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1.
Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dtsz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder. 相似文献
2.
Although dystonias are a common group of movement disorders, the mechanisms by which brain dysfunction results in dystonia are not understood. Rapid-onset Dystonia-Parkinsonism (RDP) is a hereditary dystonia caused by mutations in the ATP1A3 gene. Affected individuals can be free of symptoms for years, but rapidly develop persistent dystonia and Parkinsonism-like symptoms after a stressful experience. Using a mouse model, we found that an adverse interaction between the cerebellum and basal ganglia can account for the symptoms of these individuals. The primary instigator of dystonia was the cerebellum, whose aberrant activity altered basal ganglia function, which in turn caused dystonia. This adverse interaction between the cerebellum and basal ganglia was mediated through a di-synaptic thalamic pathway that, when severed, alleviated dystonia. Our results provide a unifying hypothesis for the involvement of cerebellum and basal ganglia in the generation of dystonia and suggest therapeutic strategies for the treatment of RDP. 相似文献
3.
Anna Kuukasjrvi Juan C. Landoni Jyrki Kaukonen Mika Juhakoski Mari Auranen Tommi Torkkeli Vidya Velagapudi Anu Suomalainen 《European journal of human genetics : EJHG》2021,29(12):1833
The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.Subject terms: Movement disorders, Disease genetics 相似文献
4.
TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice 总被引:3,自引:0,他引:3
Kuner R Teismann P Trutzel A Naim J Richter A Schmidt N Bach A Ferger B Schneider A 《Neuroscience letters》2004,355(1-2):126-130
Early-onset torsion dystonias are caused by a mutation in TorsinA, a protein widely expressed in the nervous system. Here we report the cloning of the murine TorsinA cDNA and a mRNA in situ hybridization analysis of the expression patterns of TorsinA over developmental periods relevant to the etiology of early-onset dystonias. Several studies have demonstrated a functional involvement of the nigrostriatal dopaminergic system in pathological mechanisms underlying dystonia. In this study, we show that the expression of TorsinA is significantly increased in the brain within hours of treatment with the dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, suggesting that the TorsinA gene is regulated by cellular stress. These results provide insights into the pathophysiology of early-onset dystonia and strengthen links between the dopaminergic system and dystonia. 相似文献
5.
《Molecular genetics and metabolism》2023,138(1):106970
BackgroundCerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described.ObjectivesTo report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic.MethodsWe conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP.ResultsFour children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech.ConclusionADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions. 相似文献
6.
A family study of 32 patients with torsion dystonia has shown at least two forms of generalized dystonia with onset in childhood. These two forms, an autosomal dominant and an autosomal recessive, are clinically indistinguishable. There were at least three families and probably about six to eight patients with the autosomal recessive variety. The remaining nine to 11 patients with generalized childhood dystonia are thought, because of a probable paternal age effect, to be examples of new dominant mutations. Since fitness with childhood onset is 1/20 of normal, most childhood dominant cases appear sporadically. Most of the other 15 patients (12 with onset in adult life) appear to have a non-genetic torsion dystonia, although an example of a benign adult-onset dominant form associated with a tremor has been observed. It is concluded that there are at least two forms of genetic torsion dystonia, an autosomal recessive form with onset in childhood, which, on evidence from America, is particularly common in Ashkenazi Jews, and one or more dominant forms, with onset in childhood or adult life. The majority of adult-onset isolated cases of idiopathic torsion dystonia seem to be due to exogenous but unidentified causes. 相似文献
7.
Nicoline Schiess David S. Zee Khurram A. Siddiqui Miklos Szolics Ayman W. El-Hattab 《Journal of neurogenetics》2017,31(1-2):23-25
The phenotypic and genetic spectrum of ataxia with oculomotor apraxia (AOA) disorders is rapidly evolving and new technologies such as genetic mapping using whole exome sequencing reveal subtle distinctions among the various subtypes. We report a novel PNKP mutation in two siblings with progressive ataxia, abnormal saccades, sensorimotor neuropathy and dystonia consistent with the AOA type 4 phenotype. Laboratory evaluation revealed hypoalbuminemia, hypercholesterolemia with elevated LDL, elevated IgE levels and normal α fetoprotein levels. Eye movement examination demonstrated a marked saccade initiation defect with profound hypometric horizontal saccades. Vertical saccades were also affected but less so. Also present were conspicuous thrusting head movements when attempting to change gaze, but rather than an apraxia these were an adaptive strategy to take advantage of an intact vestibulo-ocular reflex to carry the eyes to a new target of interest. This is demonstrated in accompanying videos. 相似文献
8.
Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes 总被引:2,自引:0,他引:2
Tezenas du Montcel S Clot F Vidailhet M Roze E Damier P Jedynak CP Camuzat A Lagueny A Vercueil L Doummar D Guyant-Maréchal L Houeto JL Ponsot G Thobois S Cournelle MA Durr A Durif F Echenne B Hannequin D Tranchant C Brice A;French Dystonia Network 《Journal of medical genetics》2006,43(5):394-400
Background
Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon‐sarcoglycan gene (SGCE) on chromosome 7q21.Methods
We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M‐D), essential myoclonus (E‐M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested.Results
Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M‐D and five E‐M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non‐carriers. None of the patients had severe psychiatric disorders.Conclusion
This large cohort of index patients shows that SGCE mutations are primarily found in patients with M‐D and to a lesser extent E‐M, but are present in only 30% of these patients combined (M‐D and E‐M). 相似文献9.
Mihara K Kondo T Higuchi H Takahashi H Yoshida K Shimizu T Kaneko S 《American journal of medical genetics》2002,114(6):693-695
Tardive dystonia is an uncommon but intractable and distressing complication of neuroleptic treatment. It is suggested that individual predisposing vulnerability plays a major role in the development of the side effect. This study aimed to investigate relationship tardive dystonia and several genetic factors such as polymorphism of cytochrome P4502D6, and receptor polymorphisms of dopamine D(2) (TaqI A and -141C Ins/Del polymorphisms) and D(3) (Ser(9)Gly polymorphism). Nine patients with tardive dystonia were genotyped for these genetic polymorphisms. No specific genotypes or alleles were overpresented in the patients. This study suggests that these polymorphisms are not related to the development of tardive dystonia. 相似文献
10.
N. Diederich C. G. Goetz C. L. Comella 《Journal of molecular medicine (Berlin, Germany)》1990,68(19):935-941
Summary At this point the treatment of dystonias remains highly empirical. Secondary dystonias, especially those related to specific drug treatment, have to be ruled out carefully. A few dystonic subgroups respond well to levodopa medication. In the other syndromes, anticholinergics are the usual first choice. In focal conditions botulinum toxin injections seem to be the most effective regimen, although there are only a few long-term studies. Surgical procedures are an ultimate option.Abbreviations PET
positron emission tomography
- CT
computer tomography
- MRI
magnetic resonance imaging
- HIV
human immundeficiency virus
- EMG
electromyography
- AIDS
acquired immunodeficiency virus
- PTH
parathyroid hormone
- DMD
dystonia musculorum deformans 相似文献
11.
The authors present three patients from a consanguineous family afflicted with novel recessive myoclonic epilepsy characterized by very early onset and a steadily progressive course. The onset is in early infancy, and death occurs in the first decade. In addition to various types of myoclonic seizures, episodic phenomena such as dystonias, postictal enduring hemipareses, autonomic involvements, and periods of obtundation and lethargy were also observed. Developmental and neurological retardation, coupled with systemic infections, leads to a full deterioration. The authors designated the disease progressive myoclonic epilepsy with dystonia (PMED). A genome scan for the family and subsequent fine mapping localized the gene responsible for the disease to the most telomeric 6.73 mega base pairs at the p-terminus of chromosome 16, with a maximum multipoint logarithm-of-odds score of 7.83 and a maximum two-point score of 4.25. A candidate gene was analyzed for mutations in patients, but no mutation was found. 相似文献
12.
