Autosomal Dominant Dopa-responsive Dystonia (Segawa's Syndrome)
The most well described and widely identified entity among this group of disorders is autosomal dominant dopa-responsive dystonia caused by GTP cyclohydrolase deficiency, or Segawa's disease. Identification and treatment of this disorder can be extremely rewarding because patients often benefit greatly with directed treatment of the associated dopamine deficiency state. Patients with a classic presentation of exercise-induced dystonia are not difficult to recognize. This diagnosis should also be considered in patients with spastic diplegia, especially when significant fluctuation in gait or worsening gait at the end of the day is noted, and in patients with more atypical presentations, including writer's cramp, asymmetric limb dystonia, tremor, or restless leg type symptoms. In patients with a classic presentation, many clinician can make the diagnosis on a presumptive basis, after observing remission of symptoms with a trial of L-dopa/carbidopa.
Although inheritance is autosomal dominant, penetrance is incomplete, and variable expressivity among family members with the same mutation are well-documented. For instance, one might see spastic diplegia, writer’s cramp, restless leg syndrome, and more typical exercise-induced dystonia phenotypes among different members of the same family. The female-to-male ratio in sporadic cases is 4:1, and investigators have confirmed increased penetrance of GTPCH I mutations in females.
Not surprisingly, mood and sleep disorders appear to be unusually prevalent in families with the disorder, although these issues have not been systematically studied. However, preliminary data in an ongoing study of prospectively ascertained family members supports an increased burden of attentional difficulties, anxiety, dysphoria, depression and sleep disorders.
CSF neurotransmitter metabolite and pterin studies are helpful in confirming the diagnosis in these patients, and can help characterize the degree of associated dopamine and serotonin deficiency. Phenylalanine loading is also valuable in confirming a suspected diagnosis, but is not specific to the disorder, as PKU heterozygotes also manifest delayed phenylalanine clearance. GTPCH activity can be measured directly in skin fibroblasts. CSF analysis should be performed before institution of a treatment trial of L-dopa/carbidopa, because treatment results in increased levels of HVA and 3-O-methyldopa. The typical pattern in CSF in dopa-responsive dystonia due to GTPCH deficiency is a low HVA level, normal or low 5-HIAA level, and reduced BH4 levels in CSF. Patients who are heterozygous for a GTPCH mutation, despite their normal blood phenylalanine levels on routine screening, can be shown to have abnormal phenylalanine metabolism if stressed by administration of an oral phenylalanine load (100 mg/kg). Therefore, if cytokine stimulated fibroblast enzyme analysis of biopterin metabolism is not feasible or patients decline a CSF examination and have an otherwise typical presentation, an oral phenylalanine load, with serial serum phenylalanine levels over the following 4 to 6 hours, can help confirm the clinical diagnosis. Gene sequencing is available for confirmation of diagnosis, and may be a valuable adjunct to biochemical diagnostic studies, but will miss gene deletions, which are fairly common in this disorder.
Treatment with L-dopa/carbidopa leads to significant benefit or resolution of motor symptoms in the large majority of patients with Segawa’s disease within a few weeks time. However, compound heterozygotes or patients with longstanding or more severe motor manifestations such as parkinsonism or longstanding spastic paraparesis may require more careful titration of dosing, with gradual adjustment over a period of several months. Mood manifestations such as depression or anxiety often respond to L-dopa treatment to some degree, but some patients have additional benefit from directed treatment of their associated serotonin deficiency, either with the serotonin precursor 5-HTP, or a serotonin reuptake inhibitor.
