Diagnosing Dopamine-Responsive Dystonias
Diagnosing Dopamine-Responsive Dystonias
The clinical spectrum of dopamine-responsive dystonias (DRDs) has expanded over the last decade to comprise several distinct disorders. At the milder end of the clinical spectrum is the autosomal-dominant guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), and at the more severe end is the much less common autosomal recessive tyrosine hydroxylase deficiency syndrome (TH-DRD), with intermediate forms in between. Understanding the pathophysiology of DRDs can help in their optimal diagnosis and management. These are conditions with the potential to be either underdiagnosed when not considered or overdiagnosed if there is an equivocal L-dopa (levo-3,4-dihydroxyphenylalanine) response. In this article, we discuss the clinical phenotypes of these disorders, and we outline how investigations can help in confirming the diagnosis.
In 1976, Segawa et al recognised levo-3,4-dihydroxyphenylalanine (l-dopa) responsiveness in a Japanese family and described 'hereditary progressive dystonia with marked diurnal fluctuation'. However, it was the 1980s before Nygaard et al coined the term 'dopa-responsive dystonia'.
Dopamine-responsive dystonias (DRDs) represent a small proportion of the total number of patients with dystonia seen in a typical movement disorder clinic, yet they remain of considerable diagnostic importance because of their dramatic l-dopa response. The estimated prevalence of DRD in Japan and England is 0.5 per million population. While DRD was considered a single entity before elucidation of the underlying pathophysiology, the various syndromes that comprise DRD are clinically, biochemically and genetically distinct. DRD can result from several distinct enzymatic defects within the dopamine biosynthetic pathway (figure 1), which are bypassed when patients are treated with l-dopa. Accordingly, while the treatment for the different DRD syndromes may be the same, the phenotypes and prognosis show considerable heterogeneity.
(Enlarge Image)
Figure 1.
The dopamine synthetic pathway, illustrating the enzymatic defects (in boxes with dashed lines) that cause the phenotype of dopamine-responsive dystonia (DRD) BH 4, tetrahydrobiopterin; COMT, catechol-O-methyl transferase; DHNTP, dihydroneopterin triphosphate; DOPAC, 3,4-dihydroxyphenylacetic acid; GTP, guanosine triphosphate; HVA, homovanillic acid; LTP, lactoyltetrahydropterin; MAO, monoamine oxidase; PTP, pyruvoyltetrahydropterin.
Abstract and Introduction
Abstract
The clinical spectrum of dopamine-responsive dystonias (DRDs) has expanded over the last decade to comprise several distinct disorders. At the milder end of the clinical spectrum is the autosomal-dominant guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), and at the more severe end is the much less common autosomal recessive tyrosine hydroxylase deficiency syndrome (TH-DRD), with intermediate forms in between. Understanding the pathophysiology of DRDs can help in their optimal diagnosis and management. These are conditions with the potential to be either underdiagnosed when not considered or overdiagnosed if there is an equivocal L-dopa (levo-3,4-dihydroxyphenylalanine) response. In this article, we discuss the clinical phenotypes of these disorders, and we outline how investigations can help in confirming the diagnosis.
Introduction
In 1976, Segawa et al recognised levo-3,4-dihydroxyphenylalanine (l-dopa) responsiveness in a Japanese family and described 'hereditary progressive dystonia with marked diurnal fluctuation'. However, it was the 1980s before Nygaard et al coined the term 'dopa-responsive dystonia'.
Dopamine-responsive dystonias (DRDs) represent a small proportion of the total number of patients with dystonia seen in a typical movement disorder clinic, yet they remain of considerable diagnostic importance because of their dramatic l-dopa response. The estimated prevalence of DRD in Japan and England is 0.5 per million population. While DRD was considered a single entity before elucidation of the underlying pathophysiology, the various syndromes that comprise DRD are clinically, biochemically and genetically distinct. DRD can result from several distinct enzymatic defects within the dopamine biosynthetic pathway (figure 1), which are bypassed when patients are treated with l-dopa. Accordingly, while the treatment for the different DRD syndromes may be the same, the phenotypes and prognosis show considerable heterogeneity.
(Enlarge Image)
Figure 1.
The dopamine synthetic pathway, illustrating the enzymatic defects (in boxes with dashed lines) that cause the phenotype of dopamine-responsive dystonia (DRD) BH 4, tetrahydrobiopterin; COMT, catechol-O-methyl transferase; DHNTP, dihydroneopterin triphosphate; DOPAC, 3,4-dihydroxyphenylacetic acid; GTP, guanosine triphosphate; HVA, homovanillic acid; LTP, lactoyltetrahydropterin; MAO, monoamine oxidase; PTP, pyruvoyltetrahydropterin.