A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3?years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation.     

Extraocular muscle dystonia due to acquired (non‐Wilsonian) hepatocerebral degeneration

We present a video report of a patient with advanced non‐Wilsonian cirrhotic liver disease who developed extraocular muscle dystonia (oculogyric crisis) and severe orofaciolingual dyskinesias. Acquired hepatocerebral degeneration causes choreic movements, especially of cranial muscles, but dystonic ocular spasm is an infrequent manifestation of this disorder. This case illustrates that AHD should be considered in the differential diagnosis of extraocular muscle dystonia. © 2008 Movement Disorder Society     

Bayesian Interpretation of Essential Tremor Plus

Essential tremor (ET) plus is a new tremor classification that was introduced in 2018 by a task force of the International Parkinson and Movement Disorder Society. Patients with ET plus meet the criteria for ET but have one or more additional systemic or neurologic signs of uncertain significance or relevance to tremor (“soft signs”). Soft signs are not sufficient to diagnose another tremor syndrome or movement disorder, and soft signs in ET plus are known to have poor interrater reliability and low diagnostic sensitivity and specificity. Therefore, the clinical significance of ET plus must be interpreted probabilistically when judging whether a patient is more likely to have ET or a combined tremor syndrome, such as dystonic tremor. Such a probabilistic interpretation is possible with Bayesian analysis. This review presents a Bayesian analysis of ET plus in patients suspected of having ET versus a dystonic tremor syndrome, which is the most common differential diagnosis in patients referred for ET. Bayesian analysis of soft signs provides an estimate of the probability that a patient with possible ET is more likely to have an alternative diagnosis. ET plus is a distinct tremor classification and should not be viewed as a subtype of ET. ET plus covers a more-comprehensive phenotyping of people with possible ET, and the clinical interpretation of ET plus is enhanced with Bayesian analysis of associated soft signs.     

Diagnosis of dystonic syndromes--a new eight-question approach

Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Dystonia may be generalized or focal, and can occur as a primary syndrome or secondary to another disease--over 50 clinical conditions are reported to cause dystonia. Classification of dystonia is based on genetic background, anatomical distribution, age at onset, and neurodegenerative processes. In many cases, manifestations of dystonia are identical regardless of the aetiology, which makes accurate diagnosis challenging, if not impossible, without additional investigations. Exhaustive lists of the causes of dystonia are not practical to aid clinicians when attempting to determine if a hyperkinetic movement can be diagnosed as dystonic. The existing diagnostic algorithms for dystonic syndromes rely on the clinician's experience, without a streamlined diagnostic pathway. Non-specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. In this Review, an eight-question approach is proposed, with a summary of the evidence for investigations that enable successful diagnosis of dystonic syndromes. The aim of this approach is to inform both specialists and general neurologists on the appropriate diagnostic test for each patient who presents with a possible dystonic syndrome.     

Concurrent nocturnal and diurnal paroxysmal dystonia

The authors describe a case of a 15-year-old girl who presented with a progressive sequence of nocturnal dystonic episodes, generalized seizures, and diurnal dystonic episodes. A diagnosis of nocturnal paroxysmal dystonia has been proposed in view of the association between nocturnal episodes and epileptic seizures, while the diurnal episodes are atypical. Neurophysiological data recorded during critical episodes are reported. A linkage between dystonic attacks and epilepsy is hypothesized.     

Episodic focal lingual dystonic spasms.

We present the clinical history of a woman with idiopathic episodic focal lingual dystonic spasms. Although dystonic spasms of the tongue have been reported as a primary persistent phenomenon and as a feature of secondary dystonias, primary episodic lingual dystonias are rare, tend to be unilateral, and in contrast to most other paroxysmal movement disorders, do not appear responsive to anti-epileptic drugs.     

Dystonia: diagnosis and management

Clinical practice in dystonia has greatly evolved in recent years; a synthetic review on patient management is provided here. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both. A recent classification has innovated clinical practice and serves as guidance for clinical assessment: Axis I describes clinical features, whereas Axis II indicates etiology. Dystonia presents with different syndromic aggregations with varied somatic involvement and some common features. There are five recognizable physical signs of dystonia: two main signs (dystonic postures and movements) and three additional signs (gestes antagonistes or tricks, mirror dystonia and overflow dystonia). There is still no validation of diagnostic criteria for the different dystonia syndromes, and many cases with mild phenomenology remain undiagnosed. Patients with dystonia also present non‐motor features that are variably combined with the movement disorder. The features of the most common inherited and acquired dystonia syndromes are reviewed here. There is clear evidence of genetic–environmental interaction in the determinism of dystonia. The diagnostic process is guided by clinical examination and based on specific laboratory examinations. Symptomatic treatments are available for dystonia: botulinum neurotoxin injections are the primary choice for most focal dystonia syndromes; deep brain stimulation is useful in some generalized and non‐generalized syndromes. Additional treatment strategies are currently being assessed.     

