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© 2021 International Parkinson and Movement Disorder Society, Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms.

Limitation of functional ability is a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the appraisal of the use and clinimetric properties of clinical measures of functional ability that have been applied in HD studies and trials to date, to make recommendations regarding their use based on standardized criteria. After a systematic literature search, we included a total of 29 clinical measures grouped into two categories: (1) performance-based measures (e.g., balance, walking, and reaching/grasping), and (2) rating scales. Three performance-based measures are rated as "recommended": the Tinetti Mobility Test for screening of fall risk and for severity assessment of mobility in patients with manifest HD (up to stage III); the Berg Balance Scale for severity of balance impairment; and the Six-Minute Walk Test for assessment of walking endurance (severity) in HD subjects with preserved ambulation. No rating scale targeting functional ability reached a "recommended" status either for screening or severity measurement. The main challenges identified in this review include applying widely accepted conceptual frameworks to the identified measures, the lack of validation of clinical measures to detect change over time, and absence of validated measures for upper limb function. Furthermore, measures of capacity or ability to perform activities of daily living had ceiling effects in people with early and pre-manifest HD. We recommend that the MDS prioritize the development of new scales that capture small, but meaningful changes in function over time for outcome assessment in clinical trials, particularly in earlier stages of HD.

Background The clinical assessment of motor symptoms in Huntington's disease is usually performed with the Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS). A high interrater reliability is desirable to monitor symptom progression. Therefore, a teaching video and a system for annual online certification has been developed and implemented. Objectives The aim of this study is to investigate the interrater reliability of the UHDRS-TMS and of its subitems, and to examine the performance of raters in consecutive years. Methods Data from the online UHDRS-TMS certification were used. The interrater reliability was assessed for all first-time participants (n = 944) between 2009 and 2016. Intraclass correlation coefficients (ICC) were calculated for each year separately and the mean was taken as the total ICC. Results The UHDRS-TMS (ICC = 0.847), tandem walking (0.824), pronate/supinate hands left (0.713), and retropulsion pull test (0.706) showed good interrater reliability. Poor interrater reliability was found for maximal dystonia of the left and right upper extremity (0.187 and 0.322, respectively), maximal dystonia of the left and right lower extremity (0.200 and 0.256, respectively), and maximal dystonia of the trunk (0.389), tongue protrusion (0.266), and rigidity arms left (0.390). Raters performed significantly worse on follow-up certification compared to their first certification. Conclusions Our results suggest that the rating of dystonia (absent, slight, mild, moderate, or marked) is subjective and difficult to interpret, especially on video. Therefore, changing the dystonia items of the UHDRS-TMS should be explored. We also recommend that raters should watch the UHDRS-TMS teaching video before each certification.

The compromise of quality of life in Huntington's disease is a major issue, both for individuals with the disease as well as for their caregivers. The International Parkinson and Movement Disorder Society commissioned a review of the use and clinimetric validation status of measures used in Huntington's disease to assess aspects related with quality of life and to make recommendations on their use following standardized criteria. We included both patient‐centered measures (patient health‐related quality‐of‐life measures) and caregiver‐centered measures (caregiver quality‐of‐life measures). After conducting a systematic literature search, we included 12 measures of patient health‐related quality of life and 2 measures of caregiver quality of life. Regarding patient‐centered measures, the Medical Outcomes Study 36‐Item Short‐Form Health Survey is “recommended” as a generic assessment of health‐related quality of life in patients with Huntington's disease. The 12‐Item Short Form Health Survey, the Sickness Impact Profile, the 12‐item World Health Organization Disability Assessment Schedule, and the Huntington's Disease Health‐Related Quality of Life questionnaire are “suggested.” No caregiver‐centered quality‐of‐life measure obtained a “recommended” status. The Alzheimer's Carer's Quality of Life Inventory and the Huntington's Disease Quality of Life Battery for Carers are “suggested.” Recognizing that the assessment of patient health‐related quality of life can be challenging in Huntington's disease, as patients may lack insight and there is insufficient clinimetric testing of these scales, the committee concluded that further validation of currently available health‐related quality‐of‐life measures should be undertaken, namely, those Huntington's disease–specific health‐related quality‐of‐life measures that have recently been reported and used.

