Nonmotor Symptoms in Dopa‐Responsive Dystonia

Abstract

Background: Dopa-responsive dystonia (DRD) is a rare inherited dystonia, caused by an autosomal dominantly inherited defect in the gene GCH1 that encodes guanosine triphosphate cyclohydrolase 1. It catalyzes the first and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is the essential co-factor for aromatic amino acid hydroxylases. Mutation results in the typical scenario of a young-onset lower-limb dystonia with diurnal fluctuations, concurrent or subsequent development of parkinsonism and excellent response to levodopa. Given the myriad functions of tetrahydrobiopterin, it is reasonable that other systems, apart from motor, would also be impaired. So far, non-motor symptoms have been overlooked and very few and often contrasting data are currently available on the matter. Methods: Here by searching the Medline database for publications between 1971 to March 2015, we render an in-depth analysis of all published data on non-motor symptoms in DRD. Results: Depression and subtle sleep quality impairment have been reported among the different cohorts, while current data do not support any alterations of the cardiologic and autonomic systems. However, there is debate about the occurrence of sleep-related movement disorders and cognitive function. Non-motor symptoms are instead frequently reported among the clinical spectrum of other neurotransmitter disorders which may sometimes mimic DRD phenotype, ie, DRD plus diseases. Conclusions: Further studies in larger and treatment-na€ ıve cohorts are needed to better elucidate the extend of non-motor symptoms in DRD and also to consider treatment for these.

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

“…Dopa-responsive dystonia (DRD) is a group of disorders that typically present with childhood onset diurnally fluctuating limb dystonia, thus also referred to as hereditary progressive dystonia with marked diurnal fluctuation [1,2]. The conditions that manifest as DRD are clinically heterogenous and non-motor symptoms with neuropsychiatric features, for example, depression, may also be present in some cases [3]. DRD is rare, with an estimated prevalence of 0.5-1 per million worldwide [4,5], and it is mainly caused by abnormalities affecting the biosynthesis of catecholamines (CAs).…”

Myoclonus-Dystonic Presentation of Childhood Onset DYT-GCH1: A Report From India

“…1 In addition, nonmotor symptoms such as depression, anxiety and sleep quality impairment have been reported and can predate motor symptom onset. 2 Occasionally, the phenotypic spectrum may include upper-limb (UL) onset of dystonia, focal dystonia, and adult-onset parkinsonism and may mimic cerebral palsy or spastic paraplegia. Apart from these, there can be additional atypical features (DRD-plus), such as infantile onset, developmental delay, hypotonia, ptosis, cerebellar dysfunction, and poor LD responsiveness.…”

“…Nonmotor symptoms, predominantly neuropsychiatric, such as depression, anxiety and obsessive-compulsive disorders, are well reported in patients with inherited dystonia, especially the DRD spectrum, including DYT-GCH1, and can even predate motor symptom onset. 2 Impairment in monoamine, catecholamines and serotonin synthesis with mutations in DRD-spectrum genes may be the underlying mechanism for the range of nonmotor symptoms. The onset of psychiatric symptoms, especially depression and anxiety followed by movement disorders, may sometimes lead to a wrong diagnosis of functional movement disorder; thus, may lead to an avoidable delay in investigations and adequate therapy to improve the quality of life.…”

“…GTP cyclohydrolase-1 (GCH1)-deficient dystonia (DYT-GCH1/DYT5) is an autosomal-dominant dopa-responsive dystonia (DRD) of childhood onset typically presenting with foot dystonia progressing to generalized dystonia and parkinsonism with diurnal fluctuation and a dramatic and persistent response to levodopa (LD) [ 1 ]. In addition, nonmotor symptoms such as depression, anxiety and sleep quality impairment have been reported and can predate motor symptom onset [ 2 ]. Occasionally, the phenotypic spectrum may include upper-limb (UL) onset of dystonia, focal dystonia, and adult-onset parkinsonism and may mimic cerebral palsy or spastic paraplegia.…”

“…Nonmotor symptoms, predominantly neuropsychiatric, such as depression, anxiety and obsessive-compulsive disorders, are well reported in patients with inherited dystonia, especially the DRD spectrum, including DYT-GCH1, and can even predate motor symptom onset [ 2 ]. Impairment in monoamine, catecholamines and serotonin synthesis with mutations in DRD-spectrum genes may be the underlying mechanism for the range of nonmotor symptoms.…”