“Jerky” dystonia in children: Spectrum of phenotypes and genetic testing

Hyperkinetic dystonia is characterized by phasic, tremulous, and “jerky” movements in addition to twisting postures. We studied longitudinally 23 index patients with hyperkinetic dystonia from a quaternary pediatric movement disorder clinic in Ireland. Four clinical categories emerged: (1) Eight patients were diagnosed with myoclonus‐dystonia, of whom seven carried heterozygous epsilon sarcoglycan (SGCE) mutations, including a novel deletion of exon 10. Gait disorder, unsteadiness, or frequent falls before 18 months were detected in all SGCE mutation carriers, whereas the typical neck‐predominant presentation developed only years later. (2) One patient classified as benign hereditary chorea, because jerks were choreiform and continuous rather than action‐induced, carried a heterozygous stop mutation of the TITF‐1 gene (Y114X, exon 2). (3) Three mutation‐negative patients were grouped as “myoclonic dystonia” with jerks only in the body regions affected by dystonia. (4) Eleven patients presented with a novel combination of dystonia and low amplitude poly‐mini myoclonus of the upper limbs and pectoral muscles (D‐PMM). In early childhood up to 3 years of age, an initial presentation with predominant gait impairment with only subtle jerks should prompt consideration of SGCE mutation analysis in addition to testing for DYT1 mutations. A causative gene for D‐PMM remains to be identified. © 2008 Movement Disorder Society     

Paroxysmal dyskinesia with interictal myoclonus and dystonia: a report of two cases

Idiopathic paroxysmal dyskinesias (PxD) are characterized by attacks of hyperkinetic movement, with no inter-ictal symptoms. We report two cases, one with paroxysmal kinesigenic dyskinesia and another with paroxysmal exercise-induced dystonia, both of whom had myoclonus and dystonia between attacks. This previously unreported association highlights the heterogeneity of paroxysmal movement disorders.     

A prospective study of acute movement disorders in children

Aim The purpose of this study was to report a prospective cohort of children with acute‐onset movement disorders. Method We report on 52 individuals (31 females, 21 males; mean age 6y 5mo, range 2mo–15y) with acute‐onset movement disorders managed at a busy tertiary paediatric referral hospital over a 40‐month period. Results In descending order of frequency, the movement disorders reported were chorea, dystonia, tremor, myoclonus, and parkinsonism. It was possible to divide the participants into three groups: (1) those with inflammatory or autoimmune disorders (n=22), (2) those with non‐inflammatory disorders (n=18), and (3) those with psychogenic disorders (n=12). The inflammatory or autoimmune aetiologies included N‐methyl‐d ‐aspartate receptor encephalitis (n=5), opsoclonus–myoclonus syndrome (n=4), Sydenham chorea (n=3), systemic lupus erythematosus (n=3), acute necrotizing encephalopathy (n=3), and other types of encephalitis (n=4). Other important non‐inflammatory movement disorder aetiologies included drug‐induced movement disorder (n=6), post‐pump chorea (n=5), metabolic (n=3) and vascular (n=2) disease. The participants with psychogenic movement disorders (n=12) were all over 10 years of age and were more likely to be female. Tremor and myoclonus were significantly over‐represented in the psychogenic movement disorder subgroup. The outcomes of the total cohort were variable, and included full recovery, severe morbidity, and death. Interpretation Acute‐onset movement disorders in children are important and may be treatable. Management should focus upon identifying the cause and treating the underlying disease process, as symptomatic treatment of the abnormal movements is variably effective.     

Nomenclature of Genetically Determined Myoclonus Syndromes: Recommendations of the International Parkinson and Movement Disorder Society Task Force

