance to movement (rigidity), balance difficulties, and postural instability. Approximately 25 percent also have abnormally exaggerated reflex responses (hyperreflexia), particularly in the legs.

Many patients experience improvement with sleep, are relatively free of symptoms in the morning, and develop increasingly severe symptoms as the day progresses (i.e., diurnal fluctuation). Accordingly, this disorder has sometimes been referred to as "progressive hereditary dystonia with diurnal fluctuations." Yet some DRD patients do not experience such diurnal fluctuations, causing many researchers to prefer other disease terms.

For example, in those with DRD, symptoms typically dramatically improve with low-dose administration of levodopa (L-dopa), an amino acid that is a biologic "forerunner" or precursor of the neurotransmitter dopamine. (Neurotransmitters are naturally produced chemicals that may transfer nerve impulses across the spaces between neurons, enabling nerve cells to communicate.) Low-dose L-dopa usually results in near-complete or total reversal of all associated symptoms for these patients. In addition, the effectiveness of such therapy is typically long term, without the complications that often occur for those with Parkinson's disease who undergo L-dopa treatment. Thus, most experts indicate that this disorder is most appropriately known as dopa-responsive dystonia (DRD).

DRD is an autosomal dominant disorder that usually appears to result from mutations of a gene known as guanosine triphosphate (GTP) cyclohydrolase I (GCH1 or DYT5). The GCH1 gene, which has been mapped to chromosome 14q22.1, regulates production of an enzyme that speeds (catalyzes) the first step in the "building up" of a compound (i.e., the cofactor tetrahydrobiopterin) required for tyrosine hydroxylase and other enzymes. In turn, these enzymes are required for the production (synthesis) of certain neurotransmitters, such as dopamine. In patients with DRD, there are significantly reduced dopamine concentrations in substructures of the basal ganglia collectively known as the striatum. (As mentioned earlier, the basal ganglia are specialized nerve cell clusters deep within the brain that play an essential role in regulating motor behavior.)

As with DYT1 dystonia, DRD has reduced penetrance and variable expressivity. In other words, evidence suggests that only about 30 to 40 percent of those who carry a copy of the disease gene manifest symptoms. In addition, the severity of associated symptoms may vary greatly from patient to patient, including among affected members of the same family (kindred).

Related genetic disorders have been described that may result in similar symptoms and signs (phenotype), with improvement from therapy with L-dopa or certain agents that produce dopamine-like effects (dopamine agonists). For example...

  • A rare autosomal recessive disorder has been reported in which mutation of the gene that regulates production of tyrosine hydroxylase (see above) results in symptoms similar to those of DRD. Such symptoms also respond to L-dopa therapy. In patients with this disorder, signs of dystonia and parkinsonism typically begin during infancy or early childhood.
  • Several autosomal recessive disorders have also been described in which biopterin deficiency is associated with dystonia, parkinsonism, as well as signs resulting from decreased levels of the neurotransmitters serotonin and norepinephrine. These may include rigidity, chorea, myoclonus, temperature disturbances, sudden episodes of uncontrolled electrical activity in the brain (seizures), contraction of the pupils (miosis), and abnormally increased levels of the amino acid phenylalanine in the blood (hyperphenylalaninemia). Patients with these disorders may have partial response to therapy with L-dopa.
  • Another variant of DRD is an autosomal recessive disorder characterized by deficiency of the enzyme aromatic amino acid decarboxylase, which speeds the conversion of levodopa to dopamine. Associated symptoms become apparent during infancy. Such findings may include dystonia, parkinsonism, excessive sweating (hyperhidrosis), diminished muscle tone (hypotonia), feeding difficulties, drooping of the upper eyelids (ptosis), and contraction of the pupils (miosis). There may also be episodes of sudden, transient, involuntary movements; in which the eyes are held in a fixed position, such as up, down, or sideways, potentially with spasms or closure of the eyelids (oculogyria); and/or of periods of deep sleep. Symptoms respond to therapy with dopamine agonists and monoamine oxidase inhibitors.