Dystonia: an update on phenomenology, classification, pathogenesis and treatment.

PURPOSE OF REVIEW This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene discoveries and genotype-phenotype correlations. Broadening of phenotype of some of the previously described hereditary dystonias and environmental risk factors and trends in treatment will be covered. RECENT FINDINGS Based on phenomenology, a new consensus update on the definition, phenomenology and classification of dystonia and a syndromic approach to guide diagnosis have been proposed. Terminology has changed and 'isolated dystonia' is used wherein dystonia is the only motor feature apart from tremor, and the previously called heredodegenerative dystonias and dystonia plus syndromes are now subsumed under 'combined dystonia'. The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia. Clinical and genetic heterogeneity underlie myoclonus-dystonia, dopa-responsive dystonia and deafness-dystonia syndrome. ALS2 gene mutations are a newly recognized cause for combined dystonia. The phenotypic and genotypic spectra of ATP1A3 mutations have considerably broadened. Two new genome-wide association studies identified new candidate genes. A retrospective analysis suggested complicated vaginal delivery as a modifying risk factor in DYT1. Recent studies confirm lasting therapeutic effects of deep brain stimulation in isolated dystonia, good treatment response in myoclonus-dystonia, and suggest that early treatment correlates with a better outcome. SUMMARY Phenotypic classification continues to be important to recognize particular forms of dystonia and this includes syndromic associations. There are a number of genes underlying isolated or combined dystonia and there will be further new discoveries with the advances in genetic technologies such as exome and whole-genome sequencing. The identification of new genes will facilitate better elucidation of pathogenetic mechanisms and possible corrective therapies.

[1]  J. Hardy,et al.  Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel , 2013, Movement disorders : official journal of the Movement Disorder Society.

[2]  W. Marks,et al.  Inclusion and exclusion criteria for DBS in dystonia , 2011, Movement disorders : official journal of the Movement Disorder Society.

[3]  M. Vidailhet,et al.  Assessment of patients with isolated or combined dystonia: An update on dystonia syndromes , 2013, Movement disorders : official journal of the Movement Disorder Society.

[4]  M. Edwards,et al.  Extragenetic factors and clinical penetrance of DYT1 dystonia: an exploratory study , 2013, Journal of Neurology.

[5]  M. Hallett,et al.  Phenomenology and classification of dystonia: A consensus update , 2013, Movement disorders : official journal of the Movement Disorder Society.

[6]  M. Koenig,et al.  The autosomal recessive cerebellar ataxias. , 2012, The New England journal of medicine.

[7]  D. Maraganore,et al.  Mutations in CIZ1 cause adult onset primary cervical dystonia , 2012, Annals of neurology.

[8]  S. Bressman,et al.  Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish‐Mennonites , 2014, Movement disorders : official journal of the Movement Disorder Society.

[9]  Allison Brashear,et al.  ATP1A3 mutations in infants: a new rapid‐onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia , 2012, Developmental medicine and child neurology.

[10]  E. Altenmüller,et al.  Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene , 2013, Annals of neurology.

[11]  N. Vayssiere,et al.  Stereotactic MRI in Dyt1 Dystonia: Focal Signal Abnormalities in the Basal Ganglia Do Not Contraindicate Deep Brain Stimulation , 2008, Stereotactic and Functional Neurosurgery.

[12]  Eric McWilliams,et al.  Asystole in alternating hemiplegia with de novo ATP1A3 mutation. , 2014, European journal of medical genetics.

[13]  A. Blitzer,et al.  Pathogenic variants in TUBB4A are not found in primary dystonia , 2014, Neurology.

[14]  R. Axel,et al.  Mice Deficient in Golf Are Anosmic , 1998, Neuron.

[15]  E. Roze,et al.  Excellent response to a ketogenic diet in a patient with alternating hemiplegia of childhood. , 2014, JIMD reports.

[16]  K. Bhatia,et al.  Primary and secondary dystonic syndromes: an update , 2013, Current opinion in neurology.

