BioMed Central Orphanet Journal of Rare Diseases ss Open AcceReview Early onset torsion dystonia (Oppenheim's dystonia) Christoph Kamm* Address: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany Email: Christoph Kamm* - christoph.kamm@uni-tuebingen.de * Corresponding author Abstract Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities. Disease name and synonyms Early onset torsion dystonia Oppenheim's dystonia Dystonia musculorum deformans Definition Early onset torsion dystonia (EOTD) is characterized by involuntary, repetitive, sustained muscle contractions or postures, typically of the limbs, which may spread to other body parts, in the absence of other neurological abnormalities. It is inherited in an autosomal dominant Published: 27 November 2006 Orphanet Journal of Rare Diseases 2006, 1:48 doi:10.1186/1750-1172-1-48 Received: 11 October 2006 Accepted: 27 November 2006 This article is available from: http://www.OJRD.com/content/1/1/48 © 2006 Kamm; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Page 1 of 6 (page number not for citation purposes) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17129379 http://www.OJRD.com/content/1/1/48 http://creativecommons.org/licenses/by/2.0 http://www.biomedcentral.com/ http://www.biomedcentral.com/info/about/charter/ Orphanet Journal of Rare Diseases 2006, 1:48 http://www.OJRD.com/content/1/1/48 fashion with a penetrance of only 30–40% [1], suggesting that various genetic and/or environmental factors contrib- ute to development of the disease. The majority of cases are caused by a deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. The term "Dystonia" in general refers to a large diverse group of movement disorders involving involuntary mus- cle contractions or postures. It may be classified in three ways: (1) clinically, i.e. according to age at onset or distribution of affected body regions; (2) etiologically, i.e. into primary, secondary, dystonia- plus or heredodegenerative; (3) genetically, with 15 loci described to date. Diagnostic criteria The following diagnostic criteria have been established for EOTD [1-3]: Definite dystonia Characteristic overt twisting or directional movements and postures that are consistently present. Probable dystonia Postures or movements suggestive of dystonia that are insufficient in intensity or consistency to merit classifica- tion as definite (e.g. excessively tense and labored writing with minimal posturing, flurries of blinking but no epi- sodes of sustained closure, etc.). Possible dystonia Muscle contractions not considered abnormal but remotely suggestive of dystonia (e.g. unusual hand grip with mild excess hand tension but normal flowing hand- writing, increased blinking with no flurries or sustained contractions, etc.). Only the category of "definite dystonia" was shown to be 100% specific in DYT1 families [3], suggesting that only those patients with definite signs of dystonia should be considered affected in genetic research studies. Epidemiology EOTD is a rare disease, with an estimated prevalence of 3.4:100,000 and annual incidence of 0.2:100,000 in Rochester, Minnesota [4]. The prevalence in the Ashkenazi Jewish (AJ) population is estimated to be five to ten times higher [5], due to a founder mutation which appears to have arisen approximately 350 years ago in Byelorussia/Lithuania [6]. The frequency of the DYT1 GAG deletion in the AJ population is high, between 1:2000 and 1:6000. In contrast, the prevalence in the gen- eral population of Europe seems to be lower. Estimates range from 0.3 to 0.5:100,000 although precise numbers are currently not available. Clinical description EOTD is characterized by involuntary, repetitive, sus- tained muscle contractions or postures involving one or more sites of the body. Typically, symptoms develop first in an arm or leg in middle to late childhood (mean age of onset: 12.5 years) [7] and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years [8]. "Torsion" refers to the twisting nature of body movements observed in EOTD, often affecting the trunk. Patients may be severely physically incapacitated, but are normal intellectually and show no other neurological symptoms. Distribution and severity of symptoms vary widely between affected