Illarioshkin SN 《Vestnik Rossi?sko? akademii meditsinskikh nauk / Rossi?skaia akademiia meditsinskikh nauk》1999,(10):40-45
The molecular genetic basis of a large group of monogenic hereditary neurological diseases is analyzed. Emphasis is laid on different types of mutations causing Huntington's chorea, autosomal dominant ataxias, Friedreich's disease, dopa-responsive and nondopa-responsive forms of torsion dystonia: the frequencies of these mutations and their molecular characteristics have been first investigated in the Russian population. Relationships between particular genotypes and various clinical variants of these disorders are analyzed. Genetic loci for two novel hereditary diseases of the nervous system, such as X-linked congenital cerebellar hypoplasia and an atypical form of autosomal recessive muscular dystrophy are characterized. Nosological entities of these clinical forms are substantiated in accordance with molecular genetic findings. DNA diagnostic techniques have been developed, which allows medical genetic counselling and prevention of relapses to be made in genetically burden families. 相似文献
13.
A study of Danish probands with primary torsion dystonia is presented. The probands were examined clinically and biochemically to exclude secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were performed on 107 probands; and the mutation was detected in three. All three probands had the classical phenotype of DYT1-dystonia, but only one had a family history of dystonia. The other two probands had, obviously, sporadic DYT1-dystonia, one of which was caused by a de novo mutation, while the other one had a parent being an asymptomatic carrier. De novo mutations in the DYT1 gene are seldom reported although independent founder mutations are known to have occurred. The frequency of DYT1-dystonia was low in our study even though several probands had early onset generalised dystonia. None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia exemplified by DYT1-dystonia are outlined. 相似文献
14.
Panic disorders, a subgroup of the primary anxiety disorders, have an estimated worldwide prevalence of 2.5% to 5%. Although the causes of these disorders have not been completely elucidated, it seems that environmental and genetic factors in addition to central nervous system biochemical abnormalities play important roles. Mild to moderate anxiety levels may prove advantageous in the management of asthmatics but when their anxiety level becomes maladaptive, as in the case of panic attacks, their medical care is placed in jeopardy. Herein are three case reports of asthmatics who also exhibited panic disorders and their clinical outcome. It is concluded that a team approach, involving the primary physician and psychologist or psychiatrist, is beneficial in the long-term management of these patients. 相似文献
15.
Li-Xi Li Ying Liu Jie-Hong Huang Yi Yang You-Gui Pan Xiao-Long Zhang Li-Zhen Pan Ling-Jing Jin 《Clinical genetics》2023,103(4):459-465
Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia. 相似文献
16.
Pietro Invernizzi 《Journal of autoimmunity》2010,34(3):J300-J306
Autoimmune liver diseases are characterized by immune mediated injury of bile ducts or hepatocytes, thus including cholangiopathies such as primary biliary cirrhosis, primary sclerosing cholangitis, and immunoglobulin G4-associated cholangitis, and autoimmune hepatitis. Although the liver was one of the earliest recognized sites of autoimmune aggression, the aetiology of autoimmune liver diseases remains largely obscure and their clinical management still difficult. Since an ever increasing applicability of immunology to a wide variety of chronic diseases, basic and clinical knowledge on autoimmune liver diseases grow rapidly in the last few years. This review will mainly focus on the available geoepidemiology data of these disorders, but it will deal also on their main clinical characteristics, as well as mechanisms of etiopathogenesis, for each of the above diseases, together with their overlap forms. In particular, we will discuss the major underlying immunomolecular mechanisms of development, the genetic influences, the growing number of immuno-serological diagnostic markers, and the increasingly effective therapeutic possibilities. 相似文献
17.
Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy 总被引:13,自引:0,他引:13
van Hilten BJ van de Beek WJ Hoff JI Voormolen JH Delhaas EM 《The New England journal of medicine》2000,343(9):625-630
BACKGROUND AND METHODS: Patients with reflex sympathetic dystrophy (also known as the complex regional pain syndrome) may have dystonia, which is often unresponsive to treatment. Some forms of dystonia respond to the intrathecal administration of baclofen, a specific gamma-aminobutyric acid-receptor (type B) agonist that inhibits sensory input to the neurons of the spinal cord. We evaluated this treatment in seven women who had reflex sympathetic dystrophy with multifocal or generalized tonic dystonia. First, we performed a double-blind, randomized, controlled crossover trial of bolus intrathecal injections of 25, 50, and 75 microg of baclofen and placebo. Changes in the severity of dystonia were assessed by the woman and by an investigator after each injection. In the second phase of the study, six of the women received a subcutaneous pump for continuous intrathecal administration of baclofen and were followed for 0.5 to 3 years. RESULTS: In six women, bolus injections of 50 and 75 microg of baclofen resulted in complete or partial resolution of focal dystonia of the hands but little improvement in dystonia of the legs. During continuous therapy, three women regained normal hand function, and two of these three women regained the ability to walk (one only indoors). In one woman who received continuous therapy, the pain and violent jerks disappeared and the dystonic posturing of the arm decreased. In two women the spasms or restlessness of the legs decreased, without any change in the dystonia. CONCLUSIONS: In some patients, the dystonia associated with reflex sympathetic dystrophy responds markedly to intrathecal baclofen. 相似文献
18.
Washington K 《Advances in anatomic pathology》2002,9(4):244-250
Variant forms of chronic cholestatic liver disease in adults, such as autoimmune cholangitis, primary biliary cirrhosis-autoimmune hepatitis overlap, and primary sclerosing cholangitis-autoimmune hepatitis overlap constitute approximately 20% of cases of autoimmune liver disease. Retrospective study design may obscure subtle differences in clinical features. Careful prospective studies are needed to help clarify classification of these disorders. Autoimmune cholangitis is often considered synonymous with antimitochondrial antibody-negative primary biliary cirrhosis, but may instead be a heterogeneous group of disorders including some cases of isolated small duct primary sclerosing cholangitis. The variable response of variant syndromes to established therapies such as corticosteroids provides justification for continued efforts to define their clinicopathologic features. 相似文献
19.
Recent application of genetic linkage analysis to the affective disorders has suggested that there are at least three genotypic forms. This is an important step toward defining the genetic etiology involved, as it had previously been suggested that the complex nature of the clinical phenotype would preclude any attempt to apply such a technique. However, to date no clinical evidence exists to discriminate these genotypes at the phenotypic level. Molecular geneticists now face a formidable task of identifying the aberrant gene and relating the gene product, a protein, to the observed psychopathology. Current molecular genetic research in the affective disorders is discussed and similar work applied to the study of nonpsychiatric disorders such as cystic fibrosis and Duchenne muscular dystrophy is reviewed. The clinical value of genetic risk analysis for individuals with a family history of the affective disorders is also considered.The preparation of this paper was supported by a Berenice Clarke Legacy Research Grant (University College London), the Mental Health Foundation (M.J.M.), and the Wellcome Trust (H.M.D.G.). 相似文献
20.
Antibody deficiencies may arise as primary disorders or secondary to a variety of diseases, drugs and other environmental/iatrogenic factors. Significant primary antibody deficiencies are relatively rare but, collectively, account for the majority of primary immunodeficiency syndromes encountered in clinical practice. The genetic basis of a number of primary deficiencies has been clarified, although there is considerable genotype/phenotype heterogeneity and the role of gene/environment interactions has yet to be fully elucidated. Primary antibody deficiency can present at any age. The hallmark clinical presentation is recurrent bacterial infection, but these disorders are also associated with a wide variety of other infectious and non-infectious complications and with a high incidence of chronic, structural tissue damage, particularly in the respiratory tract. Clinical recognition of primary antibody deficiency is frequently delayed with consequent increased morbidity, diminished quality of life and early mortality. Clinical laboratories can contribute to improved and timely detection through awareness of routine test results which may be overtly or indirectly suggestive of antibody deficiency. Secondary deficiency is associated with increased awareness, better recognition and earlier diagnosis than in primary disorders. Early liaison and referral of patients with suspected antibody deficiency for specialist opinion and prompt, appropriate therapy is central to the achievement of good clinical outcomes. 相似文献