Dystonic opisthotonus: A “red flag” for neurodegeneration with brain iron accumulation syndromes?

Back arching was reported in one of the very first patients with neurodegeneration with brain iron accumulation syndrome (NBIAs) published in 1936. However, recent reports have mainly focused on the genetic and imaging aspects of these disorders, and the phenotypic characterization of the dystonia has been lost. In evaluating patients with NBIAs in our centers, we have observed that action‐induced dystonic opisthotonus is a common and characteristic feature of NBIAs. Here, we present a case series of patients with NBIAs presenting this feature demonstrated by videos. We suggest that dystonic opisthotonus could be a useful “red flag” for clinicians to suspect NBIAs, and we discuss the differential diagnosis of this feature. This would be particularly useful in identifying patients with NBIAs and no iron accumulation as yet on brain imaging (for example, as in phospholipase A2, group IV (cytosolic, calcium‐independent) [PLA2G6]‐related disorders), and it has management implications. © 2013 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Classification and genetics of dystonia

Dystonia is a syndrome characterised by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. The dystonic syndromes include a large group of diseases that have been classified into various aetiological categories, such as primary, dystonia-plus, heredodegenerative, and secondary. The diverse clinical features of these disorders are reflected in the traditional clinical classification based on age at onset, distribution of symptoms, and site of onset. However, with an increased awareness of the molecular and environmental causes, the classification schemes have changed to reflect different genetic forms of dystonia. To date, at least 13 dystonic syndromes have been distinguished on a genetic basis and their loci are referred to as DYT1 to DYT13. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances.     

Pallidal stimulation for segmental dystonia: Long term follow up of 11 consecutive patients

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6‐12‐24‐36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective. © 2009 Movement Disorder Society     

Paroxysmal myoclonic dystonia with vocalisations: new entity or variant of preexisting syndromes?

From among 1377 patients with movement disorders, four patients had an unusual movement disorder characterised by paroxysmal bursts of involuntary, regular, repetitive, rhythmic, bilateral, coordinated, simultaneous, stereotypic myoclonus and vocalisations, often associated with tonic symptoms, interference with voluntary functioning, presence of hyperactivity, attention and learning disabilities, and resistance to treatment with haloperidol and other drugs. This symptom complex may represent a new disease entity, referred to here as paroxysmal myoclonic dystonia with vocalisations or a variant or combination of other movement disorders such as Gilles de la Tourette, myoclonic, or dystonic syndromes.     

The genetics of autistic disorders

Autistic disorders are heterogeneous. Affected individuals show impairments in communication and social interaction, as well as stereotypic, repetitive behaviour and special interests. The majority of autistic disorders are genetic in origin. The current article presents an overview of cytogenetic findings, as well as of results of molecular genetic linkage and association studies. Important differential diagnoses will be described. The results of genetic studies are especially relevant with regard to genetic counselling for affected families.     

Ziprasidone-induced tardive laryngeal dystonia: a case report

Tardive laryngeal dystonia, a rare form of dystonic syndrome, was only reported to be induced by typical antipsychotics. Here, we report one case of ziprasidone-induced tardive laryngeal dystonia in a schizophrenic female patient, who showed dysphonia, hoarseness and dyspnea after taking ziprasidone 120 mg/day for 8 months. These symptoms were significantly improved after discontinuing ziprasidone and increasing the dose of trihexyphenidyl for 1 week. Although atypical antipsychotics are associated with a lower risk of extrapyramidal symptoms, caution should be taken for any tardive dystonic movement when using these medications.     

Sporadic and familial myoclonic dystonia: Report of three cases and review of literature

Myoclonic dystonia refers to a clinical syndrome characterized by rapid jerky movements along with dystonic posturing of the limbs. Clinically, it is characterized by sudden, brief, electric shock-like movements, mostly involving the upper extremities, shoulders, neck and trunk. Characteristically, the movements wane with consumption of small dose of alcohol in about 50% of cases. Additionally, dystonic contractions are observed in most of the patients in the affected body parts and some patients may exhibit cervical dystonia or graphospasm as well. It may manifest as an autosomal dominant condition or sometimes, as a sporadic entity, though there are doubts whether these represent cases with reduced penetrance. The condition is usually treated with a combination of an anticholinergic agent like, benztropine, pimozide and tetrabenazine. We report one sporadic case and one familial case where the father and the son are affected. The cases were collected from the Movement Disorders Clinic of Bangur Institute of Neurosciences, Kolkata, West Bengal in a period of ten months. Myoclonic dystonia is a rare condition and to the best of our knowledge, this series is the first one reported from our country. Videos of the patients are also provided with the article.     