[17]  G. Deuschl,et al.  Genome‐wide association study in musician's dystonia: A risk variant at the arylsulfatase G locus? , 2014, Movement disorders : official journal of the Movement Disorder Society.

[18]  E. Leshinsky‐Silver,et al.  Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene , 2014, neurogenetics.

[19]  Akihiro Yasuhara,et al.  Genotype–phenotype correlations in alternating hemiplegia of childhood , 2014, Neurology.

[20]  C. Marsden,et al.  Myoclonic dystonia , 1983, Neurology.

[21]  P. Thompson,et al.  Hereditary myoclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion. , 1988, Advances in neurology.

[22]  Kamran Khodakhah,et al.  The neural substrates of Rapid-Onset Dystonia-Parkinsonism , 2011, Nature Neuroscience.

[23]  Paul Gissen,et al.  Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. , 2009, The Journal of clinical investigation.

[24]  R. Axel,et al.  Mice deficient in G(olf) are anosmic. , 1998, Neuron.

[25]  E. Puffenberger,et al.  Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood , 2014, Brain : a journal of neurology.

[26]  L. Ozelius.  Clinical spectrum of disease associated with ATP1A3 mutations , 2012, The Lancet Neurology.

[27]  Robert Steinfeld,et al.  The expanding clinical and genetic spectrum of ATP1A3-related disorders , 2014, Neurology.

[28]  A. Lang,et al.  Expanding the Phenomenology of Benign Hereditary Chorea : Evolution from Chorea to Myoclonus and Dystonia , 2011 .

[29]  A. Szekely,et al.  Primary dystonias and genetic disorders with dystonia as clinical feature of the disease. , 2014, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[30]  J. Kuratsu,et al.  Long Disease Duration Interferes With Therapeutic Effect of Globus Pallidus Internus Pallidal Stimulation in Primary Cervical Dystonia , 2013, Neuromodulation : journal of the International Neuromodulation Society.

[31]  A. Batla,et al.  Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report , 2014, Journal of Neurology.

[32]  A. Lang,et al.  Mutations in GNAL cause primary torsion dystonia , 2012, Nature Genetics.

[33]  S. Fahn.  Classification of movement disorders , 2011, Movement disorders : official journal of the Movement Disorder Society.

[34]  G. Deuschl,et al.  ALS2 mutations , 2014, Neurology.

[35]  M. Stacy,et al.  Psychiatric disorders in rapid-onset dystonia-parkinsonism , 2012, Neurology.

[36]  Lin Wang,et al.  No mutations in CIZ1 in twelve adult‐onset primary cervical dystonia families , 2013, Movement disorders : official journal of the Movement Disorder Society.

[37]  M. Edwards,et al.  Defining the Epsilon‐Sarcoglycan (SGCE) Gene Phenotypic Signature in Myoclonus‐Dystonia: A Reappraisal of Genetic Testing Criteria , 2013, Movement disorders : official journal of the Movement Disorder Society.

[38]  M. Vidailhet,et al.  Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[39]  T. Gasserc,et al.  EFNS guidelines on diagnosis and treatment of primary dystonias , 2010 .

[40]  M. Stacy,et al.  Cognitive impairment in rapid‐onset dystonia‐parkinsonism , 2014, Movement disorders : official journal of the Movement Disorder Society.

[41]  C. Wider,et al.  Overview of primary monogenic dystonia. , 2012, Parkinsonism & related disorders.

[42]  E. Moro,et al.  What's new in surgical treatment for dystonia? , 2013, Movement disorders : official journal of the Movement Disorder Society.

[43]  P. Nissen,et al.  Distribution of Na/K‐ATPase alpha 3 isoform, a sodium‐potassium P‐type pump associated with rapid‐onset of dystonia parkinsonism (RDP) in the adult mouse brain , 2011, The Journal of comparative neurology.

[44]  J. Hardy,et al.  Mutations in the Autoregulatory Domain of β-Tubulin 4a Cause Hereditary Dystonia , 2013, Annals of neurology.