Genetically determined myoclonus disorders are a result of a large number of genes. They have wide clinical variation and no systematic nomenclature. With next‐generation sequencing, genetic diagnostics require stringent criteria to associate genes and phenotype. To improve (future) classification and recognition of genetically determined movement disorders, the Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders (2012) advocates and renews the naming system of locus symbols. Here, we propose a nomenclature for myoclonus syndromes and related disorders with myoclonic jerks (hyperekplexia and myoclonic epileptic encephalopathies) to guide clinicians in their diagnostic approach to patients with these disorders. Sixty‐seven genes were included in the nomenclature. They were divided into 3 subgroups: prominent myoclonus syndromes, 35 genes; prominent myoclonus syndromes combined with another prominent movement disorder, 9 genes; disorders that present usually with other phenotypes but can manifest as a prominent myoclonus syndrome, 23 genes. An additional movement disorder is seen in nearly all myoclonus syndromes: ataxia (n = 41), ataxia and dystonia (n = 6), and dystonia (n = 5). However, no additional movement disorders were seen in related disorders. Cognitive decline and epilepsy are present in the vast majority. The anatomical origin of myoclonus is known in 64% of genetic disorders: cortical (n = 34), noncortical areas (n = 8), and both (n = 1). Cortical myoclonus is commonly seen in association with ataxia, and noncortical myoclonus is often seen with myoclonus‐dystonia. This new nomenclature of myoclonus will guide diagnostic testing and phenotype classification. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Proline‐rich transmembrane protein 2–negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients

Background : Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline‐rich transmembrane protein 2 mutations. Objective : The objective of this study was to investigate potential causative genes and clinical characteristics in proline‐rich transmembrane protein 2–negative patients with paroxysmal kinesigenic dyskinesia. Methods : We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline‐rich transmembrane protein 2–negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. Results : The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium‐activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage‐gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage‐gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl‐10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl‐10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. Conclusions : Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society     

Genetics of paroxysmal dyskinesias

Paroxysmal dyskinesias (PDs) are a heterogeneous group of disorders characterized by sudden attacks of involuntary movements that are mostly a combination of dystonia, chorea, athetosis, and ballism. They can sometimes be symptomatic, but usually an underlying cerebral lesion is not present. Most PDs have a genetic background and are divided into kinesigenic, nonkinesigenic, and exercise-induced forms. Recently, the first genes have been identified for paroxysmal nonkinesigenic dyskinesia (MR1) and paroxysmal exercise-induced dyskinesia (PED) (SLC2A1). Whereas the function of the MR-1 protein and the pathophysiology are still poorly understood, mutations in SLC2A1 and their functional characterization predict a reduced transport of glucose across the blood-brain barrier as the underlying mechanism of PED. A locus on chromosome 16 has been described for the kinesigenic forms, but the underlying genetic alterations are unknown. This review summarizes clinical symptoms of the PDs, imaging findings, therapeutic options, and the pathophysiologic background.     

Paroxysmal dystonia as an initial presentation of multiple sclerosis posing a diagnostic challenge

Tremor is the most common and frequently reported movement disorder in multiple sclerosis (MS). Paroxysmal dystonia (PD), also known as painful tonic spasm (PTS), is a relatively less common but well-recognized movement disorder in multiple sclerosis (MS). These are characterized by episodic attacks of involuntary flexion, extension movements of body. Such paroxysmal symptoms as an initial presenting feature raise many differential diagnoses and can often be mistaken as epileptic seizures as well as psychogenic events and may sometimes lead to delay in diagnosis as well. Diagnosis is clinical with the help of supportive investigations to rule out other paroxysmal disorders, especially epileptic seizures. We describe a case of a young lady, who was referred to us as a case of refractory seizure and diagnosed as having paroxysmal dystonia as a first manifestation of MS, with complete resolution of her symptoms after successful treatment with anti-epileptic drugs.

Paroxysmal dystonia (PD), also called Painful tonic spasm (PTS), is a well-recognized and the most frequently observed movement disorder in multiple sclerosis.1 The PD is classified as 4 types according to the precipitating factors, phenomenology, duration of attacks, and etiology. Paroxysmal kinesigenic dyskinesia (PKD) is induced by sudden movement, paroxys¬mal non-kinesigenic dyskinesia occurs spontaneously, paroxysmal exertion-induced dyskinesia appears after prolonged exercise, and paroxysmal hypnogenic dyskinesia occurs during sleep.2 These disorders have often been misdiagnosed as partial onset epilepsy initially and later identified as movement disorder secondary to MS. Treatment of underlying disease along with symptomatic treatment may alleviate the symptoms significantly. We described a case of a young lady who was referred to us as a case of psychogenic non-epileptic events. Diagnosis of MS manifesting with PD was established. She was started on disease modifying therapy for MS as well as Carbamazepine for her PD. She showed a remarkable improvement on these treatments and was followed up in MS clinic with no new MS relapse or recurrence of PD for 18 months after the initial presentation.     

