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Objectives: In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies. We here describe the rare association of dystonia with anarthria/aphonia, by examining a large cohort of patients, to provide a narrow field of underlying conditions and a practical algorithmic approach to reach diagnosis., Methods: We retrospectively reviewed cases, which were evaluated between 2005 and 2014, to identify those with dystonia combined with marked anarthria and/or aphonia. We reviewed demographic information, clinical characteristics, as well as clinico-genetic investigations. We evaluated video material where available., Results: From 860 cases with dystonia as the predominant motor feature, we identified 32 cases (3.7%) with anarthria/aphonia. Age at neurological symptom onset was variable, but the majority of cases (n = 20) developed symptoms within their first eight years of life. A conclusive diagnosis was reached in 27 cases. Monoamine neurotransmitter disorders, neurodegeneration with brain iron accumulation syndromes, hypomyelination with atrophy of the basal ganglia and cerebellum, and syndromes with inborn errors of metabolism were the most common diagnoses. Brain MRI was crucial for reaching a diagnosis by examining the structural integrity of the basal ganglia, the cerebral cortex, brain myelination and whether there was abnormal metal deposition. Pathophysiological mechanisms underlying anarthria/aphonia included dystonia, corticobulbar involvement, apraxia and abnormalities of brain development., Conclusions: The spectrum of conditions that may present with the syndrome of dystonia with anarthria/aphonia is broad. Various causes may account for the profound speech disturbance. A practical brain MRI-based algorithm is provided to aid the diagnostic procedure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as "DYT2 dystonia," have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether "DYT2 dystonia" is a genetically homogeneous condition or not., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Tremor of the upper/middle part of the face, including the perinasal region and the forehead has been very rarely described in some patients with Parkinson's disease or Essential Tremor. It has not yet been reported in patients with idiopathic dystonia., Methods: We describe here a series of 8 patients with common forms of idiopathic focal/segmental dystonia with tremor involving the upper/middle part of the face, along with demonstrative videos and electrophysiological recordings., Results: The distribution of the tremor was confined to the face in two patients, whereas in six patients tremor was also evident either in the head/lower part of the face or in their upper limbs. Electrophysiological recordings disclosed a slightly irregular tremor with a frequency at about 3-5 Hz., Conclusions: A number of patients with classical forms of dystonia can show a tremor involving the upper/middle part of the face., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Functional movement disorders (FMDs) are thought to be rare in the elderly. Clinical characteristics of the elderly people who develop FMDs are rarely reported. The objective of this study was to highlight the clinical characteristics of FMD in the elderly and compared these with a cohort of patients with a younger age of onset., Methods: The authors performed a retrospective review of the clinical records of patients with FMD who were seen at their center in the last 5 years and had consented to be included in research studies. Patients fulfilling currently accepted diagnostic criteria for FMD as documented, clinically established, or probable were included., Results: Of 151 patients with FMD who were identified and had sufficient information, 21.0% (n=33) had an onset after age 60 years (elderly group). The mean age of onset of FMD was 63.5 years (standard deviation, 5.2 years) in the elderly group and 35.5 years (standard deviation, 12.6 years) in the younger group. Tremor was the most common movement disorder in both groups (elderly group, 33.3%; younger group: 38.9%). Fixed dystonia was not observed in any patient who had an FMD onset after age 60 years. Gait abnormalities were significantly more common in the elderly group (69.7%) than in younger patients (23.5%; P<0.001). Associated psychogenic nonepileptic seizures tended to be more common in elderly patients (18.2%) compared with younger patients (13%; P=0.06)., Conclusions: Contrary to common perceptions, FMDs are not uncommon in the elderly, and 1 in 5 patients in the current cohort, onset of FMD occurred after age 60 years. Gait abnormalities and psychogenic nonepileptic seizures may be more common in older patients., (Copyright © 2013 Movement Disorder Society.)

THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society., (Copyright © 2012 Movement Disorder Society.)

Background: The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia., Methods: We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10., Results: The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging., Conclusions: We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society., (Copyright © 2012 Movement Disorder Society.)

Dystonia is considered one of the classical features of corticobasal degeneration and is reported in up to 83% in clinical, not pathologically confirmed, series. Here, we aimed to establish the frequency and the clinical characteristics of dystonia in CBD by reviewing the literature on 404 pathologically proven cases. Further, we aimed to identify the frequency and characteristics of dystonia in all described phenotypes with CBD pathology. Dystonia was present in only 37.5% of the 296 cases with adequate information. The majority of the cases with dystonia presented with a corticobasal syndrome, and dystonia occurred in the first 2 years from disease onset, affecting the upper limb. In cases with dystonia that presented with a "dementia" phenotype, dystonia tended to appear later in the disease course and to more affect the cervical region and the face. With regard to the distribution of the phenotypes, fifty-four percent of 374 cases presented as corticobasal syndrome, 15% as frontotemporal dementia, and 10.7% as progressive supranuclear palsy. Dystonia and myoclonus were present in about half of all cases with corticobasal syndrome, implying that these features may not be as frequent in corticobasal syndrome as are akinetic-rigid syndrome and apraxia (100% and 86.3%, respectively). Dystonia and myoclonus almost co-occurred in our analysis, suggesting a possible association. In conclusion, despite dystonia being an inclusion criterion in all sets of clinical criteria for corticobasal degeneration, this was present in only one third of the pathologically proven cases presented here. More accurate characterization of dystonia in corticobasal degeneration would be of importance for clinical diagnosis and development of treatment strategies., (Copyright © 2012 Movement Disorder Society.)

