Meaningful and measurable health domains in Huntington’s: large-scale validation of the Huntington’s disease health-related quality of life questionnaire (HDQoL) across severity stages

Objectives: While health-related quality of life is key for patients with long-term neurodegenerative conditions, measuring this is less straightforward and complex in Huntington’s disease. This study aimed to refine and validate a fully patient-derived instrument, the Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), and to elucidate health domains that are meaningful to patients’ lived experience. Methods: Five-hundred and forty-one participants, from pre-manifest to end-stage disease completed the HDQoL, together with generic quality of life measures, and in-person motor, cognitive and behavioural assessments. The psychometric properties of the HDQoL were examined using factor analysis and Rasch analysis. Results: Four HDQoL domains emerged reflecting the classical triad of HD features - they were Physical-Functional, Cognitive, and two different behavioural aspects i.e. Mood-Self domain, as well as a distinct Worries domain. These domains clarify the behavioural sequelae as experienced by patients, and all showed good to excellent internal consistency. Known groups analyses illustrated significant and graded changes in clinical assesments and corresponding HDQoL domains across severity levels. Convergent and discriminant validity was demonstrated by the expected pattern of correlations between specific HDQoL domains and corresponding domain-relevant clinical assesments as well as patient-reported measures. The data demonstrate robust support for the refined HDQoL across disease stages. Conclusions: The HDQoL with its two distinct behavioural domains of Mood-Self and of Worries, as well as a Physical-Functional and a Cognitive domain, is a relevant, reliable and valid patient-derived instrument to measure the impact of Huntington’s disease across all severity stages

U7 snRNAs induce correction of mutated dystrophin pre-mRNA by exon skipping.

Most cases of Duchenne muscular dystrophy are caused by dystrophin gene mutations that disrupt the mRNA reading frame. Artificial exclusion (skipping) of a single exon would often restore the reading frame, giving rise to a shorter, but still functional dystrophin protein. Here, we analyzed the ability of antisense U7 small nuclear (sn)RNA derivatives to alter dystrophin pre-mRNA splicing. As a proof of principle, we first targeted the splice sites flanking exon 23 of dystrophin pre-mRNA in the wild-type muscle cell line C2C12 and showed precise exon 23 skipping. The same strategy was then successfully adapted to dystrophic immortalized mdx muscle cells where exon-23-skipped dystrophin mRNA rescued dystrophin protein synthesis. Moreover, we observed a stimulation of antisense U7 snRNA expression by the murine muscle creatine kinase enhancer. These results demonstrate that alteration of dystrophin pre-mRNA splicing could correct dystrophin gene mutations by expression of specific U7 snRNA constructs

Progression of motor subtypes in Huntington’s disease. a 6-year follow-up study

The objective of this study is to investigate the progression of predominantly choreatic and hypokinetic-rigid signs in Huntington's disease (HD) and their relationship with cognitive and general functioning over time. The motor signs in HD can be divided into predominantly choreatic and hypokinetic-rigid subtypes. It has been reported in cross-sectional studies that predominantly choreatic HD patients perform better on functional and cognitive assessments compared to predominantly hypokinetic-rigid HD patients. The course of these motor subtypes and their clinical profiles has not been investigated longitudinally. A total of 4135 subjects who participated in the European HD Network REGISTRY study were included and classified at baseline as either predominantly choreatic (n = 891), hypokinetic-rigid (n = 916), or mixed-motor (n = 2328), based on a previously used method. The maximum follow-up period was 6 years. The mixed-motor group was not included in the analyses. Linear mixed models were constructed to investigate changes in motor subtypes over time and their relationship with cognitive and functional decline. Over the 6-year follow-up period, the predominantly choreatic group showed a significant decrease in chorea, while hypokinetic-rigid symptoms slightly increased in the hypokinetic-rigid group. On the Total Functional Capacity, Stroop test, and Verbal fluency task the rate of change over time was significantly faster in the predominantly choreatic group, while on all other clinical assessments the decline was comparable for both groups. Our results suggest that choreatic symptoms decrease over time, whereas hypokinetic-rigid symptoms slightly increase in a large cohort of HD patients. Moreover, different motor subtypes can be related to different clinical profiles

Auditory time perception in Huntington’s disease

Huntington's disease (HD) is characterized by early involvement of the striatum. It affects the pace of repetitive motor activity, as motor timing depends on basal ganglia activity. However, data are lacking on the impact of this process on auditory time perception in motor non-affected gene carriers.Objective: This work aims to test the performance in time perception of a group of mutation carriers, either without motor symptoms or at an early stage of motor involvement. This should allow designing therapies targeting compensation strategies and possibly be used as a disease progression marker.Method: Time was assessed using two different tasks. An absolute, duration-based time perception was assessed in a first task and a relative, beat-based time perception was assessed in a second one. HD-mutation carriers with low-to-middle grades of motor involvement (HD-motor, n = 10) or without motor signs (HD-premotor n = 21), were compared with age- and sex-matched healthy controls (control (n = 27)). Thresholds of time difference perception where assessed.Results: For both tasks, poorer performances were found in HD-motor patients as compared with HD-premotor and controls. Thresholds of time difference perception correlated positively with the CAP score for the whole group of HD-gene carriers in both tasks. In a post-hoc exploratory analysis performed by a multiple regression, a negative correlation was found between the thresholds in both tasks and the Stroop interference test. Furthermore, in the first task, a positive correlation was found between thresholds and a trail making B test and a negative one with a total functional score.Conclusion: Our data confirm that the impairment in time perception in persons affected by HD correlates with the advancing disease. They also suggest that time perception depends on similar cognitive mechanisms as the ones sub-serving the Stroop interference test

Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2

Summary We report the clinical features of 12 families with autosomal dominant spastic paraplegia (ADSP) linked to the SPG4 locus on chromosome 2p, the major locus for this disorder that accounts for ∼40% of the families. Among 93 gene carriers, 32 (34%) were unaware of symptoms but were clinically affected. Haplotype reconstruction showed that 90% of the asymptomatic gene carriers presented increased reflexes and/or extensor plantar responses independent of age at examination. The mean age at onset was 29 years, ranging from 1 to 63 years. Intra- as well as inter-familial variability of age at onset was important, but did not result from anticipation. Phenotype—genotype correlations and comparison with SPG3 and SPG5 families indicated that despite the variability of age at onset, SPG4 is a single genetic entity but no clinical features distinguish individual SPG4 patients from those with SPG3 or SPG5 mutation

DYT1 mutations amongst adult primary dystonia patients in Singapore with review of literature comparing East and West

10.1016/j.jns.2006.03.009Journal of the Neurological Sciences247135-3

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias

Background and purpose:  These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders.Methods:  Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members.Results and conclusion:  This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided

Systematic investigation of projectile fragmentation using beams of unstable B and C isotopes

Background: Models describing nuclear fragmentation and fragmentation fission deliver important input for planning nuclear physics experiments and future radioactive ion beam facilities. These models are usually benchmarked against data from stable beam experiments. In the future, two-step fragmentation reactions with exotic nuclei as stepping stones are a promising tool for reaching the most neutron-rich nuclei, creating a need for models to describe also these reactions. Purpose: We want to extend the presently available data on fragmentation reactions towards the light exotic region on the nuclear chart. Furthermore, we want to improve the understanding of projectile fragmentation especially for unstable isotopes. Method: We have measured projectile fragments from C10,12-18 and B10-15 isotopes colliding with a carbon target. These measurements were all performed within one experiment, which gives rise to a very consistent data set. We compare our data to model calculations. Results: One-proton removal cross sections with different final neutron numbers (1pxn) for relativistic C10,12-18 and B10-15 isotopes impinging on a carbon target. Comparing model calculations to the data, we find that the epax code is not able to describe the data satisfactorily. Using abrabla07 on the other hand, we find that the average excitation energy per abraded nucleon needs to be decreased from 27 MeV to 8.1 MeV. With that decrease abrabla07 describes the data surprisingly well. Conclusions: Extending the available data towards light unstable nuclei with a consistent set of new data has allowed a systematic investigation of the role of the excitation energy induced in projectile fragmentation. Most striking is the apparent mass dependence of the average excitation energy per abraded nucleon. Nevertheless, this parameter, which has been related to final-state interactions, requires further study

The Mitochondrial Genome Is a “Genetic Sanctuary” during the Oncogenic Process

Since Otto Warburg linked mitochondrial physiology and oncogenesis in the 1930s, a number of studies have focused on the analysis of the genetic basis for the presence of aerobic glycolysis in cancer cells. However, little or no evidence exists today to indicate that mtDNA mutations are directly responsible for the initiation of tumor onset. Based on a model of gliomagenesis in the mouse, we aimed to explore whether or not mtDNA mutations are associated with the initiation of tumor formation, maintenance and aggressiveness. We reproduced the different molecular events that lead from tumor initiation to progression in the mouse glioma. In human gliomas, most of the genetic alterations that have been previously identified result in the aberrant activation of different signaling pathways and deregulation of the cell cycle. Our data indicates that mitochondrial dysfunction is associated with reactive oxygen species (ROS) generation, leading to increased nuclear DNA (nDNA) mutagenesis, but maintaining the integrity of the mitochondrial genome. In addition, mutational stability has been observed in entire mtDNA of human gliomas; this is in full agreement with the results obtained in the cancer mouse model. We use this model as a paradigm of oncogenic transformation due to the fact that mutations commonly found in gliomas appear to be the most common molecular alterations leading to tumor development in most types of human cancer. Our results indicate that the mtDNA genome is kept by the cell as a “genetic sanctuary” during tumor development in the mouse and humans. This is compatible with the hypothesis that the mtDNA molecule plays an essential role in the control of the cellular adaptive survival response to tumor-induced oxidative stress. The integrity of mtDNA seems to be a necessary element for responding to the increased ROS production associated with the oncogenic process