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Existing scales for rating the severity of blepharospasm (BSP) are limited by a number of potential drawbacks. We therefore developed and validated a novel scale for rating the severity of BSP. The development of the scale started with careful examination of the clinical spectrum of the condition by a panel of experts who selected phenomenological aspects thought to be relevant to disease severity. Thereafter, selected items were first checked for reliability, then reliable items were combined to generate the scale, and clinimetric properties of the scale were evaluated. Finally, the confidence with which the scale could be used by people without high levels of movement disorders skill was assessed. The new scale, based on objective criteria, yielded moderate to almost perfect reliability, acceptable internal consistency, satisfactory scaling assumptions, lack of floor and ceiling effects, partial correlations with a prior severity scale and with a quality of life scale, and good sensitivity to change. Despite a few limitations, the foregoing features make the novel scale more suitable than existing scales to assess the severity of BSP in natural history and pathophysiologic studies as well as in clinical trials., (© 2015 International Parkinson and Movement Disorder Society.)

Background: We developed a novel secured web-based dystonia video repository for the Dystonia Coalition, part of the Rare Disease Clinical Research network funded by the Office of Rare Diseases Research and the National Institute of Neurological Disorders and Stroke. A critical component of phenotypic data collection for all projects of the Dystonia Coalition includes a standardized video of each participant. We now describe our method for collecting, serving and securing these videos that is widely applicable to other studies., Methods: Each recruiting site uploads standardized videos to a centralized secured server for processing to permit website posting. The streaming technology used to view the videos from the website does not allow downloading of video files. With appropriate institutional review board approval and agreement with the hosting institution, users can search and view selected videos on the website using customizable, permissions-based access that maintains security yet facilitates research and quality control., Results: This approach provides a convenient platform for researchers across institutions to evaluate and analyze shared video data. We have applied this methodology for quality control, confirmation of diagnoses, validation of rating scales, and implementation of new research projects., Conclusions: We believe our system can be a model for similar projects that require access to common video resources., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The dystonias are a group of disorders characterized by excessive involuntary muscle contractions leading to abnormal postures and/or repetitive movements. A careful assessment of the clinical manifestations is helpful for identifying syndromic patterns that focus diagnostic testing on potential causes. If a cause is identified, specific etiology-based treatments may be available. In most cases, a specific cause cannot be identified, and treatments are based on symptoms. Treatment options include counseling, education, oral medications, botulinum toxin injections, and several surgical procedures. A substantial reduction in symptoms and improved quality of life is achieved in most patients by combining these options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Several case reports and small series have indicated that tardive dystonia is responsive to globus pallidus deep brain stimulation. Whether different subtypes or distributions of tardive dystonia are associated with different outcomes remains unknown., Methods: We assessed the outcomes and temporal profile of improvement of eight tardive dystonia patients who underwent globus pallidus deep brain stimulation over the past six years through record review. Due to the retrospective nature of this study, it was not blinded or placebo controlled., Results: Consistent with previous studies, deep brain stimulation improved the overall the Burke-Fahn-Marsden motor scores by 85.1 ± 13.5%. The distributions with best responses in descending order were upper face, lower face, larynx/pharynx, limbs, trunk, and neck. Patients with prominent cervical dystonia demonstrated improvement in the Toronto Western Spasmodic Torticollis Rating Scale but improvements took several months. In four patients the effects of deep brain stimulation on improvement in Burke Fahn Marsden score was rapid, while in four cases there was partial rapid response of neck and trunk dystonia followed by was gradual resolution of residual symptoms over 48 months., Conclusion: Our retrospective analysis shows excellent resolution of tardive dystonia after globus pallidus deep brain stimulation. We found instantaneous response, except with neck and trunk dystonia where partial recovery was followed by further resolution at slower rate. Such outcome is encouraging for using deep brain stimulation in treatment of tardive dystonia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: We sought to examine brain white matter abnormalities based on MRI in adults with Lesch-Nyhan disease (LND) or an attenuated variant (LNV) of this rare, X-linked neurodevelopmental disorder of purine metabolism., Methods: In this observational study, we compared 21 adults with LND, 17 with LNV, and 33 age-, sex-, and race-matched healthy controls using voxel-based morphometry and analysis of covariance to identify white matter volume abnormalities in both patient groups., Results: Patients with classic LND showed larger reductions of white (26%) than gray (17%) matter volume relative to healthy controls. Those with LNV showed comparable reductions of white (14%) and gray (15%) matter volume. Both patient groups demonstrated reduced volume in medial inferior white matter regions. Compared with LNV, the LND group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. These regions likely include such long association fibers as the superior longitudinal and uncinate fasciculi., Conclusions: Despite earlier reports that LND primarily involves the basal ganglia, this study reveals substantial white matter volume abnormalities. Moreover, white matter deficits are more severe than gray matter deficits in classic LND, and also characterize persons with LNV. The brain images acquired for these analyses cannot precisely localize white matter abnormalities or determine whether they involve changes in tract orientation or anisotropy. However, clusters of reduced white matter volume identified here affect regions that are consistent with the neurobehavioral phenotype., (© 2014 American Academy of Neurology.)

Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), cause Lesch-Nyhan disease (LND) and more mildly affected Lesch-Nyhan variants. Prior studies have suggested a strong correlation between residual hypoxanthine recycling activity and disease severity. However, the relevance of guanine recycling and compensatory changes in the de novo synthesis of purines has received little attention. In the current studies, fibroblast cultures were established for 21 healthy controls and 36 patients with a broad spectrum of disease severity related to HGprt deficiency. We assessed hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis. There was a strong correlation between disease severity and either hypoxanthine or guanine recycling. Intracellular purines were normal in the HGprt-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from the cells. The normal intracellular purines in the HGprt-deficient fibroblasts were likely due in part to a compensatory increase in purine synthesis, as demonstrated by a significant increase in purinosomes. However, the increase in purine synthesis did not appear to correlate with disease severity. These results refine our understanding of the potential sources of phenotypic heterogeneity in LND and its variants., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Many cases of myoclonus-dystonia (M-D) are due to mutations in SGCE (DYT11). For the majority of patients, myoclonus is relatively more severe than dystonia and can lead to significant functional disability. Deep brain stimulation has been chosen as a treatment option in some patients given that M-D often responds poorly to oral pharmacotherapy., Methods: Two siblings with M-D due to the same SGCE deletion mutation were evaluated with the Global Dystonia Rating Scale (GDRS), Fahn-Marsden Rating Scale (FM) and Unified Myoclonus Rating Scale (UMRS) on and off tetrabenazine., Results: Both subjects showed marked improvement in myoclonus and mild-to-moderate improvement in dystonia with tetrabenazine. In addition, the response to tetrabenazine has been sustained for years., Conclusions: A therapeutic trial of tetrabenazine should be considered in patients with M-D, especially before consideration of deep brain stimulation. An adequately powered multi-center, double-blind study of tetrabenazine will be required to determine the relative contributions of tetrabenazine therapy to myoclonus, dystonia, quality of life, and activities of daily living in patients with M-D., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Early onset isolated dystonia (DYT1) is linked to a three base pair deletion (ΔGAG) mutation in the TOR1A gene. Clinical manifestation includes intermittent muscle contraction leading to twisting movements or abnormal postures. Neuropathological studies on DYT1 cases are limited, most showing no significant abnormalities. In one study, brainstem intraneuronal inclusions immunoreactive for ubiquitin, torsinA and lamin A/C were described. Using the largest series reported to date comprising 7 DYT1 cases, we aimed to identify consistent neuropathological features in the disease and determine whether we would find the same intraneuronal inclusions as previously reported., Result: The pathological changes of brainstem inclusions reported in DYT1 dystonia were not replicated in our case series. Other anatomical regions implicated in dystonia showed no disease-specific pathological intracellular inclusions or evidence of more than mild neuronal loss., Conclusion: Our findings suggest that the intracellular inclusions described previously in DYT1 dystonia may not be a hallmark feature of the disorder. In isolated dystonia, DYT1 in particular, biochemical changes may be more relevant than the morphological changes.

Introduction: Generalized dystonia, both primary and secondary forms, and axial dystonias such as tardive dystonia, and idiopathic cervical dystonia are responsive to globus pallidus interna (GPi) DBS. There is a paucity of investigations probing the impact of DBS on adult-onset axial dystonia. We assessed the efficacy of GPi DBS in four patients with rare adult-onset axial dystonia., Methods: Primary outcome measure was improvement in the motor component of the Burke-Fahn-Marsden (BFM) rating scale. Secondary outcome measures were quality of life as determined by the SF-36 questionnaire, time to achieve best possible benefit and DBS parameters that accounted for the best response. In patients with prominent concomitant cervical dystonia we also used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)., Results: GPi DBS improved BFM scores by 87.63 ± 11.46%. Improvement in total severity scale of TWSTRS was 71.5 ± 12.7%. Quality of life also remarkably improved as evidenced by 109.38 ± 82.97 and 7.05 ± 21.48% percent change in psychometrically-based physical component summary (PCS), and a mental component summary (MCS) score respectively., Conclusions: GPi DBS is a very effective treatment for adult-onset axial dystonia. Considering its refractoriness to medical therapy and significant impact on quality of life DBS should be considered for this disorder., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: This study used a randomized control design to evaluate the effectiveness of AgTeen, an in-home, family-based farm safety intervention, in decreasing extra riding on tractors by youth. Having children as extra riders on tractors has deep roots in farm culture, but it can result in serious injury or death., Methods: The study randomized 151 families into 3 groups: parent-led intervention (fathers taught their families about farm safety), staff-led intervention (staff members who were peer farmers taught families), and a no-treatment control. Mothers, fathers, and all children aged 10-19 participated in the lessons., Findings: At study entry, 93% of youth reported that they had been an extra rider on a tractor in the past year. Although they were aware of the injury risk, fathers frequently gave tractor rides to their children. After the intervention, fathers in both AgTeen groups were less likely than control fathers to give youth tractor rides. Intervention youth were less likely than control youth to be extra riders. The intervention positively affected the extra-riding attitudes and injury risk perceptions of mothers and fathers. The parent-led and staff-led groups did not significantly differ across study outcomes., Conclusions: Findings confirm the effectiveness of a family-based intervention in decreasing extra riding on tractors by youth., (© 2014 National Rural Health Association.)