Background and purposeDespite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization.MethodsThe Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members.ResultsSurvey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe.ConclusionsThis survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Background: Little is known about factors modulating pain and pain‐related functional impairment in isolated cervical dystonia (CD). Objective: The aim was to assess the prevalence and interrelationship between pain‐modulating factors and pain‐related determinants of functional impairment and quality of life in CD. Methods: We analyzed pain‐aggravating and pain‐relieving external factors, the degree of pain‐related functional impact on routine activities, and the relationship between these and pain severity, using cross‐sectional data collected using the Pain in Dystonia Scale (PIDS) from 85 participants with CD. Pairwise correlation analyses and age‐ and sex‐adjusted linear regression models estimated the relationship between pain‐modulating factors and pain severity, and the impact of pain severity, dystonia severity, and psychiatric symptoms on pain‐related functional impairment and disease‐specific quality of life (measured using the Craniocervical Dystonia Questionnaire‐24). Results: Stress and prolonged fixed position were the most frequent and impacting pain triggers, with women reporting larger impact. The average impact of pain‐relieving factors was lower than that of pain triggers. Physical exercise and social gatherings were the most impacted activities by pain in CD. The intensity of external modulating factors was a predictor of pain severity. Severity of pain, CD, and psychiatric symptoms independently predicted pain‐related functional impairment, whereas quality of life was predicted by pain severity, pain‐related functional impairment, and psychiatric symptom severity, but not dystonia severity. Conclusion: The PIDS provides insight into external modulation and functional impact of pain in CD. The pattern of external modulation of pain in CD is in line with a multifactorial modulation and complex physiology. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy account for approximately 10% of neurodegenerative parkinsonism. Considerable clinical overlap exists between these disorders that extends to features considered characteristic of each disease. Clinical diagnostic criteria have attempted to increase the accuracy of clinical diagnosis as accurate diagnosis is necessary to inform prognosis and to facilitate the recognition of disease-modifying treatments. Currently no such treatment exists. Nevertheless, many clinical trials aiming to change the natural history of these diseases are ongoing. The spread and accumulation of abnormal proteins are among the pathophysiological mechanisms targeted. For the time being, however, only symptomatic treatment is available. Levodopa is used to treat parkinsonism, but patients usually show a poor or transient response. Amantadine is also used in practice for the same indication. Botulinum toxin can alleviate focal dystonic manifestations. Addressing non-motor manifestations is limited by the potential of available drugs to impact on other aspects of the disease. Most of the new symptomatic formulations under study are focused on orthostatic hypotension in multiple system atrophy. Exercise, occupational, physical, and speech therapy and psychotherapy should always accompany pharmacological approaches. [ABSTRACT FROM AUTHOR]

Background Dopa-responsive dystonia ( DRD) is a rare inherited dystonia, caused by an autosomal dominantly inherited defect in the gene GCH1 that encodes guanosine triphosphate cyclohydrolase 1. It catalyzes the first and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is the essential co-factor for aromatic amino acid hydroxylases. Mutation results in the typical scenario of a young-onset lower-limb dystonia with diurnal fluctuations, concurrent or subsequent development of parkinsonism and excellent response to levodopa. Given the myriad functions of tetrahydrobiopterin, it is reasonable that other systems, apart from motor, would also be impaired. So far, non-motor symptoms have been overlooked and very few and often contrasting data are currently available on the matter. Methods Here by searching the Medline database for publications between 1971 to March 2015, we render an in-depth analysis of all published data on non-motor symptoms in DRD. Results Depression and subtle sleep quality impairment have been reported among the different cohorts, while current data do not support any alterations of the cardiologic and autonomic systems. However, there is debate about the occurrence of sleep-related movement disorders and cognitive function. Non-motor symptoms are instead frequently reported among the clinical spectrum of other neurotransmitter disorders which may sometimes mimic DRD phenotype, ie, DRD plus diseases. Conclusions Further studies in larger and treatment-naïve cohorts are needed to better elucidate the extend of non-motor symptoms in DRD and also to consider treatment for these. [ABSTRACT FROM AUTHOR]

Commentary: Insulinoma-Induced Hypoglycemia with Generalized Chorea, Dystonia, and Ataxia: A Neurological Kaleidoscope Keywords: insulinoma; paroxysmal; hypoglycemia; dystonia; ataxia; treatable EN insulinoma paroxysmal hypoglycemia dystonia ataxia treatable S9 S10 2 09/06/21 20210802 NES 210802 Paroxysmal movement disorders (PMDs) often pose diagnostic difficulties. References 1 Mishra A, Bhattad S, Pandey S. Insulinoma-induced hypoglycemia with generalized chorea, dystonia, and ataxia: a neurological kaleidoscope. [Extracted from the article]

Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson’s disease. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Multiple system atrophy (MSA) presents with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement. Marked asymmetry in atypical parkinsonism suggests alternative diagnosis like Corticobasal syndrome (CBS). Methods: We describe five unusual cases, who presented initially with markedly asymmetric parkinsonism, rigid dystonic abnormal limb posturing and subsequently developed clinical and/or radiological features consistent with probable MSA-P. Results: Using the internationally accepted diagnostic criteria, the patients fulfilled the diagnostic criteria for probable MSA-P after 5 years from disease onset. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. Conclusions: We use these cases to highlight that MSA-P MSA-P can present rarely with very marked asymmetry, dystonic limb and myoclonic jerks leading to a diagnosis of CBS at onset. [Copyright &y& Elsevier]

Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications. [ABSTRACT FROM PUBLISHER]

Introduction: ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated.Methods: We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders.Results: We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence.Conclusion: Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations. [ABSTRACT FROM AUTHOR]

In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia. Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca2+-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca2+ imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca2+ signaling. We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia. The locus DYT23 has been reserved as a synonym for this gene. The implication of an ion channel in the pathogenesis of dystonia provides insights into an alternative mechanism that opens fresh avenues for further research. [ABSTRACT FROM AUTHOR]