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Int J Mol Sci 2022 Apr 21;23(9). Epub 2022 Apr 21.

Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.

DYT1 dystonia is a debilitating neurological movement disorder that arises upon Torsin ATPase deficiency. Nuclear envelope (NE) blebs that contain FG-nucleoporins (FG-Nups) and K48-linked ubiquitin are the hallmark phenotype of Torsin manipulation across disease models of DYT1 dystonia. While the aberrant deposition of FG-Nups is caused by defective nuclear pore complex assembly, the source of K48-ubiquitylated proteins inside NE blebs is not known. Read More

Stem Cell Res 2022 Jul 5;62:102807. Epub 2022 May 5.

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. Electronic address:

Childhood-onset torsin dystonia (DYT1) is a rare hereditary movement disorder and usually caused by a heterozygous GAG deletion (c.907-909) in the TOR1A gene (ΔE, p.Glu303del). Read More

Mov Disord 2022 May 14;37(5):949-961. Epub 2022 Apr 14.

IRCCS Fondazione Mondino, Pavia, Italy.

Background: The neuronal protein alpha-synuclein (α-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with α-Syn. Both proteins act as molecular chaperones and control synaptic machinery. Read More

Cureus 2022 Jan 28;14(1):e21699. Epub 2022 Jan 28.

College of Medicine, West Visayas State University, Iloilo City, PHL.

Objective: This study aims to describe the demographic profile in terms of age, marital status, annual family income, and educational attainment; to describe the physical, psychological, and social manifestations; to determine and describe coping mechanisms; to determine the goals, aspirations, and needs; and to determine the interaction and impact of the lived experiences on the quality of life of X-linked dystonia-parkinsonism (XDP) patients.

Methods: This qualitative-phenomenological study was conducted in the island of Panay. Purposive sampling was utilized. Read More

Ann Clin Transl Neurol 2021 12 21;8(12):2302-2308. Epub 2021 Nov 21.

Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA.

The primary dystonia DYT6 is caused by mutations in the transcription factor Thanatos-associated protein 1 (THAP1). To understand THAP1's functions, we generated mice lacking THAP1 in the nervous system. THAP1 loss causes locomotor deficits associated with transcriptional changes. Read More

Hum Mol Genet 2022 03;31(7):1096-1104

Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Read More

PLoS Comput Biol 2021 09 30;17(9):e1009364. Epub 2021 Sep 30.

Integrated Systems Biology Laboratory, Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan.

In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0. Read More

Mov Disord 2021 12 26;36(12):2768-2779. Epub 2021 Jun 26.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Acetylcholine-mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear.

Objective: The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention. Read More

Exp Neurol 2021 09 10;343:113783. Epub 2021 Jun 10.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Department of Neurology, University of Florida, Gainesville, FL, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.

DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. Read More

Behav Brain Res 2021 08 24;411:113381. Epub 2021 May 24.

Norman Fixel Institute for Neurological Diseases, McKnight Brain Institute, and Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, 32610-0236, USA. Electronic address:

DYT1 dystonia is a movement disorder mainly caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), coding for torsinA. DYT1 dystonia patients show trends of decreased striatal ligand-binding activities to dopamine receptors 1 (D1R) and 2 (D2R). Dyt1 ΔGAG knock-in (KI) mice, which have the corresponding ΔGAG deletion, similarly exhibit reduced striatal D1R and D2R-binding activities and their expression levels. Read More

Indian J Pediatr 2021 06 9;88(6):596. Epub 2021 Apr 9.

Department of Pediatric Medicine, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India.

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.

We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/- knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. Read More

Mov Disord 2021 06 5;36(6):1463-1464. Epub 2021 Mar 5.

Unit of Neuroradiology, Foundation IRCCS Carlo Besta Neurological Institute, Milan, Italy.

Brain 2021 04;144(3):909-923

Institut des Maladies Neurodégénératives (IMN, CNRS U5393), Université de Bordeaux, 33076, Bordeaux, France.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. Read More

J Clin Invest 2021 03;131(6)

Peter O'Donnell Jr. Brain Institute.

In inherited neurodevelopmental diseases, pathogenic processes unique to critical periods during early brain development may preclude the effectiveness of gene modification therapies applied later in life. We explored this question in a mouse model of DYT1 dystonia, a neurodevelopmental disease caused by a loss-of-function mutation in the TOR1A gene encoding torsinA. To define the temporal requirements for torsinA in normal motor function and gene replacement therapy, we developed a mouse line enabling spatiotemporal control of the endogenous torsinA allele. Read More

Parkinsonism Relat Disord 2021 02 13;83:54-55. Epub 2021 Jan 13.

Department of Neurology, Faculty of Medicine, P. J. Safarik University, Kosice, Slovakia; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia.

DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease. Read More

Behav Brain Res 2021 04 18;403:113137. Epub 2021 Jan 18.

Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States; Genetics Institute, University of Florida, Gainesville, FL, United States. Electronic address:

DYT1 or DYT-TOR1A dystonia is early-onset, generalized dystonia. Most DYT1 dystonia patients have a heterozygous trinucleotide GAG deletion in DYT1 or TOR1A gene, with a loss of a glutamic acid residue of the protein torsinA. DYT1 dystonia patients show reduced striatal dopamine D2 receptor (D2R) binding activity. Read More

J Neurosci 2021 03 19;41(9):2024-2038. Epub 2021 Jan 19.

Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in (), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Read More

Clin Neurol Neurosurg 2021 02 28;201:106449. Epub 2020 Dec 28.

Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran; Skull Base Research Center, Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Objectives: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases.

Methods: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Read More

J Pediatr Orthop 2021 Jan;41(1):33-39

Rady Children's Hospital, San Diego, San Diego, CA.

Background: Low-dose biplanar radiographs (LDBRs) significantly reduce ionizing radiation exposure and may be of use in evaluating lower extremity torsion in children. In this study, we evaluated how well femoral and tibial torsional profiles obtained by LDBR correspond with 3-dimensional (3D) computed tomography (CT) and magnetic resonance axial imaging (MRI) in pediatric patients with suspected rotational abnormalities.

Methods: Patients who had both LDBR and CT/MRI studies performed for suspected lower extremity rotational deformities were included. Read More

Neurology 2021 04 17;96(14):e1887-e1897. Epub 2020 Sep 17.

From the Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic (J.F.B., A.E.L.), Toronto Western Hospital and University of Toronto, Ontario, Canada; Department of Neurology (J.F.B.), University of Geneva and University Hospitals of Geneva, Switzerland; Department of Internal Medicine (S.C., F.C.), Universidade Federal de Minas Gerais, Belo Horizonte; Hospital Israelita Albert Einstein (C.O.d.S., R.D.P., P.d.C.A.), Sao Paulo, SP, Brazil; Departments of Neurology (D.S.K., T.L.) and Neurosurgery (D.S.K.), University of Colorado School of Medicine; Aurora; Department of Neurology and Neurosurgery (F.P.d.S.-J., E.R.B., P.d.C.A.), Universidade Federal de Sao Paulo, SP, Brazil; and Department of Neurology (R.Y., L.J.O.), Massachusetts General Hospital, Boston. Dr. Bally is currently at Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland.

Objective: To report 4 novel mutations leading to laryngeal and cervical dystonia with frequent generalization.

Methods: We screened 4 families including a total of 11 definitely affected members with a clinical picture resembling the original description.

Results: Four novel variants in the gene have been identified: D295N, R46M, Q424H, and R121W. Read More

Rinsho Shinkeigaku 2020 Aug 7;60(8):520-526. Epub 2020 Jul 7.

Department of Brain Disease Research, Shinshu University School of Medicine.

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. Read More

Pharmacol Biochem Behav 2020 09 30;196:172977. Epub 2020 Jun 30.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany. Electronic address:

The metabotropic glutamate 5 (mGlu) receptor is critically involved in corticostriatal plasticity which is disturbed in various animal models of dystonia. Recently, the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) exerted prodyskinetic effects in a phenotypic model of episodic dystonia. In the DYT1 knock-in (KI) mouse, a model for a persistent type of dystonia, previous ex vivo electrophysiological experiments indicated that mGlu receptors are involved in abnormal striatal plasticity. Read More

PLoS One 2020 4;15(5):e0226790. Epub 2020 May 4.

Department of Neurology, Ninewells Hospital & Medical School, Dundee, United Kingdom.

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. Read More

Zhonghua Er Ke Za Zhi 2020 Feb;58(2):123-128

Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.

To explore the clinical characteristics and genotyping results of childhood-onset myoclonus dystonia syndrome caused by SGCE variants. The clinical data of 9 children with SGCE-related myoclonus dystonia syndrome admitted at either the Department of Neurology, Beijing Children's Hospital, Capital Medical University or the Department of Pediatrics, Peking University First Hospital from May 2018 to October 2019 were collected and the patients were followed up. The definite diagnosis was made on the basis of whole exome sequencing and multiple ligation-dependent probe amplification. Read More

Behav Brain Res 2020 03 28;381:112451. Epub 2019 Dec 28.

Department of Neurology and Norman Fixel Institute of Neurological Diseases, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address:

DYT1 dystonia is an inherited movement disorder without obvious neurodegeneration. Multiple mutant mouse models exhibit motor deficits without overt "dystonic" symptoms and neurodegeneration. However, some mouse models do. Read More

PLoS One 2019 5;14(12):e0226080. Epub 2019 Dec 5.

Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

In early-onset generalized torsion dystonia, caused by a GAG deletion in TOR1A (DYT1), enhanced striatal cholinergic activity has been suggested to be critically involved. Previous studies have shown increased acetylcholine levels in the striatum of DYT1 knock-in (KI) mice. Ex vivo data indicated that muscarinic receptor antagonists normalize the activity of striatal cholinergic interneurons. Read More

Neurobiol Dis 2020 02 13;134:104638. Epub 2019 Oct 13.

Norman Fixel Institue for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, United States. Electronic address:

DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Read More

Prog Brain Res 2019 21;249:251-260. Epub 2019 Jun 21.

Motor Control and Movement Disorder Group, Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom.

Clinical movement disorders are classified by an algorithm implemented by a practising movement disorder specialist based on information extracted during the history and clinical examination of a patient. Most simply, dystonia, is a classifier which is reached when a predominant abnormality of posture is noted. In this chapter we summarize studies that have used a variety of techniques to probe beyond the clinical examination and study kinematic features experimentally. Read More

Neurobiol Dis 2019 12 10;132:104529. Epub 2019 Jul 10.

Departments of Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine; Kyiv Academic University, Ukraine. Electronic address:

A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca-dependent translocation to the plasma membrane. Read More