Lesch-Nyhan disease and its attenuated variants are caused by deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). All patients exhibit excessive production of uric acid, which increases the risk for nephrolithiasis, renal failure, gouty arthritis and tophi. The mildest phenotype includes only problems related to overproduction of uric acid. The most severe clinical phenotype includes prominent neurological abnormalities and the universal feature is self-injurious behavior. In between the mildest and most severe syndromes is a broad spectrum of phenotypes with varying degrees of neurological, neurocognitive and behavioral abnormalities. The effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy., Methods: Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS)., Results: Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line., Interpretation: These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype., (© 2014 American Neurological Association.)

The underlying etiology of parkinsonian anterocollis has been the subject of recent debate. The purpose of this study is to test the hypothesis that anterocollis in parkinsonian syndromes is associated with dystonia of the deep cervical flexors (longus colli and capitis). Eight patients with anterocollis, six in the setting of parkinsonism and two primary cervical dystonia control subjects with anterocollis underwent prospective structured clinical evaluations (interview, examination and rating scales), systematic electromyography of the cervical extensor musculature and (18)F-FDG PET/CT studies of cervical muscles to examine evidence of hypermetabolism or overactivity of deep cervical flexors. Subjects with parkinsonian anterocollis were found to have hypermetabolism of the extensor and sub-occipital muscles but not in the cervical flexors (superficial or deep). EMG abnormalities were observed in all evaluated patients, but only one patient was definitely myopathic. Meanwhile, both dystonia controls exhibited hypermetabolism of cervical flexors (including the longus colli). In conclusion, we were able to demonstrate hypermetabolism of superficial and deep cervical flexors with muscle (18)F-FDG PET/CT in dystonic anterocollis patients, but not in parkinsonian anterocollis patients. The hypermetabolic changes seen in parkinsonian anterocollis patients in posterior muscles may be compensatory. Alternative explanations for anterocollis include myopathy of the cervical extensors, or unbalanced rigidity of the cervical flexors, but this remains to be proven., (Published by Elsevier B.V.)

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM&#95;018105) to Isoform 2 (NM&#95;199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia.

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.

Purpose: Farm youth continue to experience high rates of injury and deaths as a result of agricultural activities. Farm machinery, especially tractors, is the most common cause of casualties to youth. A Roll-Over Protection Structure (ROPS) along with a fastened seatbelt can prevent almost all injuries and fatalities from tractor overturns. Despite this knowledge, the use of seatbelts by farmers on ROPS tractors remains low. This study treats farm safety as a family issue and builds on the central role of parents as teachers and role models of farm safety for youth., Methods: This research study used a longitudinal, repeated-measures, randomized-control design in which youth 10-19 years of age were randomly assigned to either of two intervention groups (parent-led group and staff-led group) or the control group., Results: Fathers in the parent-led group were less likely to operate ROPS tractors without a seatbelt compared with other groups. They were more likely to have communicated with youth about the importance of wearing seatbelts on ROPS tractors. Consequently, youth in the parent-led group were less likely to operate a ROPS tractor without a seatbelt than the control group at post-test., Conclusions: This randomized control trial supports the effectiveness of a home-based, father-led farm safety intervention as a promising strategy for reducing youth as well as father-unsafe behaviors (related to tractor seatbelts) on the farm. This intervention appealed to fathers' strong motivation to practice tractor safety for the sake of their youth. Involving fathers helped change both father as well as youth unsafe tractor-seatbelt behaviors., (Copyright © 2014 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

The dystonias are a group of disorders defined by sustained or intermittent muscle contractions that result in involuntary posturing or repetitive movements. There are many different clinical manifestations and causes. Although they traditionally have been ascribed to dysfunction of the basal ganglia, recent evidence has suggested dysfunction may originate from other regions, particularly the cerebellum. This recent evidence has led to an emerging view that dystonia is a network disorder that involves multiple brain regions. The new network model for the pathogenesis of dystonia has raised many questions, particularly regarding the role of the cerebellum. For example, if dystonia may arise from cerebellar dysfunction, then why are there no cerebellar signs in dystonia? Why are focal cerebellar lesions or degenerative cerebellar disorders more commonly associated with ataxia rather than dystonia? Why is dystonia more commonly associated with basal ganglia lesions rather than cerebellar lesions? Can answers obtained from animals be extrapolated to humans? Is there any evidence that the cerebellum is not involved? Finally, what is the practical value of this new model of pathogenesis for the neuroscientist and clinician? This article explores potential answers to these questions., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The dystonias are a group of disorders characterized by involuntary twisting and repetitive movements. DYT1 dystonia is an inherited form of dystonia caused by a mutation in the TOR1A gene, which encodes torsinA. TorsinA is expressed in many regions of the nervous system, and the regions responsible for causing dystonic movements remain uncertain. Most prior studies have focused on the basal ganglia, although there is emerging evidence for abnormalities in the cerebellum too. In the current studies, we examined the cerebellum for structural abnormalities in a knock-in mouse model of DYT1 dystonia. The gross appearance of the cerebellum appeared normal in the mutant mice, but stereological measures revealed the cerebellum to be 5% larger in mutant compared to control mice. There were no changes in the numbers of Purkinje cells, granule cells, or neurons of the deep cerebellar nuclei. However, Golgi histochemical studies revealed Purkinje cells to have thinner dendrites, and fewer and less complex dendritic spines. There also was a higher frequency of heterotopic Purkinje cells displaced into the molecular layer. These results reveal subtle structural changes of the cerebellum that are similar to those reported for the basal ganglia in the DYT1 knock-in mouse model., (© 2013.)