[45]  Anand I. Rughani,et al.  Surgical treatment of myoclonus dystonia syndrome , 2013, Movement disorders : official journal of the Movement Disorder Society.

[46]  Steven J. M. Jones,et al.  A novel recurrent mutation in ATP1A3 causes CAPOS syndrome , 2014, Orphanet Journal of Rare Diseases.

[47]  A. Ferbert,et al.  Mutations in GNAL: a novel cause of craniocervical dystonia. , 2014, JAMA neurology.

[48]  K. Lohmann,et al.  Whispering dysphonia in an Australian family (DYT4): A clinical and genetic reappraisal , 2011, Movement disorders : official journal of the Movement Disorder Society.

[49]  M. Vidailhet,et al.  The multiple faces of the ATP1A3‐related dystonic movement disorder , 2013, Movement disorders : official journal of the Movement Disorder Society.

[50]  L. Lagae,et al.  A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. , 2013, American journal of human genetics.

[51]  F. Baas,et al.  DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation , 2010, Movement disorders : official journal of the Movement Disorder Society.

[52]  B. D. de Vries,et al.  Mutations in TITF-1 are associated with benign hereditary chorea. , 2002, Human molecular genetics.

[53]  T. Meitinger,et al.  Mutations in the gene encoding ɛ-sarcoglycan cause myoclonus–dystonia syndrome , 2001, Nature Genetics.

[54]  V. Visser-Vandewalle,et al.  Efficacy and safety of deep brain stimulation in patients with medication-induced tardive dyskinesia and/or dystonia: a systematic review. , 2012, The Journal of clinical psychiatry.

[55]  M. Stacy,et al.  New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. , 2012, Parkinsonism & related disorders.

[56]  R. Alterman,et al.  Pallidal deep brain stimulation for DYT6 dystonia , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[57]  A. Lang,et al.  A novel locus for inherited myoclonus-dystonia on 18p11 , 2002, Neurology.

[58]  Z. Wszolek,et al.  Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. , 2013, Human molecular genetics.

[59]  A. Lozano,et al.  Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years. , 2013, Brain : a journal of neurology.

[60]  J. Jankovic.  Medical treatment of dystonia , 2013, Movement disorders : official journal of the Movement Disorder Society.

[61]  S. Schneider,et al.  Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. , 2012, American journal of human genetics.

[62]  Nicholas W Wood,et al.  Ataxia telangiectasia presenting as dopa-responsive cervical dystonia , 2013, Neurology.

[63]  P. Bauer,et al.  Screening of mutations in GNAL in sporadic dystonia patients , 2014, Movement disorders : official journal of the Movement Disorder Society.

[64]  Günther Deuschl,et al.  Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial , 2012, The Lancet Neurology.

[65]  S. Schneider,et al.  Familial dopa-responsive cervical dystonia , 2006, Neurology.

[66]  K. Bhatia,et al.  No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia , 2014, Movement disorders : official journal of the Movement Disorder Society.

[67]  M. Hariz,et al.  Which patients with dystonia benefit from deep brain stimulation? A metaregression of individual patient outcomes , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[68]  C. Gerloff,et al.  Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families , 2010, Movement disorders : official journal of the Movement Disorder Society.

[69]  J. Hardy,et al.  Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency , 2012, Neurology.

[70]  I. Parees,et al.  The syndrome of deafness‐dystonia: Clinical and genetic heterogeneity , 2013, Movement disorders : official journal of the Movement Disorder Society.

[71]  C. Gieger,et al.  Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls , 2014, Movement disorders : official journal of the Movement Disorder Society.

[72]  P. Starr,et al.  Shorter disease duration correlates with improved long-term deep brain stimulation outcomes in young-onset DYT1 dystonia. , 2012, Neurosurgery.

[73]  D. Zafeiriou,et al.  Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. , 2010, Brain : a journal of neurology.

[74]  J Jankovic,et al.  Paroxysmal dyskinesias: Clinical features and classification , 1995, Annals of neurology.