SAMMY-seq reveals early alteration of heterochromatin and deregulation of bivalent genes in Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis.

Movement Disorders - Childhood Rating Scale 4-18 revised in children with dyskinetic cerebral palsy.

BACKGROUND: Movement Disorders - Childhood Rating Scale for age 4-18 (MD-CRS 4-18) is a tool aimed to evaluate movement disorders in developmental age, validated since 2008 and applied in the literature. Psychometric properties, including inter- and intra-reliability and construct validity have been evaluated over time on children and adolescents with different types of movement disorders. AIM: The aim of the study is to revise the Movement Disorders - Childhood Rating Scale 4-18 (MD-CRS 4-18 R) and evaluate its psychometric properties, compared to previous version of the scale, in dyskinetic cerebral palsy. DESIGN: This is a measurement-focused study of video recorder sessions. SETTING: Video session carried out inpatient and outpatient. POPULATION: This measurement-focused study was carried out on a cohort of 57 participants with DCP (37 males; mean age 9 years and 6 months ±3 years and 8 months) evaluated through video-recorded sessions by experienced scorers using MD-CRS 4-18 and MR-CRS 4-18 R. METHODS: Inter-rater reliability, intra-rater reliability of MD-CRS 4-18 and MD-CRS 4-18 R were performed. RESULTS: This study supports the relevant contribution of MD-CRS 4-18 R to identify the severity of movement disorders in dyskinetic cerebral palsy, as indicated by the higher ICC values on Index II compared to previous MD-CRS 4-18 results. Standard Error Measurement (SEM) and Minimally Detectable Difference (MDD) of MD-CRS 4-18 R in DCP were all very low, with SEMs ranging from 0.01 to 0.02 and MDD from 0.03 to 0.06. CONCLUSIONS: Data obtained with MD-CRS 4-18 R are in accordance with previous scale on individuals with movement disorders due to different etiologies, tested with MD-CRS 4-18. CLINICAL REHABILITATION IMPACT: MD-CRS 4-18 R is able to verify natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP. Also MD-CRS 4-18 Revised form is a feasible tool, now easier to understand than the previous one, more available for incoming clinical trials.

Inter and intra-rater reliability and minimal detectable difference of Movement Disorder-Childhood Rating Scale.

BACKGROUND: Movement Disorder-Childhood Rating Scales (MD-CRS) have been designed in two forms (0-3 and 4-18 years) to accurately evaluate various movement disorders in children. AIM: The aim of this study is to evaluate the MD-CRS reliability when used by clinicians and professionals of rehabilitation after a one-day training on scoring it. DESIGN: This is a measurement-focused study of video-recorded sessions. SETTING: Video session carried out inpatient and outpatient. POPULATION: Children with different types of movement disorders. METHODS: After brief training in scoring MD-CRS, five health professionals (a resident doctor, a child neurologist and three physical therapists) independently scored 40 patient videotapes, of children with movement disorders for inter-rater reliability. In addition, the resident doctor scored 80 videos of 40 patients evaluated twice for intra-rater reliability. Reliability was assessed by Intraclass Correlation Coefficient (ICC) and was calculated separately for the two forms of the scale and for each score (Index I, Index II and Global Index). Standard Error of Measurement (SEM) and Minimal Detectable Difference (MDD) were also calculated. RESULTS: For both forms, inter-rater reliability of Global Index and Index I were good with an ICC ranged between 0.83 and 0.95. Instead, results of Index II were substantially moderate for both forms, with an ICC of 0.53 and 0.57, respectively. Intra-rater reliability for all Indexes in both forms was substantial or almost perfect, with values of ICCs ranging from 0.74 to 0.99. MDD values were between 0.05 and 0.17. CONCLUSIONS: MD-CRS 0-3 and MD-CRS 4-18 remain reliable clinical measurement tools for evaluation of movement disorders in developmental age when used by clinicians and professionals of rehabilitation after a specific short training. CLINICAL REHABILITATION IMPACT: MD-CRS 0-3 and MD-CRS 4-18 appear to be a promising outcome measurement tool in large scale studies with children and adolescents affected by various movement disorders either to verify natural history of the disorder or to plan pharmacological and/or surgical intervention programs.

Movement Disorder-Childhood Rating Scale: A Sensitive Tool to Evaluate Movement Disorders.

BACKGROUND: The Movement Disorder-Childhood Rating Scale represents a new tool for assessment of movement disorders during developmental age. In this study, we evaluated a cohort of 68 patients affected by various types of movement disorders and treated with specific drugs over one year to verify the usefulness of the Movement Disorder-Childhood Rating Scale. METHOD: The participants were divided into two groups according to their ages (0-3 years; 4-18 years) and were evaluated using Movement Disorder-Childhood Rating Scale 0-3 or 4-18 at baseline (i.e., before starting pharmacological treatment [T0], after 6 months [T1], and after 12 months [T2] of treatment. Univariate repeated measures analysis of variance with a Greenhouse-Geisser correction by SPSS 20 was performed to analyze the scale responsiveness for the three indices (e.g., Index I, Index II, Global Index) in each group with time (T0, T1, and T2). In addition, the Bonferroni test was performed to identify the source of significant differences among means. RESULTS: Significant differences were found between time points (T1 versus T0, T2 versus T0, and T2 versus T1) in both scales for all indexes with the exception for T2 versus T1 for Index II in both scales and for T2 versus T1 for the Global Index in the older age group. There was no significant correlation between observed changes in the scores and the age of the children, either for Movement Disorder-Childhood Rating Scale 0-3 or 4-18. CONCLUSION: Our results suggest that Movement Disorder-Childhood Rating Scale is a suitable tool to detect changes independently from age and could be used as outcome measure for clinical trials.

Responsiveness of the MD-childhood rating scale in dyskinetic cerebral palsy patients undergoing anticholinergic treatment.

BACKGROUND: Movement Disorder-Childhood Rating Scale (MD-CRS) is a new tool for assessment of movement disorders during developmental age. AIM: In this study we evaluated a cohort of 47 patients affected by dyskinetic cerebral palsy and treated with anticholinergic drug (trihexyphenidyl) over one year in order to verify the responsiveness of the new scale. METHODS: The participants were divided into two groups according to their age (0-3 years; 4-18 years) and were evaluated using MD-CRS 0-3 or MD-CRS 4-18 at baseline, i.e., before starting pharmacological treatment (T0), after 6 (T1) and 12 months (T2) of treatment. Univariate repeated measures ANOVA with a Greenhouse-Geisser correction was performed to analyse the scale responsiveness for the three indexes (e.g., Index I, Index II and Global Index) in each group with time (T0, T1 and T2). In addition, Bonferroni test was performed to identify the source of significant differences among means. RESULTS: Significant differences were found between time points (T1 vs T0, T2 vs. T0 and T2 vs. T1) in both scales for all indexes with the exception for T2 vs. T1 for Index II in both scales and for T2 vs. T1 for the Global Index in the older age group. There was not significant correlation between observed changes in the scores and age of children, either for MD-CRS 0-3 or MD-CRS 4-18. CONCLUSIONS: Our results suggest that MD-CRS is a suitable tool to detect changes and could be used as outcome measure for clinical trials. Further studies will be necessary to prove the efficacy of trihexyphenidyl for dyskinetic cerebral palsy.