Background Previous studies on human brain tissue alterations caused by deep brain stimulation described glial and reactive inflammatory changes. In the current pathoanatomical study, we extended the analysis to signs of axonal changes and the influence of concomitant disease. Methods Brains of 10 patients with Parkinson's disease or essential tremor and a total of 18 electrodes were systematically examined up to 7.5 y after surgery. Results In general, tissue that had long-term contact with the electrode material exhibited astrogliosis in all, T-lymphocytes in 93%, and multinucleated giant cells in 68% of patients. Immunohistochemistry showed an increase in amyloid precursor protein immunoreactive axonal swellings in the brain at the electrically active parts of the electrodes. Patients who died of septicemia showed a more severe astrogliosis and giant cell reaction than patients who died of cardiovascular events. Parkinson's disease or essential tremor did not differentially produce histopathological changes around the electrodes. Conclusion Long-term electrical stimulation by deep brain stimulation causes minor axonal changes. The cause of death, but not the underlying neurological disease, affects the histopathological changes around the electrode. The findings need to be reproduced by examining larger patient subgroups. © 2015 International Parkinson and Movement Disorder Society

BACKGROUND: Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. METHODS: In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n?=?528) or hypokinetic-rigid (n?=?432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. RESULTS: Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P?.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P?

Background: Clinical presentation and DYT1 status amongst Chinese patients with primary dystonia have not been well studied. Methods: One hundred and twenty patients with primary dystonia from South-West China were studied in a prospective survey for 3.5 years. Severity and the resulting disability were assessed using the Burke–Fahn–Marsden dystonia rating scale (BFMDRS). Health related quality of life (HRQL) was measured through the 36-item short-form (SF-36). The Hospital Anxiety and Depression Scale (HADS) was utilized to identify and quantify depression and anxiety. Mutations in the DYT1 exon 5 were screened by direct sequencing. Results: Cervical dystonia was found to be the most frequent form of focal dystonia and was discovered to occur at an early age. Pain and tremor were the common associated symptoms. Family history was positive in 19.5% of the cases, with a trend of earlier onset. Depression (14.5%) and anxiety (6.6%) were the main HRQL impairments. Multiple linear regression analysis suggested that gender, depression, anxiety and functional disability were amongst the principal determinants of lower HRQL. Only one instance of DYT1 GAG deletion (1.4%) was detected in 71 patients. Conclusion: Our data on a cohort of Chinese patients show some difference from descriptions in other ethnic groups. This includes an earlier age of onset, a lower incidence of depression and female serving as a predictor factor of a HRQL. Similar to other cohorts, DYT1 gene mutations are rare.

Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han-Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60-6.17, P < 0.01]. Considering the age at onset, this difference was found only in late-onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90-7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han-Chinese population.

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

The alpha-subunit of dystroglycan, a member of the dystrophin associated protein complex, binds to extracellular laminin-alpha2, while its beta-subunit interacts with cytoskeletal dystrophin. The exact biological role of dystroglycan, especially during human skeletal muscle development, has not been fully explored. Here, we analysed the distribution and expression characteristics of both dystroglycan subunits and laminin-alpha2 in primary human skeletal muscle cells. During development, expression levels of all three proteins increased with differentiation. The proteins were relocated from the sarcoplasm to the sarcolemma. The size of alpha-dystroglycan decreased from 150-220 kDa at the proliferation stage to 100-120 kDa at the late developmental stage. Both alpha- and beta-dystroglycan were involved in forming a complex with their respective partners laminin-alpha2 and dystrophin/utrophin. Our data show that, during development, cells may employ tightly regulated post-translational species-specific modification to produce different isoforms of alpha-dystroglycan to participate in appropriate functions.

Primary dystonia is a movement disorder characterized by involuntary and sustained muscle contractions causing twisting or abnormal postures and mutations in several genes have been identified. Our goal was to investigate, whether the clinical presentation would differ between patients with a positive family history, and patients without. Furthermore, we have performed mutation analysis in the subgroup of patients with a positive family history. A total of 175 patients with primary dystonia were evaluated. Data on gender, presence and frequency of pain and tremor, age of onset, and the distribution of affected body parts were compared between patients with positive and negative family history. All exons of the torsion dystonia 1, GTP cyclohydrolase 1 and epsilon-sarcoglycan genes were examined in 40 patients by SSCP analysis of PCR products followed by sequencing of variant conformers. Dystonia patients with a positive family history of dystonia had an earlier age of onset and those with a positive family history of tremor more often associated tremor than those with a negative family history. Four new polymorphisms in the epsilon-sarcoglycan gene were found and others confirmed, but no known or new mutations could be detected. Our study supports the notion that primary dystonia is a genetically heterogeneous disease.

