A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype

Background We describe a 4-generation Dutch pedigree with a unique dominantly inherited clinical phenotype of a combined progressive chorea and cervical dystonia carrying a novel heterozygous dopamine D2 receptor (DRD2) variant. Objectives The objective of this study was to identify the genetic cause of the disease and to further investigate the functional consequences of the genetic variant. Methods After detailed clinical and neurological examination, whole-exome sequencing was performed. Because a novel variant in the DRD2 gene was found as the likely causative gene defect in our pedigree, we sequenced the DRD2 gene in a cohort of 121 Huntington-like cases with unknown genetic cause (Germany). Moreover, functional characterization of the DRD2 variant included arrestin recruitment, G protein activation, and G protein-mediated inhibition of adenylyl cyclase determined in a cell model, and G protein-regulated inward-rectifying potassium channels measured in midbrain slices of mice. Result We identified a novel heterozygous variant c.634A > T, p.Ile212Phe in exon 5 of DRD2 that cosegregated with the clinical phenotype. Screening of the German cohort did not reveal additional putative disease-causing variants. We demonstrated that the D2(S/L)-(IF)-F-212 receptor exhibited increased agonist potency and constitutive activation of G proteins in human embryonic kidney 239 cells as well as significantly reduced arrestin3 recruitment. We further showed that the D2(S)-(IF)-F-212 receptor exhibited aberrant receptor function in mouse midbrain slices. Conclusions Our results support an association between the novel p.Ile212Phe variant in DRD2, its modified D2 receptor activity, and the hyperkinetic movement disorder reported in the 4-generation pedigree. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Paramedical treatment in primary dystonia: a systematic review

Dystonia is a disabling movement disorder with a significant impact on quality of life. The current therapeutic armamentarium includes various drugs, botulinum toxin injections, and occasionally (neuro)surgery. In addition, many patients are referred for paramedical (including allied health care) interventions. An enormous variation in the paramedical treatment is provided, largely because evidence-based, accepted treatment regimes are not available. We have conducted a systematic review of studies that explored the effect of various paramedical interventions in primary dystonia. Only studies that have used clinical outcome measures were included. There were no class A1 or A2 studies and therefore, level 1 or 2 practice recommendations for a specific intervention could not be deducted. Many papers were case reports, mostly with a very limited number of patients and a clear publication bias for beneficial effects of a particular paramedical intervention. Some potentially interesting interventions come from class B studies, which include physical therapy in addition to botulinum toxin injections (BoNT-A) in cervical dystonia; sensorimotor training and transcutaneous electrical nerve stimulation (TENS) in writer's cramp; and speech therapy added to BoNT-A injections in laryngeal dystonia. Good quality clinical studies are therefore warranted, which should have the aim to be generally applicable. A design in which the paramedical intervention is added to a current gold standard, for example, BoNT-A injections in cervical dystonia, is recommende

Between-group effects for the SMN, ECN and PVN.

<p>Depicted here are the between-group effects for three RSNs. Between-group effects are corrected for family-wise errors (p≤0.013 for <b>A.</b> and <b>B.;</b> p≤0.05 (blue) and p≤0.013 (orange) for <b>C.</b>). <b>A.</b> shows frontal regions and precentral regions abnormally connected to the <i>SMN</i>, indicating <i>de</i>creased connectivity within the CD group. <b>B.</b> shows brain regions linked to the <i>ECN</i>, exhibiting <i>in</i>creased connectivity for the CD group. <b>C.</b> The <i>PVN</i> shows CD-related <i>de</i>creased connectivity of several regions including PFC, PMC, SM1, and visual and temporal areas. *The right column (green) shows the original RSNs used in the dual regression approach, thresholded at Z = 2,0. These are PICA spatial maps of healthy subjects derived from Smith et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062877#pone.0062877-Smith1" target="_blank">[22]</a> Images are t-statistics overlaid on the MNI-152 standard brain. The left hemisphere of the brain corresponds to the right side in this image.</p

Local maxima of regions with altered connectivity within the PVN.

<p>C = controls, P = patients, RSN = resting state network. Between-group effects are corrected for family-wise errors (p≤0.05).</p

Patience is the key: Contraceptive induced chorea in a girl with Down Syndrome

Background: Isolated (sub)acute chorea in young patients is a relatively rare movement disorder with a broad differential diagnosis, including drug-induced, post-infectious, auto immunological and vascular aetiologies. Case presentation: We describe an adolescent girl with Down's syndrome presenting with chorea due to oral contraceptive usage. After discontinuation of the oral contraceptive it took several months before the symptoms disappeared. Although generally well recognised, it is important to realise this delayed effect. Rejecting the diagnosis too soon may lead to unnecessary treatment for other possible underlying aetiologies, especially in patients with Down Syndrome, known to be vulnerable for autoimmune disorders. Conclusion: We plead for discontinuation for at least three months before exclusion of oral contraceptives as cause of chorea. (C) 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved

Local maxima of regions with altered connectivity in relation to BoNT treatment.

<p>PMv = ventral premotor cortex, RSN = resting state network. Between-group effects are corrected for family-wise errors (p≤0.05).</p

Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia

Aminoacylase 1 (ACY1) deficiency is an organic aciduria due to mutations in the ACY1 gene. It is considered much underdiagnosed. Most individuals known to be affected by ACY1 deficiency have presented with neurologic symptoms. We report here a cognitively normal 63-year-old woman who around the age of 12 years had developed dystonic symptoms that gradually evolved into generalized dystonia. Extensive investigations, including metabolic diagnostics and diagnostic exome sequencing, were performed to elucidate the cause of dystonia. Findings were only compatible with a diagnosis of ACY1 deficiency: the urinary metabolite pattern with N-acetylated amino acids was characteristic, there was decreased ACY1 activity in immortalized lymphocytes, and two compound heterozygous ACY1 mutations were detected, one well-characterized c.1057C>T (p.Arg353Cys) and the other novel c.325A>G (p.Arg109Gly). Expression analysis in HEK293 cells revealed high residual activity of the enzyme with the latter mutation. However, following co-transfection of cells with stable expression of the c.1057C>T variant with either wild-type ACY1 or the c.325A>G mutant, only the wild-type enhanced ACY1 activity and ACY1 presence in the Western blot, suggesting an inhibiting interference between the two variants. Our report extends the clinical spectrum of ACY1 deficiency to include dystonia and indicates that screening for organic acidurias deserves consideration in patients with unexplained generalized dystonia

Current and future medical treatment in primary dystonia.

Contains fulltext : 110753.pdf (publisher's version ) (Open Access)Dystonia is a hyperkinetic movement disorder, characterized by involuntary and sustained contractions of opposing muscles causing twisting movements and abnormal postures. It is often a disabling disorder that has a significant impact on physical and psychosocial wellbeing. The medical therapeutic armamentarium used in practice is quite extensive, but for many of these interventions formal proof of efficacy is lacking. Exceptions are the use of botulinum toxin in patients with cervical dystonia, some forms of cranial dystonia (in particular, blepharospasm) and writer's cramp; deep brain stimulation of the pallidum in generalized and segmental dystonia; and high-dose trihexyphenidyl in young patients with segmental and generalized dystonia. In order to move this field forward, we not only need better trials that examine the effect of current treatment interventions, but also a further understanding of the pathophysiology of dystonia as a first step to design and test new therapies that are targeted at the underlying biologic and neurophysiologic mechanisms.1 juli 201