Rethinking status dystonicus

Status dystonicus is a movement disorder emergency that has been a source of controversy in terms of terminology, phenomenology, and management since it was first described in 1982. Here we argue that the current use of the term status dystonicus falls well short of the precision needed for either clinical or academic use. We performed a critical review on this topic, describing possible pathophysiological mechanisms and areas of uncertainties. This review also addresses the problems derived by the extreme clinical heterogeneity of this condition, as the lack of an objective criterion useful for the definition, or the fact that status dystonicus may present not only in the context of a known dystonic syndrome. We propose a new possible definition that includes not only dystonia but also other hyperkinetic movements in the wide range of movement disorders that can be seen during an episode. The new definition keeps the term status dystonicus and highlights the fact that this is a medical emergency based on the impairment of bulbar and/or respiratory function requiring hospital admission as the principal feature. Furthermore, the new definition should not consider as necessary unspecific features as patient's condition at baseline, the distribution of dystonia, occurrence of systemic symptoms such as fever or laboratory findings. We hope that this proposal will stimulate the debate on this subject among our peers, further developing a clinical and pathophysiological understanding of status dystonicus. © 2017 International Parkinson and Movement Disorder Society     

A reflection on plasticity research in writing dystonia

Much attention has focused on the hypothesis that there is enhanced plasticity of sensorimotor circuits in patients with dystonia. A common experimental method to assess plasticity in dystonia research is paired associative stimulation (PAS). Excessive, nonfocal effects of PAS were observed in early studies of dystonia; however, these large effects have not been uniformly replicated. In this viewpoint, data from 15 patients with writing dystonia are presented. We suggest that, as in healthy individuals, the effects of PAS are highly variable. A review of previous studies examining PAS in writing dystonia highlights the range of results that have been observed. We conclude that current experimental evidence cannot be fully explained by the notion that PAS responses in writing dystonia are consistently excessive or nonspecific. The variability of PAS responses is such that enhanced plasticity should not be considered a dystonic fingerprint, because the direction of response can vary, and there is overlap between patient and healthy data. We also discuss evidence questioning the assumption that PAS responses are a clear correlate to levels of synaptic plasticity; we need to define more specifically what PAS responses signify in the dystonic brain. Our conclusions are limited to PAS in writing dystonia; however, much variation exists with other plasticity protocols. Large multicenter studies of both focal and generalized forms of dystonia, probing variability of individual neurophysiological profiles, are encouraged. This will reveal the true role of plasticity in the pathophysiology of dystonia and may expose subject‐specific therapeutic interventions that are currently concealed. © 2014 International Parkinson and Movement Disorder Society     

Cytogenetic and molecular-cytogenetic studies of Rett syndrome (RTT): a retrospective analysis of a Russian cohort of RTT patients (the investigation of 57 girls and three boys)

Rett syndrome (RTT) is a severe neurodevelopmental disorder with an incidence of 2.5% in mentally retarded girls in Russia. We have performed cytogenetic studies of 60 patients (57 girls and three boys) with a clinical picture of RTT, selected according to the criteria for diagnosis of RTT defined by B. Hagberg et al. in 1996. Collection of DNA samples and fixed cell suspensions of RTT patients (37 girls and two boys) and their parents (27 patients) was established for molecular studies, for example analysis of MECP2 mutations in a Russian cohort of RTT patients. Among 60 patients 57 girls with a clinical picture of RTT had normal female karyotype (46,XX), one boy had normal male karyotype in peripheral lymphocytes (46,XY) and two boys had a mosaic form of Kleinfelter's syndrome (47,XXY/46,XY) in peripheral lymphocytes or muscle cells (with MeCP2 mutation R270X). Twenty-four mothers and parents of RTT girls had normal karyotype, two mothers had mosaic forms of Turner syndrome (45,X/46,XX) and one had mosaic karyotype (47,XX,+mar/48,XXX,+mar). We analyzed chromosome X in lymphocytes of 57 affected girls with a clinical picture of RTT using the 5-bromo-2′-deoxyuridine+Giemsa staining technique. A specific type of inactive chromosome X (so-called type ‘C’) with unusual staining of chromatin in the long arm of chromosome X was found in 55 (from 57) girls with RTT. This technique was positively used for presymptomatic diagnosis of RTT in five girls in earlier stages of the disease. We believe that the phenomenon of altered chromatin conformation in inactive chromosome X could be used as a laboratory test for preclinical diagnosis of the RTT.     

Atypical Hallervorden-Spatz disease with preserved cognition and obtrusive obsessions and compulsions.

We describe the case of an adult female with Hallervorden-Spatz disease (HSD), "eye-of-the-tiger" sign on cranial magnetic resonance imaging scan, and two mutations in the pantothenate kinase 2 (PANK2) gene. Symptomatic presentation included stuttering dysarthria, dystonic posturing, increased limb and axial muscle tone, choreoathetosis, stereotyped motor behaviors, and obsessive-compulsive symptomatology since adolescence. Extensive neuropsychological testing at 40 and 44 years of age revealed a relatively normal IQ and stable cognitive pattern overall. This case demonstrates that HSD patients who survive into middle age should not be assumed to have a progressive dementia. In such cases, atypical behavioral problems such as persistent obsessions and compulsions may be present instead.