A Systematic Review of Treatment Outcome in Patients with Dopa‐responsive Dystonia (DRD) and DRD‐Plus

Abstract

Background: Dopa-responsive dystonia (DRD) and DRD-plus are inherited metabolic disorders of the dopamine synthetic pathway that have considerable clinical, biochemical, and genetic heterogeneity. Dopamine is the main deficient neurotransmitter; however, a deficiency in norepinephrine and serotonin can coexist, depending on the gene and its degree of defect. Therefore, even though levodopa is the mainstay of therapy, response to levodopa can be suboptimal and, thus, other drugs are tried. Methods and Results: The authors searched for reports of DRD and DRD-plus and reviewed the drugs used, their response and side effects, and neurologic outcomes, including motor and cognition. Based on the current results, a recommended treatment plan is presented according to the type of enzyme defect in patients with DRD and DRD-plus. Conclusions: It is important to recognize the features of DRD and DRD-plus, because many of them have a good clinical response to the appropriate treatment. The aim of this review is to help guide clinicians with planning treatment for patients with DRD and DRD-plus.

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike

“…It was amply discussed in our previous publications on this topic, and will be presented only in brief. 4 21 38 The enzymatic defects in dopamine biosynthetic pathway can be divided into 3 sub-parts according to the step: 1) the enzymatic defects in synthesizing tetrahydrobiopterin (BH 4 ) (GTP cyclohydrolase I [GCH-1], 6-pyruvoyltetrahydropterin synthase [PTPS], sepiapterin reductase [SR], dihydropteridine reductase [DHPR]), 2) the enzymatic defect in synthesizing levodopa (tyrosine hydroxylase [TH]), 3) the enzymatic defect in synthesizing dopamine and serotonin (aromatic L-amino acid decarboxylase [AADC]) ( Fig. 1 ).…”

“…Among enzyme deficiencies in dopamine synthetic pathway, DRD phenotype was most often reported in autosomal dominant (AD) GCH-1, and rarely in autosomal recessive (AR) SR, and TH deficiencies. 38 AD GCH-1 deficiency generally shows less severe deficiency than AR GCH-1 deficiency because only one allele is affected in AD GCH-1 mutation. The enzymatic defect in SR deficiency is also less severe because of the alternative pathway ( Fig.…”

“…In general, there is no mental retardation, seizure, myoclonic attack, or autonomic dysfunction. 4 38 The response to levodopa is dramatic and long-term complications such as motor fluctuation and dyskinesia are infrequent. Even though there were several cases with levodopa-induced dyskinesia (LID), it disappears with time 40 or by adding amantadine.…”

“… 41 Most of AD GCH-1 deficient cases showed good response at 100–300 mg/day of levodopa. 38 Some patients with AD GCH-1 mutation were reported to have residual symptoms even with levodopa treatment. 42 …”

“… 18 43 Many patients with AR GCH-1 mutation tend to respond only partially to levodopa. 38 However, some cases with homozygous mutations presented as classic DRD with excellent response to levodopa and mild residual symptoms but the earlier age of onset. 43 44 It was suggested that the severity of functional impairment, not the number of mutation, determines the phenotype.…”