Juvenile-onset Huntington disease pathophysiology and neurodevelopment: a review

Huntington disease is an autosomal dominant inherited brain disorder that typically becomes manifest in adulthood. Juvenile-onset Huntington disease refers to approximately 5% of patients with symptom onset before the age of 21 years. The causal factor is a pathologically expanded CAG repeat in the Huntington gene. Age at onset is inversely correlated with CAG repeat length. Juvenile-onset patients have distinct symptoms and signs with more severe pathology of involved brain structures in comparison with disease onset in adulthood. The aim of this review is to compare clinical and pathological features in juvenile- and adult-onset Huntington disease and to explore which processes potentially contribute to the observed differences. A specific focus is placed on molecular mechanisms of mutant huntingtin in early neurodevelopment and the interaction of a neurodegenerative disease and postnatal brain maturation. The importance of a better understanding of pathophysiological differences between juvenile- and adult-onset Huntington disease lies in development and implementation of new therapeutic strategies. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyFunctional Genomics of Muscle, Nerve and Brain Disorder

Износ кругов из СТМ при зубошлифовании

The problems of increasing the efficiency of grinding highly precision gearwheels of the 3–4 degree of precision using superhard material tools are discussed. The efficiency of cubic boron nitride dish grinding wheels in various bonds has been studied. Recommendations how to use cubic boron nitride wheels in gear grinding are given

The prevalence of pain in Huntington’s Disease in a large worldwide cohort

Introduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers.Methods: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons.Results: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use.Conclusions: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain.Development and application of statistical models for medical scientific researc

De novo SPAST mutations may cause a complex SPG4 phenotype

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Study protocol of IMAGINE-HD: imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington's disease

IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.Radiolog

Toward an internally consistent astronomical distance scale

Accurate astronomical distance determination is crucial for all fields in astrophysics, from Galactic to cosmological scales. Despite, or perhaps because of, significant efforts to determine accurate distances, using a wide range of methods, tracers, and techniques, an internally consistent astronomical distance framework has not yet been established. We review current efforts to homogenize the Local Group's distance framework, with particular emphasis on the potential of RR Lyrae stars as distance indicators, and attempt to extend this in an internally consistent manner to cosmological distances. Calibration based on Type Ia supernovae and distance determinations based on gravitational lensing represent particularly promising approaches. We provide a positive outlook to improvements to the status quo expected from future surveys, missions, and facilities. Astronomical distance determination has clearly reached maturity and near-consistency.Comment: Review article, 59 pages (4 figures); Space Science Reviews, in press (chapter 8 of a special collection resulting from the May 2016 ISSI-BJ workshop on Astronomical Distance Determination in the Space Age

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes—CACNA1A, ITPR1, SPTBN2, and KCNC3—were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist. Neurological Motor Disorder

Hereditary spastic paraplegias in the Netherlands. Clinical aspects and mutational spectrum

Contains fulltext : 120592.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 20 december 2013Promotores : Kremer, H.P.H., Willemsen, M.A.A.P. Co-promotores : Warrenburg, B.P.C. van de, Scheffer, H

Raising Awareness of Therapeutic Misconception and Optimism Around Clinical Trials in Huntington's Disease

Neurological Motor Disorder

[From psychiatric symptoms to paraneoplastic syndrome]

Contains fulltext : 69299.pdf (publisher's version ) (Open Access)Two patients, a 38-year-old man and a 32-year-old woman, were admitted to a psychiatric ward. The first patient suffered from a mood disorder, personality changes and complained of several, hitherto unexplained physical symptoms. Finally the patient was diagnosed with paraneoplastic cerebellar degeneration associated with Hodgkin's disease. The second patient presented with psychosis and panic disorders, but the condition was later found to be caused by paraneoplastic limbic encephalitis due to ovarian teratomas. These cases illustrate that patients with paraneoplastic neurological syndromes may present with psychiatric symptoms which can hamper an early diagnosis