Dystrophin and associated proteins form a complex with an important role at the sarcolemma. Expression of this protein complex is highly regulated during development and regeneration. In order to better understand assembling patterns of these proteins, we have studied their expression in targetoid-like phenomena found in human muscle after chronic denervation, a situation known to give rise to abnormal protein trafficking. In eight biopsies of patients with chronic denervation, mainly resulting from amyotrophic lateral sclerosis, we found a number of targetoid phenomena. Selective accumulation of a number of sarcolemmal and sarcoplasmatic proteins occurred in targetoid phenomena. The larger majority of them contained gamma-sarcoglycan (gammaSG), but none contained the developmental heavy chain myosin isoform. In a series of 166 targetoid phenomena which could be studied with 17 different antibodies recognizing sarcolemmal and cytoplasmatic proteins, a high level of colocalization of gammaSG with desmin and alpha-actinin was found. Colocalization rate was much lower with other proteins, including other members of the dystrophin-associated protein complex. These data show that selective changes in expression of otherwise closely related proteins occur during disturbed trafficking leading to target formation. Because members of the dystrophin-associated protein complex do not accumulate in a similar fashion within targets, we suggest that a complex molecular control of gene expression and trafficking of this complex is involved after chronic muscle denervation.

Hereditary spastic paraplegia is a rare disorder with gait disturbance due to a degeneration of the corticospinal tract, sometimes accompanied by involvement of other systems. Out of the 20 loci known so far, eight genes have now been identified, allowing the first molecular and cell studies in the pathophysiology of the disorder. These should also help to understand the function of the corticospinal tract at the molecular level and design strategies to prevent and treat spasticity due to more common causes. The proteins encoded by these genes play a role in development, in signal transduction between axons and myelinating cells, in cellular, particularly axonal trafficking or in energy metabolism. Some of them have actions in several areas of cellular function. Here we review the present knowledge about the genes involved in hereditary spastic paraplegia, a field presently undergoing rapid change.

The D216H single-nucleotide polymorphism (SNP) (rs1801968) in DYT1 exon 4 has been suggested to be a genetic modifier in primary dystonia.

In addition to vascular and supraspinal influences, contraction of craniofacial muscles or central sensitization processes following continuous nociceptive input of craniofacial muscles may play an important role in the pathogenesis of tension-type headache. Chemodenervation induced by botulinum toxin injection is successfully used to decrease muscle tension. If muscle tension is important in this type of headache, then botulinum toxin could be helpful in its treatment. We conducted a randomized, placebo-controlled study to examine the effect of 20 U botulinum toxin injected into frontal and temporal muscles in patients with chronic tension-type headache. During a baseline of 4 weeks and a posttreatment period of 8 weeks, the effect was evaluated with daily records and the West Haven-Yale Multidimensional Pain Inventory. Some improvement in affective variables were demonstrated in the botulinum group, but important outcome variables, such as pain intensity, the number of pain-free days, and consumption of analgesics, were not statistically different between the groups. Reasons for these moderate effects may include the injection sites, dose of botulinum toxin, and duration of treatment.

The aim of the study was to investigate force regulation in patients with writer's cramp when performing a drawer-opening task using the precision grip. Experimental conditions included intervening load pulses and vibratory manipulations for examining grip force responses to sensory disturbances. The data revealed that grip force was increased in patients with writer's cramp compared with normal subjects, with a stronger modulation in the symptomatic compared with the asymptomatic hand. This denotes a change in force scaling capabilities and most notably for the preferred hand used in manipulative activities. Vibratory stimulation of the extrinsic hand/finger muscles resulted in an increased grip force of both hands in the patients with writer's cramp. The latter was not observed in normal subjects and supports a bilateral dysfunction in sensorimotor integration resulting from focal dystonia. In conclusion, the disturbed regulation of the precision grip during a drawer-opening task is illustrative for the inability of patients with writer's cramp to efficiently control the force output during manipulative activities.

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose 'wearing-off' phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by ~ 35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated 'wearing-off' phenomenon.