The spectrum of movement disorders in Glut‐1 deficiency

To assess the spectrum of movement disorders, we reviewed video recordings and charts of 57 patients with Glut‐1 deficiency. Eighty‐nine percent of patients with Glut‐1 deficiency syndrome had a disturbance of gait. The most frequent gait abnormalities were ataxic‐spastic and ataxic. Action limb dystonia was observed in 86% of cases and mild chorea in 75%. Cerebellar action tremor was seen in 70% of patients, myoclonus in 16%, and dyspraxia in 21%. Nonepileptic paroxysmal events occurred in 28% of patients, and included episodes of ataxia, weakness, Parkinsonism and nonkinesogenic dyskinesias. The 40 patients (70%) who were on the ketogenic diet had less severe gait disturbances but more dystonia, chorea, tremor, myoclonus, dyspraxia, and paroxysmal events compared with the 17 patients on a conventional diet. Poor dietary compliance and low ketonuria appear to trigger the paroxysmal events in some patients. Gait disturbances and movement disorders are frequent in patients with Glut‐1 deficiency and are signs of chronic and intermittent pyramidal, cerebellar and extrapyramidal circuit dysfunction. These clinical symptoms reflect chronic nutrient deficiency during brain development and may be mitigated by chronic ketosis. © 2009 Movement Disorder Society     

Genetics of Primary Torsion Dystonia

Advances in the genetics of dystonia have further elucidated the pathophysiology of this clinically and etiologically heterogeneous group of movement disorders. Currently, 20 monogenic forms of dystonia, designated by the acronym DYT, are grouped as 1) pure dystonias, 2) dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes and loci, including the 1) detection of two primary dystonia genes (DYT6, DYT16), 2) identification of the DYT17 locus, 3) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 (glucose transporter of the blood–brain barrier) deficiency syndrome (DYT18), 4) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, and 5) redefinition of DYT14 as DYT5. Further, we review current knowledge regarding genetic modifiers and susceptibility factors. Because recognizing and diagnosing monogenic dystonias have important implications for patients and their families with regard to counseling, prognosis, and treatment, we highlight clinical “red flags” of individual subtypes and review guidelines for genetic testing.     

Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders.

We sought to review the long-term tolerability of tetrabenazine (TBZ) and seek determinants of tolerability in the treatment of hyperkinetic movement disorders. A retrospective chart review was performed on patients treated with TBZ between 1997 and 2004. Efficacy of TBZ was assessed by a 1- to 5-point response scale (1 = marked reduction in abnormal movements, 5 = worsening). All adverse events (AEs) were captured according to their relationship with study drug. A total of 448 patients (42% male) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19). The mean age at onset of the movement disorder was 43.0 +/- 24.2 years, with TBZ starting at a mean age of 50.0 +/- 22.3 years. Patients remained on treatment for a mean of 2.3 +/- 3.4 years. An efficacy response rating of 1 or 2 was sustained in the majority of patients between the first and last visit. Common AEs included drowsiness (25.0%), Parkinsonism (15.4%), depression (7.6%), and akathisia (7.6%). Comparison of log-likelihood ratios revealed that age was a reliable predictor of Parkinsonism (P < 0.0001). TBZ is a safe and effective drug for the long-term treatment of hyperkinetic movement disorders.     