Lesch-Nyhan disease (LND) is an X-linked metabolic disease caused by various mutations in the gene HPRT1 encoding an enzyme of purine metabolism, hypoxanthine guanine phosphoribosyltransferase (HPRT). In its most severe form, LND patients suffer from overproduction of uric acid along with neurological or behavioural difficulties including self-injurious behaviours. To gain more insight into pathogenesis, we compared the transcriptome from human LND fibroblasts to normal human fibroblasts using a microarray with 60,000 probes corresponding to the entire human genome. Using stringent criteria, we identified 25 transcripts whose expression was significantly different between LND and control cells. These genes were confirmed by quantitative RT-PCR to be dysregulated in LND cells. Moreover, bioinformatic analysis of microarray data using gene ontology (GO) highlighted clusters of genes displaying biological processes most significantly affected in LND cells. These affected genes belonged to specific processes such as cell cycle and cell-division processes, metabolic and nucleic acid processes, demonstrating the specific nature of the changes and providing new insights into LND pathogenesis.

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

Background: Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. The neck is among the most commonly affected regions, and diagnosis can be made readily through a simple clinical evaluation. The goal of this study was to explore how long it took patients to receive a diagnosis of cervical dystonia after symptom onset., Methods: A structured questionnaire was administered at outpatient clinics of a tertiary care academic medical center to 146 consecutively evaluated patients. The questionnaire addressed the length of time from symptom onset to diagnosis, the numbers and types of providers seen before reaching a diagnosis, and treatments attempted prior to receiving botulinum toxin., Results: A total of 108 patients saw a mean of 3.5 providers over a mean period of 44 months from symptom onset to diagnosis. For patients with symptom onset in the last decade only, patients saw a mean of 3.0 providers over a mean of 14 months., Conclusions: Although cervical dystonia is the most common form of dystonia with clinical features readily identifiable by a simple history and examination, patients typically see multiple providers over more than a year before reaching a diagnosis and receiving optimal therapy. Improved awareness of the clinical features will enable patients to obtain appropriate therapy more rapidly., (© 2013.)

Background: Lesch-Nyhan disease is a rare, X-linked, neurodevelopmental metabolic disorder that is caused by abnormalities in the levels of hypoxanthine-guanine phosphoribosyltransferase enzyme activity. The neural substrates associated with Lesch-Nyhan disease remain poorly understood. We aimed to use voxel-based morphometry to identify affected brain regions in classic Lesch-Nyhan disease and Lesch-Nyhan variant disease, and to identify regions that differ between the two disease types., Methods: In this cross-sectional study, we recruited patients with classic Lesch-Nyhan disease or Lesch-Nyhan variant disease from clinics, referrals, the Lesch-Nyhan Syndrome Registry, and the Matheny School and Hospital (Peapack, NJ, USA), and healthy controls from the Baltimore metropolitan area (MD, USA). We used voxel-based morphometry to analyse grey matter volume between groups using a three-group ANCOVA, followed by six pairwise post-hoc group comparisons., Findings: Between Oct 3, 1993, and April 29, 2013, we recruited 21 patients with classic Lesch-Nyhan disease, 17 patients with variant disease, and 33 healthy controls. Patients with classic Lesch-Nyhan disease had a 20% reduction in intracranial volume (17% reduction in grey matter volume; 26% reduction in white matter volume) compared with healthy adults. The largest differences were in basal ganglia, and frontotemporal and limbic regions, with sparing of parieto-occipital regions. Grey matter volumes of patients with Lesch-Nyhan variant disease were invariably between those of patients with classic Lesch-Nyhan disease and healthy controls. Compared with healthy controls, patients with classic disease showed additional grey matter volume reductions in the temporal lobe and left lateralised structures, and patients with variant disease showed additional reductions in lingual and precuneus regions with sparing of right frontal and temporal regions. Patients with classic disease had reductions of volume in the ventral striatum and prefrontal areas compared with those with the variant form., Interpretation: We noted regional abnormalities associated with known neurological and behavioural deficits in patients with classic Lesch-Nyhan disease. Patients with Lesch-Nyhan variant disease show milder grey matter abnormalities in many of the same brain regions and preservation of grey matter volume in other regions, which could provide important clues to the neural substrates of differences between the phenotypes., Funding: National Institute of Child Health and Human Development, Therapeutic Cognitive Neuroscience Fund, and Benjamin and Adith Miller Family Endowment on Aging, Alzheimer's and Autism Research.