individuals, ranging from mild focal dystonia, e.g. writer's cramp [9] to severe generalized dystonia, even within families [10]. Earlier age of onset and onset in the legs predicts a more severe clinical course, i.e. development of generalized dys- tonia [11,12]. The DYT1 GAG deletion is responsible for the majority of typical early onset dystonia cases of diverse ethnic origins, whether inherited or caused by a de novo mutation, whereas only a small minority of patients with atypical, e.g. focal dystonia, harbor this mutation [7,13-18]. If mutant gene carriers pass the age of approximately 28 years without developing symptoms, they usually escape the disease for life. Etiology Neuropathologically, EOTD is characterized by a lack of neurodegeneration, suggesting that neuronal dysfunction, rather than loss of neurons, underlies disease symptoms. However, cell bodies of dopaminergic neurons appear to be enlarged in brains from dystonia patients [19]. In the brains of four DYT1 patients, perinuclear inclusion bodies in specific brainstem areas (pedunculopontine nucleus, periaqueductal gray) have been reported [20]. These find- ings have been recapitulated in two different DYT1 animal models, both in transgenic mice overexpressing human mutant ∆E-torsinA [21] and in male DYT1 ∆GAG knock- in mice [22]. Despite the low penetrance of only 30–40% for clinical symptoms, functional imaging studies found metabolic hyperactivity in the lentiform nuclei, cerebel- lum and supplemental motor areas, and impaired sequence learning in both manifesting and non-manifest- ing carriers of the DYT1 GAG deletion, indicating that penetrance of the GAG deletion is greater than that assumed based on clinical grounds [23,24]. In addition, a recent study found that striatal D2 receptor binding was reduced in non-manifesting carriers of the DYT1 GAG Page 2 of 6 (page number not for citation purposes) Orphanet Journal of Rare Diseases 2006, 1:48 http://www.OJRD.com/content/1/1/48 deletion. This reduction may be a trait feature of DYT1 dystonia, with other factors being necessary for manifesta- tion of the signs and symptoms. Alternatively, clinical penetrance may be linked to the extent of the decrease in striatal D2 receptor binding [25]. The DYT1 gene encodes the torsinA protein. TorsinA is an endoplasmic reticulum/nuclear envelope (NE) ATP- dependent chaperone protein [26,27] involved in intrac- ellular trafficking [28]. Mutant ∆E-torsinA relocalizes to the NE [27,29,30], and postmigratory neurons from both torsinA null and homozygous mutant knock-in mice develop membrane abnormalities of the NE [31]. In addi- tion, recent studies in mammalian cell lines have shown that overexpression of wild-type torsinA appears to regu- late the intracellular trafficking of the dopamine trans- porter, whereas overexpression of mutant ∆EtorsinA had no effect. These results establish a potential link between torsinA and the dopaminergic system [59]. Several lines of evidence suggest that the disease is caused by a dysfunction of the basal ganglia: (1) Although torsinA is ubiquitously expressed, expression levels within the human brain are highest within dopaminergic neu- rons of the substantia nigra [32]; (2) Striatial [18F]dopa uptake is mildly reduced in manifesting DYT1 GAG dele- tion carriers [33]; (3) An increase in the ratio of dopamine metabolites to dopamine was found in the postmortem striatum of DYT1 dystonia brains as compared to controls [34]; (4) A phenotypically similar form of inherited dys- tonia, dopa-responsive dystonia (DRD), is caused by insufficient synthesis of dopamine [35,36], and sympto- matic dystonia frequently affects patients with acquired lesions of the basal ganglia (e.g. stroke) [37,38]. Diagnostic methods Molecular genetic diagnostic in conjunction with genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia [7]. Differential diagnosis Differential diagnosis includes other forms of primary dystonia and disorders in which dystonia is one of several neurological conditions present. The second large and diverse group includes the dystonia-plus syndromes, the heredodegenerative dystonias, the secondary ("sympto- matic") dystonias, other dystonia-like conditions, and early-onset parkinsonism. Other forms