Movement disorders at a university hospital emergency room

We prospectively evaluated the clinical features and etiologies of all common categories of movement disorder seen in the emergency room (ER) of an urban university hospital over a period of 12 months. We divided movement disorders according to the presenting phenomenology likely to dominate the clinical presentation, that is, gait disorder, tremor, dystonia, myoclonus, and acute akinetic crisis and classified a specific etiology in the individual phenomenology. In one year, there were 60,002 ER visits; of these, 58 (0.09 %) were diagnosed as a primary movement disorder. The most common clinical presentation was gait disorder (n = 21, 36.2 %), followed by myoclonus (n = 16, 27.6 %), dystonia (n = 10, 17.2 %), tremor (n = 8, 13.8 %), and acute akinetic crisis (n = 3, 5.2 %). Comparing the movement disorders, the mean age of the patients with dystonia was significantly lower than that of patients with other movement disorders (P < 0.001). Of the patients, 37 (63.8 %) had drug-related movement disorders. The contribution of drugs was significantly higher in patients with dystonia compared with the other movement disorders (P < 0.01). Our study showed that a large proportion of the movement disorders seen in the ER are drug-related. Careful selection of drugs while prescribing would decrease movement disorder-related visits to the ER.     

Myoclonus–dystonia syndrome: Clinical presentation,disease course,and genetic features in 11 families

Myoclonus–dystonia syndrome (MDS) is an inherited movement disorder with clinical and genetic heterogeneity. The epsilon sarcoglycan (SGCE) gene is an important cause of MDS. We report the results of a clinical and genetic study of 20 patients from 11 families. We disclosed six novel and two previously described mutations in nine families. The majority of patients had a phenotype of myoclonus and dystonia in combination, but clinical findings considered atypical, such a very early onset, distal myoclonus, and legs involvement, were detected in a significant proportion of cases. The disease course was variable, from progression to spontaneous remission of the motor symptoms. There were no obvious differences between mutation‐positive and ‐negative cases. © 2007 Movement Disorder Society     

Brain Calcification and Movement Disorders

Brain calcifications may be an incidental finding on neuroimaging in normal, particularly older individuals, but can also indicate numerous hereditary and nonhereditary syndromes, and metabolic, environmental, infectious, autoimmune, mitochondrial, traumatic, or toxic disorders. Bilateral calcifications most commonly affecting the basal ganglia may often be found in idiopathic cases, and a new term, primary familial brain calcification (PFBC), has been proposed that recognizes the genetic causes of the disorder and that calcifications occurred well beyond the basal ganglia. PFBC, usually inherited in an autosomal dominant fashion, is both an intrafamilial and an interfamilial heterogeneous disorder, clinically characterized by an insidious and progressive development of movement disorders, cognitive decline, and psychiatric symptoms, but also cerebellar ataxia, pyramidal signs, and sometimes isolated seizures and headaches/migraines. Heterozygous mutations in four genes (SLC20A2, PDGFRB, PDGFB, XPR1) have recently proved to be the causes of the autosomal dominant forms of PFBC, also suggesting disrupted phosphate homeostasis as “an underlying and converging” pathophysiological mechanism. However, to date, it is not possible to anticipate with acceptable certainty any of known genetic causes of PFBC on the basis of the type, severity, pattern of distribution, or combination of movement disorders (mainly parkinsonism, with or without tremor, but also dystonia, chorea, paroxysmal kinesigenic dyskinesia, orofacial dyskinesia, and gait and speech disorders).     

The paroxysmal dyskinesias

The clinical, pathophysiological and genetic features of some of the paroxysmal movement disorders are reviewed. Paroxysmal kinesigenic choreoathetosis/dyskinesias (PKC/PKD) is a condition in which brief and frequent dyskinetic attacks are provoked by sudden movement. PKC is more common in men and can be idiopathic (commonly familial) or due to a variety of causes. The pathophysiology of PKC is uncertain but it could be an ion-channel disorder. Antiepileptic drugs particularly carbamazepine are very helpful in a large proportion of cases. Paroxysmal exercise induced dystonia (PED) is a rare disorder manifesting as episodes of dystonia mostly affecting the feet induced by continuous exercise like walking or running. Although the initial cases were familial, there is a higher proportion of sporadic cases. The pathophysiology of PED is unknown and antiepileptic drugs are generally unhelpful. In paroxysmal dystonic choreoathetosis/ non-kinesigenic dyskinesias (PDC/ PNKD) the attacks are of long duration and induced by variety of factors including coffee, tea, alcohol and fatigue but not by sudden movement. PDC can be idiopathic (familial or sporadic) or symptomatic due to a variety of causes. The gene for familial PDC has been linked in 2 families to chromosome 2 q close to a cluster of ion channel genes again suggesting that this disorder may also be a channelopathy. Other paroxysmal disorders include paroxysmal nocturnal dyskinesia, a form of frontal lobe epilepsy in some cases which may be familial with autosomal dominant inheritance (ADNFLE). The gene for ADNFLE in one family has been found to be a mutation in the neuronal acetylcholine receptor gene (CHRNA4) on chromosome 20q. Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent torticollis in infants and children are other paroxysmal movement disorders. Received: 14 May 1998 Accepted: 23 May 1998     