Purines are a class of small organic molecules that are essential for all cells. They play critical roles in neuronal differentiation and function. Their importance is highlighted by several inherited disorders of purine metabolism, such as Lesch-Nyhan disease, which is caused by a deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Despite the known importance of purines in the nervous system, knowledge regarding their metabolism in neurons is limited. In the current studies, purine pools and their metabolism were examined in rat PC6-3 cells, a PC12 pheochromocytoma subclone that undergoes robust differentiation with nerve growth factor. The results were compared with five new independent PC6-3 subclones with defective purine recycling because of different mutations affecting HGprt enzyme activity. The results demonstrate an increase in most purines and in energy state following neuronal differentiation, as well as specific abnormalities when purine recycling is lost. The loss of HGprt-mediated purine recycling also is associated with significant loss of dopamine and related metabolites in the mutant PC6-3 lines, suggesting an important connection between purine and dopamine pathways. These results provide insights into how purine pools and metabolism change with neuronal differentiation, and how specific enzyme defects may cause neuronal dysfunction. Differentiation of dopaminergic PC6-3 cells is accompanied by increased purine pools and energy state. The lack of a functional purine recycling pathway causes purine limitation in both undifferentiated and differentiated cells, as well as profound loss of dopamine content. The results imply an unknown mechanism by which intracellular purine levels regulate dopamine levels., (© 2013 International Society for Neurochemistry.)

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients., (© 2013 Elsevier Inc. All rights reserved.)

Background: Blepharospasm is a form of focal dystonia that manifests as repetitive involuntary closure of the eyes. The pathogenesis of blepharospasm and the neuroanatomic substrates involved are not fully understood. Dysfunction of the basal ganglia traditionally is presumed to be the main cause of most forms of dystonia, but a growing body of evidence suggests that a network of additional cortical and subcortical structures may be involved., Methods: The medical records of 1114 patients with blepharospasm seen over past 10 years at Emory University were reviewed to identify potentially contributing brain lesions. A systematic review of the published literature was also conducted to identify potentially contributing brain lesions., Results: Among patients with blepharospasm at Emory University, 18 had focal lesions on imaging studies available for review. The literature review revealed 25 articles describing 30 additional cases of blepharospasm associated with focal lesions. Among all 48 cases, lesions were found in multiple regions including the thalamus (n=12), lower brainstem (n=11), basal ganglia (n=9), cerebellum (n=9), midbrain (n=7), and cortex (n=1)., Conclusions: These data in combination with functional imaging studies of primary blepharospasm support a model in which a network of different regions plays a role in the pathogenesis of blepharospasm., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To design and validate a clinical diagnostic guideline for aiding physicians in confirming or refuting suspected blepharospasm., Methods: The guideline was developed and validated in a 3-step procedure: 1) identification of clinical items related to the phenomenology of blepharospasm, 2) assessment of the relevance of each item to the diagnosis of blepharospasm, and 3) evaluation of the reliability and diagnostic sensitivity/specificity of the selected clinical items., Results: Of 19 clinical items initially identified, 7 were admitted by content validity analysis to further assessment. Both neurologists and ophthalmologists achieved satisfactory interobserver agreement for all 7 items, including "involuntary eyelid narrowing/closure due to orbicularis oculi spasms," "bilateral spasms," "synchronous spasms," "stereotyped spasm pattern," "sensory trick," "inability to voluntarily suppress the spasms," and "blink count at rest." Each selected item yielded unsatisfactory accuracy in discriminating patients with blepharospasm from healthy subjects and patients with other eyelid disturbances. Combining the selected items, however, improved diagnostic sensitivity/specificity. The best combination, yielding 93% sensitivity and 90% specificity, was an algorithm starting with the item "stereotyped, bilateral, and synchronous orbicularis oculi spasms inducing eyelid narrowing/closure" and followed by recognition of "sensory trick" or, alternatively, "increased blinking.", Conclusion: This study provides an accurate and valid clinical guideline for diagnosing blepharospasm. Use of this guideline would make it easier for providers to recognize dystonia in clinical and research settings.

The mechanisms by which the human brain controls eye movements are reasonably well understood, but those for the head less so. Here, we show that the mechanisms for keeping the head aimed at a stationary target follow strategies similar to those for holding the eyes steady on stationary targets. Specifically, we applied the neural integrator hypothesis that originally was developed for holding the eyes still in eccentric gaze positions to describe how the head is held still when turned toward an eccentric target. We found that normal humans make head movements consistent with the neural integrator hypothesis, except that additional sensory feedback is needed, from proprioceptors in the neck, to keep the head on target. We also show that the complicated patterns of head movements in patients with cervical dystonia can be predicted by deficits in a neural integrator for head motor control. These results support ideas originally developed from animal studies that suggest fundamental similarities between oculomotor and cephalomotor control, as well as a conceptual framework for cervical dystonia that departs considerably from current clinical views.