of primary dystonia (DYT2, 4, 6, 7 and 13) The phenotype of DYT2 dystonia, an autosomal recessive form of dystonia, resembles early onset torsion dystonia (DYT1) in three of the four families reported to date (early onset of symptoms, frequently in the feet, followed by rapid generalization) [39,40]. However, there is a debate as to whether the mode of inheritance in these families is actually autosomal recessive or autosomal dominant with reduced penetrance [41]. The DYT4 locus has been assigned to an Australian family with predominant whispering dysphonia and additional variable dystonic symptoms [42,43], clearly different phe- notypically from classical DYT1 dystonia. DYT6 refers to another autosomal dominant form of dys- tonia of mixed-type described in two German-Mennonite families [44]. In contrast to DYT1 dystonia, the average age at onset in these families was higher (18.6 years, range 5–38), and in many patients dystonic symptoms were pre- dominantly cranio-cervical, with progression to general- ized dystonia in only a few cases. DYT7 refers to a locus for adult-onset focal, predomi- nantly cervical dystonia mapped in a German family [45]. The DYT13 locus has been mapped in a non-Jewish Italian family [46] with mostly segmental dystonia with promi- nent cranio-cervical and arm involvement, more closely resembling the DYT6 than the DYT1 phenotype. Dystonia-plus (DYT5, DYT11 and DYT12) Dystonia-plus refers to conditions in which dystonia is one of only two neurological abnormalities present, the other usually being either parkinsonism or myoclonus. This group includes Dopa-Responsive Dystonia (DRD, DYT5), Myoclonus-Dystonia (DYT11) and Rapid Onset Dystonia-Parkinsonism (DYT12). Heredodegenerative dystonias (DYT3 and others) In heredodegenerative dystonias, dystonia is part of a more widespread neurodegenerative syndrome, often with known inheritance, and may or may not be a prom- inent feature. This large group includes X-linked Dysto- nia-Parkinsonism ("Lubag", DYT3), Idiopathic Parkinson's Disease (IPD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), Haller- vorden-Spatz Disease, Wilson's disease, Rett syndrome, Neuroacanthocytosis, and many others. Secondary dystonia Secondary (symptomatic) dystonias are caused by envi- ronmental insults such as stroke, tumors, infections, drugs and toxins or by metabolic disorders (e.g. homocysteinu- ria, metachromatic leukodystrophy, Lesch-Nyhan syn- drome, and others). Page 3 of 6 (page number not for citation purposes) Orphanet Journal of Rare Diseases 2006, 1:48 http://www.OJRD.com/content/1/1/48 Other dystonia-like conditions (DYT8, DYT9, and DYT10) This group includes conditions mimicking symptoms of dystonia (e.g. psychogenic dystonia or pseudodystonia) and paroxysmal disorders, such as paroxysmal non- kinesigenic dystonia (PNKD, DYT8), paroxysmal chore- oathetosis with episodic ataxia and spasticity (DYT9), par- oxysmal kinesigenic dystonia (PDK, DYT10), and others. Early onset parkinsonism A considerable proportion of early onset Parkinson's dis- ease, with onset of symptoms before 40 years of age, is caused by mutations in the Parkin gene [47] and fre- quently presents with dystonia, especially in the lower limbs [48]. Thus, this condition should be considered in the differential diagnosis of EOTD. Genetic counseling Based on a systematic genetic and clinical analysis of 267 individuals with primary torsion dystonia, including Ashkenazi Jewish and non-Jewish patients, diagnostic DYT1 testing in conjunction with genetic counseling is recommended for individuals with an age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical EOTD [7]. Genetic counseling should take into account that DYT1 dystonia is inherited in an autosomal dominant manner with a low penetrance of 30–40% and great clinical varia- bility. Few cases of de novo mutations have been reported [49,50]. Asymptomatic adult relatives should be informed before testing that onset of DYT1 dystonia after age 26 is very unlikely, and that, if it occurs, symptoms are usually mild and unlikely to progress [7]. Testing of asympto- matic at-risk individuals during childhood is not recom- mended. In addition to prenatal testing through chorionic villus sampling, preimplantation