41例发作性运动诱发性运动障碍临床与神经电生理分析

目的　观察发作性运动诱发性运动障碍 (PKMD)的临床特征及与癫的关系。方法　详细观察 4 1例PKMD的临床特征 ,影像学和脑电图改变。结果　 4 1例均由运动诱发 ,呈发作性运动诱发性舞蹈手足徐动症 30例 ,发作性运动诱发性肌张力障碍 11例 ,发作时意识清楚 ,影像学有异常者 6例 ,脑电图有样放电者 12例 ,其中 2例发作时有样放电 ,脑体感诱发电位半数以上病例有定位侧半球改变。对抗药有良效。结论　本症障碍的部位可能在感觉刺激的传入通路与发作症状的传出通路之间的反射中枢。具有某些癫性质 ,推测与癫发作可能有某些共同的生物学基础     

Movement disorders in Rett syndrome: An analysis of 60 patients with detected MECP2 mutation and correlation with mutation type

Rett syndrome (RS) is one of the best human models to study movement disorders. Patients evolve from a hyperkinetic to a hypokinetic state, and a large series of abnormal movements may be observed along their lives such as stereotypies, tremor, chorea, myoclonus, ataxia, dystonia, and rigidity. The aim of this work was to analyze movement disorders in RS patients with a detected MECP2 mutation, as well as their correlation with genotype, in a clinically and genetically well‐characterized sample of patients, and thus contribute to redefine the clinical profile of this disease. In this study, we included 60 patients with detected MECP2 mutations. These were categorized and grouped for analysis, according to (1) type of change (missense or truncating, including nonsense and frameshift but also large deletions) and (2) location of the mutation. Differences were found concerning the frequency of independent gait, dystonia, type of tremor, and global score severity when comparing the group of patients with missense and truncating mutations. We also found differences in the presence, distribution, severity, or type of movement disorders in the two groups of patients according to the median duration of the disease (less than 60 months; 60 months or more). We conclude that movement disorders seem to reflect the severity and rate of progression of Rett disorder, patients with truncating mutations presenting a higher rate and more severe dystonia and rigid‐akinetic syndrome, when comparing groups with similar time of disease evolution. © 2008 Movement Disorder Society     

A novel mutation of the ε‐sarcoglycan gene in a Chinese family with myoclonus‐dystonia syndrome

In a Chinese myoclonus‐dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the ε‐sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real‐time PCR, suggesting that the nonsense mutation might interference with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family. © 2008 Movement Disorder Society     

Substance abuse and movement disorders

An array of movement disorders is associated with ethanol, illicit drugs, and tobacco. Heavy ethanol users experience withdrawal tremor and, less often, withdrawal parkinsonism, chorea, and myoclonus. Asterixis is a feature of hepatic failure. On the other hand, ethanol can ameliorate essential tremor and myoclonus‐dystonia. Among opioid drugs, meperidine can precipitate myoclonus. Severe parkinsonism affected users of a synthetic meperidine analog contaminated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Spongiform leukoencephalopathy, sometimes with chorea and myoclonus, occurred in inhalers of heroin vapor (chasing the dragon). Psychostimulants including cocaine acutely cause stereotypies and dyskinesias. Phencyclidine toxicity causes myoclonus. Tobacco use, on the other hand, protects against Parkinson's disease. Clinicians need to consider substance abuse in patients with unexplained movement disorders. © 2010 Movement Disorder Society.     

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum

Background : Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. Objective : The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. Methods : In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video‐documented movement disorders was assessed. Voxel‐based morphometry from high‐resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. Results : Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult‐onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo‐ and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. Conclusion : This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper‐ and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult‐onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society