Background: Sapropterin dihydrochloride (BH4, tetrahydrobiopterin) can lower plasma phenylalanine (Phe) concentrations for a subset of patients with phenylketonuria (PKU), an inborn error of metabolism. Studies suggest that monoamine neurotransmitter concentrations are low in PKU patients. Sapropterin functions as a cofactor for hydroxylases specific to Phe, tyrosine, and tryptophan metabolism, pathways essential for catecholamine and serotonin synthesis., Objective: The objective of this study is to determine the impact of sapropterin on monoamine neurotransmitter status in patients with PKU., Design: 58 PKU subjects were provided 20 mg/kg of sapropterin for 1 month. Those who responded with at least a 15% decrease in plasma Phe received sapropterin for 1 year, while Non-responders discontinued it. After an additional 3 months, Responders who demonstrated increased Phe tolerance and decreased medical food dependence were classified as Definitive, whereas Responders unable to liberalize their diet without compromising plasma Phe control were identified as Provisional. At study visits, patients provided blood for plasma amino acids, 3-day diet records, and 12-hour urine samples analyzed for epinephrine (E), dopamine (DA), dihydroxyphenylacetate (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3MT), serotonin (5HT), and 5-hydroxyindole acetic acid (5HIAA) using HPLC with electrochemical detection., Results: Compared with healthy non-PKU controls, subjects with PKU had significantly lower baseline concentrations of DA, HVA, 3MT, 5HT, and 5HIAA (p < 0.001 for all). Medical food protein intake had a direct association with DA, HVA, 5HT, and 5HIAA during the study (p < 0.05 for all), while plasma Phe had an inverse association with these markers (p < 0.01 for all). DOPAC was also associated with plasma Phe throughout the year (p = 0.035), although not at baseline. Patients with PKU had a significant increase in HVA (p = 0.015) after 1 month of sapropterin. When stratifying by Responder and Non-Responder status, significance of HVA increase in Non-responders (p = 0.041) was confirmed, but not in Responders (p = 0.081). A declining trend in urinary 5HIAA, significant only after controlling for plasma Phe (p = 0.019), occurred for Definitive Responders during the 1-year study., Conclusion: Urinary monoamine concentrations are low in patients with PKU and are influenced by oral sapropterin and medical food intake, highlighting the importance of these therapies to neurotransmitter metabolism in phenylketonuria., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The clinical evaluation of a patient with dystonia is a stepwise process, beginning with classification of the phenomenology of the movement disorder(s), then formulation of the dystonia syndrome, which, in turn, leads to a targeted etiological differential diagnosis. In recent years, there have been significant advances in our understanding of the etiological basis of dystonia, aided especially by discoveries in imaging and genetics. In this review, we provide an update on the assessment of a patient with dystonia, including the phenomenology of dystonia and highlighting how to integrate clinical, imaging, blood, and neurophysiological investigations in order to formulate a dystonia syndrome. Evolving or emerging dystonia syndromes are reviewed, and potential etiologies of these as well as established dystonia syndromes listed to guide diagnostic testing. © 2013 Movement Disorder Society., (© 2013 Movement Disorder Society.)

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. © 2013 Movement Disorder Society., (© 2013 Movement Disorder Society.)

Many rating scales have been applied to the evaluation of dystonia, but only few have been assessed for clinimetric properties. The Movement Disorders Society commissioned this task force to critique existing dystonia rating scales and place them in the clinical and clinimetric context. A systematic literature review was conducted to identify rating scales that have either been validated or used in dystonia. Thirty-six potential scales were identified. Eight were excluded because they did not meet review criteria, leaving 28 scales that were critiqued and rated by the task force. Seven scales were found to meet criteria to be "recommended": the Blepharospasm Disability Index is recommended for rating blepharospasm; the Cervical Dystonia Impact Scale and the Toronto Western Spasmodic Torticollis Rating Scale for rating cervical dystonia; the Craniocervical Dystonia Questionnaire for blepharospasm and cervical dystonia; the Voice Handicap Index (VHI) and the Vocal Performance Questionnaire (VPQ) for laryngeal dystonia; and the Fahn-Marsden Dystonia Rating Scale for rating generalized dystonia. Two "recommended" scales (VHI and VPQ) are generic scales validated on few patients with laryngeal dystonia, whereas the others are disease-specific scales. Twelve scales met criteria for "suggested" and 7 scales met criteria for "listed." All the scales are individually reviewed in the online information. The task force recommends 5 specific dystonia scales and suggests to further validate 2 recommended generic voice-disorder scales in dystonia. Existing scales for oromandibular, arm, and task-specific dystonia should be refined and fully assessed. Scales should be developed for body regions for which no scales are available, such as lower limbs and trunk., (© 2013 Movement Disorder Society.)

The most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, in which the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focusing attention on less well understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders and for developing novel therapeutics., (© 2013 Movement Disorder Society.)

The dystonias are comprised of a group of disorders that share common neurological abnormalities of involuntary twisting or repetitive movements and postures. The most common inherited primary dystonia is DYT1 dystonia, which is due to loss of a GAG codon in the TOR1A gene that encodes torsinA. Autopsy studies of brains from patients with DYT1 dystonia have revealed few abnormalities, although recent neuroimaging studies have implied the existence of microstructural defects that might not be detectable with traditional histopathological methods. The current studies took advantage of a knock-in mouse model for DYT1 dystonia to search for subtle anatomical abnormalities in the striatum, a region often implicated in studies of dystonia. Multiple abnormalities were identified using a combination of quantitative stereological measures of immunohistochemical stains for specific neuronal populations, morphometric studies of Golgi-stained neurons, and immuno-electron microscopy of synaptic connectivity. In keeping with other studies, there was no obvious loss of striatal neurons in the DYT1 mutant mice. However, interneurons immunoreactive for choline acetyltransferase or parvalbumin were larger in the mutants than in control mice. In contrast, interneurons immunoreactive for neuronal nitric oxide synthase were smaller in the mutants than in controls. Golgi histochemical studies of medium spiny projection neurons in the mutant mice revealed slightly fewer and thinner dendrites, and a corresponding loss of dendritic spines. Electron microscopic studies showed a reduction in the ratio of axo-spinous to axo-dendritic synaptic inputs from glutamatergic and dopaminergic sources in mutant mice compared with controls. These results suggest specific anatomical substrates for altered signaling in the striatum and potential correlates of the abnormalities implied by human imaging studies of DYT1 dystonia., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Torpor is a physiological state characterized by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions. The hypothalamus coordinates energy homeostasis and thermoregulation and plays a key role in directing torpor. We recently showed that mice lacking the orphan G protein-coupled receptor Gpr50 readily enter torpor in response to fasting and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state. This revealed a strong induction of thioredoxin-interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses. In situ hybridization identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip. To characterize further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster. Strikingly, pronounced up-regulation of Txnip expression was only observed in wild-type mice when driven into torpor and during torpor in the Siberian hamster. Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice. Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel use during the extreme hypometabolic state of torpor.