genetic diagnosis has recently been reported [51]. Management including treatment Drug therapy As DRD (DYT5) is phenotypically very similar to EOTD, but its symptoms, in contrast to EOTD, typically respond very well to dopaminergic therapy, it is recommended that every patient with early onset focal dystonia (onset below 26 years) be given a trial of L-Dopa/decarboxylase inhibitor, starting with 1 mg/kg per day of levodopa and slowly increasing until complete benefit is achieved or dose-limiting side effects appear. Most DRD patients respond well to 4–5 mg/kg per day [52]. In general, drug therapy in EOTD is not very effective. Anticholinergics, especially in a high dosage (e.g. trihex- iphenydil up to 30–60 mg/day), are the only substance class for which controlled studies are available [53]. Dos- age should be increased very slowly to prevent side effects such as cognitive or memory deficits, which are frequently dose-limiting, although children can generally tolerate much higher doses than adults. Other substances, which may or may not be effective, include baclofen, benzodi- azepines such as diazepam or clonazepam, pimozid or tetrabenazin. In severe cases of segmental or generalized dystonia, especially of the lower body and trunk, intrath- ecal baclofen administration may be considered [54]. Botulinum toxin injections Independent of genetic background, local botulinum toxin injections directly into affected muscles now repre- sent the first line treatment of focal dystonias (reviewed in [55]). Therefore, botulinum toxin injections by trained movement disorder specialists may be a useful therapy for selected muscle groups in EOTD, such as neck muscles for torticollis, facial muscles for blepharospasm or hand/arm muscles for writer's cramp. If successful, the injections need to be repeated on a regular basis (usually every 3–6 months). Surgical approaches Due to technical advances in recent years, interest in func- tional surgical approaches in dystonia has been renewed, in particular deep brain stimulation (DBS) of the globus pallidus and pallidotomy (reviewed in [56]). Although experience with this approach is still limited, preliminary results in patients with primary generalized dystonia, especially DYT1 GAG deletion carriers, are very promising [57]. Therefore, DBS may be helpful in selected EOTD patients with severe generalized dystonia. Prognosis Only few studies on the natural history of EOTD in genet- ically confirmed patients have been conducted. In one report following the clinical course of 33 patients from Israel [58], 63.6% had progressed into generalized dysto- nia after a mean of 15.5 +/- 13.8 years of symptoms, 15% were wheelchair-bound and 9% were using walking aids. All patients had normal cognitive function. Despite the high rate of generalization, 75% of those patients were able to maintain ambulation and independence, and therefore a comparatively good quality of life, with mod- ern treatments combining drugs, botulinum toxin and functional neurosurgery. Unresolved questions Very little is known yet about the normal cellular function of the torsinA protein. Further studies are required to address how mutant torsinA causes neuronal dysfunction, and how this mutation leads to a dominantly inherited disease with a markedly low penetrance and a very selec- tive neurological phenotype. Since the age of onset is asso- ciated with a period of motor learning and high synaptic plasticity, a possible role of torsinA in coordinated neuro- nal development merits further investigation. 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Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp BioMedcentral 42. Ahmad F, Davis MB, Waddy HM, Oley CA, Marsden CD, Harding AE: Evidence for locus heterogeneity in autosomal dominant torsion dystonia. Genomics 1993, 15:9-12. 43. Parker N: Hereditary whispering dysphonia. J Neurol Neurosurg Psychiatry 1985, 48:218-224. 44. Almasy L, Bressman SB, Raymond D, Kramer PL, Greene PE, Heiman GA, Ford B, Yount J, de Leon D, Chouinard S, Saunders-Pullman R, Brin MF, Kapoor RP, Jones AC, Shen H, Fahn S, Risch NJ, Nygaard TG: Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 1997, 42:670-673. 45. 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