Objective: The anti-leukemic drugs, azathioprine and 6-mercaptopurine (6MP), are important in the treatment of inflammatory bowel disease but an alternative faster-acting, less-allergenic thiopurine, 6-thioguanine (6TG), can cause hepatic veno-occlusive disease/sinusoidal obstructive syndrome (SOS). Understanding of SOS has been hindered by inability to ethically perform serial liver biopsies on patients and the lack of an animal model., Design: Normal and C57Bl/6 mice with specific genes altered to elucidate mechanisms responsible for 6TG-SOS, were gavaged daily for upto 28d with 6TG, 6MP or methylated metabolites. Animal survival was monitored and at sacrifice a histological score of SOS, haematology and liver biochemistry were measured., Results: Only 6TG caused SOS, which was dose related. 6TG and to a lesser extent 6MP but not methylated metabolites were associated with dose-dependent haematopoietic toxicity. SOS was not detected with non-lethal doses of 6TG. SOS did not occur in hypoxanthine-phosphoribosyl transferase-deficient C57Bl/6 mice, demonstrating that 6TG-SOS requires thioguanine nucleotides. Hepatic inflammation was characteristic of SOS, and C57Bl/6 mice deficient in P- and E-selectins on the surface of vascular endothelial cells showed markedly reduced SOS, demonstrating a major role for leukocytes recruited from blood. Split dosing of 6TG markedly attenuated SOS but still effected immunosuppression and prevented spontaneous colitis in Winnie mice, which have a single nucleotide polymorphism mutation in Muc2., Conclusion: This novel model provides clinically relevant insights into how 6TG induces SOS, and how this dangerous adverse drug reaction may be avoided by either inhibition of endothelial activation or simple changes to dosing regimens of 6TG, while still being effective treatment for colitis.

The aim of this study was to search for neuropathological changes in postmortem brain tissue of individuals with cervical dystonia (CD). Multiple regions of formalin-preserved brains were collected from patients with CD and controls and examined with an extensive battery of histopathological stains in a two-stage study design. In stage one, 4 CD brains underwent a broad screening neuropathological examination. In stage two, these 4 CD brains were combined with 2 additional CD brains, and the subjective findings were quantified and compared to 16 age-matched controls. The initial subjective neuropathological assessment revealed only two regions with relatively consistent changes. The substantia nigra had frequent ubiquitin-positive intranuclear inclusions known as Marinesco bodies. Additionally, the cerebellum showed patchy loss of Purkinje cells, areas of focal gliosis and torpedo bodies. Other brain regions showed minor or inconsistent changes. In the second stage of the analysis, quantitative studies failed to reveal significant differences in the numbers of Marinesco bodies in CD versus controls, but confirmed a significantly lower Purkinje cell density in CD. Molecular investigations revealed 4 of the CD cases and 2 controls to harbor sequence variants in non-coding regions of THAP1, and these cases had lower Purkinje cell densities regardless of whether they had CD. The findings suggest that subtle neuropathological changes such as lower Purkinje cell density may be found in primary CD when relevant brain regions are investigated with appropriate methods., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells., Experimental Design: We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice. During growth of human cancers in these mice, hprt-null murine stromal cells replace their human counterparts., Results: Pancreatic and ovarian cancers explanted from these mice were grown in selection media to produce pure human cancer cell lines. We screened one cell line with a 3,131-drug panel and identified 77 U.S. Food and Drug Administration (FDA)-approved drugs with activity, and two novel drugs to which the cell line was uniquely sensitive. Xenografts of this carcinoma were selectively responsive to both drugs., Conclusion: Chemotherapy can be personalized using patient-specific cell lines derived in biochemically selectable mice., (©2012 AACR.)

Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the Ca(V)2.1 calcium channel mouse mutant tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the tottering mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in Ca(V)2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The purines are a group of molecules used by all cells for many vital biochemical processes including energy-requiring enzymatic reactions, cofactor-requiring reactions, synthesis of DNA or RNA, signaling pathways within and between cells, and other processes. Defects in some of the enzymes of purine metabolism are known to be associated with specific clinical disorders, and neurological problems may be a presenting sign or the predominant clinical problem for several of them. This chapter describes three disorders for which the clinical features and metabolic basis are well characterized. Deficiency of adenylosuccinate-lyase (ADSL) causes psychomotor retardation, epilepsy, and autistic features. Lesch-Nyhan disease is caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and is characterized by hyperuricemia, motor and cognitive disability, and self-injurious behavior. Deficiency of myoadenylate deaminase (mAMPD) is associated with myopathic features. In addition to these disorders, several other disorders are briefly summarized. These include defects of phosphoribosylpyrophosphate synthase, adenosine deaminase (ADA), purine nucleoside phosphorylase (PND), deoxyguanosine kinase (dGK), or IMP dehydrogenase (IMPDH). Each of these disorders provides an unusual window on the unique importance of purine metabolism for function of different parts of the nervous system., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Dystonia is a complex neurological syndrome broadly characterized by involuntary twisting movements and abnormal postures. The anatomical distribution of the motor symptoms varies among dystonic patients and can range from focal, involving an isolated part of the body, to generalized, involving many body parts. Functional imaging studies of both focal and generalized dystonias in humans often implicate the cerebellum suggesting that similar pathological processes may underlie both. To test this, we exploited tools developed in mice to generate animals with gradients of cerebellar dysfunction. By using conditional genetics to regionally limit cerebellar dysfunction, we found that abnormalities restricted to Purkinje cells were sufficient to cause dystonia. In fact, the extent of cerebellar dysfunction determined the extent of abnormal movements. Dysfunction of the entire cerebellum caused abnormal postures of many body parts, resembling generalized dystonia. More limited regions of dysfunction that were created by electrical stimulation or conditional genetic manipulations produced abnormal movements in an isolated body part, resembling focal dystonia. Overall, these results suggest that focal and generalized dystonias may arise through similar mechanisms and therefore may be approached with similar therapeutic strategies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: There is evidence supporting an association between depression and anxiety in patients with chronic disease. Spasmodic dysphonia (SD) is a chronic, incurable, and disabling voice disorder. Reported rates of depression and anxiety in SD range from 7.1% to 72%, with a maximum number of 18 patients. The goal of this study was to define the coprevalence of depression and anxiety with SD., Materials and Methods: A single-institution case-control study was performed from May to July 2010. Consecutive patients with SD and benign voice disorders were enrolled prospectively. On enrollment, patients were asked to fill out a questionnaire that reviewed the duration of the voice disorder and personal history of anxiety and depression, including current and lifetime diagnosis., Results: One hundred forty-six controls with benign voice disorders and 128 patients with SD were enrolled. Patients with SD were no more likely to be diagnosed with depression or anxiety than those of the control group (odds ratio [OR]=0.985, 95% confidence interval [CI]=0.59-1.63; and OR=1.314; 95% CI=0.75-2.3, respectively). Additionally, duration of disease was a risk factor for depression in both the SD group and the control group, and the association was not significantly different between groups., Conclusion: Patients with SD were no more likely to have depression or anxiety than those with other voice disorders. It is important for otolaryngologists to be aware of the increased rates of depression in patients diagnosed with chronic diseases, including voice disorders, and to refer to a psychiatrist when appropriate., (Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Restless Legs Syndrome (RLS), first chronicled by Willis in 1672 and described in more detail by Ekbom in 1945, is a prevalent sensorimotor neurological disorder (5%-10% in the population) with a circadian predilection for the evening and night. Characteristic clinical features also include a compelling urge to move during periods of rest, relief with movement, involuntary movements in sleep (viz., periodic leg movements of sleep), and fragmented sleep. Although the pathophysiology of RLS is unknown, dopaminergic neurotransmission and deficits in iron availability modulate expressivity. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS. Here, we report that loss of the Drosophila homolog CG1826 (dBTBD9) appreciably disrupts sleep with concomitant increases in waking and motor activity. We further show that BTBD9 regulates brain dopamine levels in flies and controls iron homeostasis through the iron regulatory protein-2 in human cell lines. To our knowledge, this represents the first reverse genetic analysis of a "novel" or heretofore poorly understood gene implicated in an exceedingly common and complex sleep disorder and the development of an RLS animal model that closely recapitulates all disease phenotypes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Disproportionate anterocollis is a debilitating condition which occurs in the later stages of parkinsonian syndromes and for which there is no effective therapy. Multiple hypotheses have been proposed to explain its underlying etiology, including myopathy of the cervical extensors, and dystonia of the cervical flexors., Methods: We examined the records of 39 patients (8 prospectively) with anterocollis and parkinsonian syndromes to explore demographics, historical and clinical data, findings from electromyography and response to therapies. We classified our patients based on whether or not they were weak on neck extension and also based on primary diagnosis (PD vs atypical parkinsonian syndrome). Demographic, clinical, historical and EMG features are reported for each group., Results: There were no significant demographic differences between clinical subtypes, or primary diagnosis. Electromyographic (EMG) findings demonstrated myopathic changes in both groups, although they were more prominent in the group which was weak in extension. Historical features were similar between groups except for dopamine agonist use, which was more common in the myopathic subgroup (p=0.02). There were no other significant clinical differences between clinical subtypes or primary diagnosis with the exception that patients with atypical parkinsonian syndromes had more advanced motor symptoms., Conclusions: We conclude that anterocollis is a heterogeneous condition in which at least two distinct subtypes exist. Recognizing these subtypes may help guide therapy and future research., (Copyright © 2011 Elsevier B.V. All rights reserved.)