De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

Quantitative magnetic resonance imaging of the upper trapezius muscles - assessment of myofascial trigger points in patients with migraine.

BACKGROUND: Research in migraine points towards central-peripheral complexity with a widespread pattern of structures involved. Migraine-associated neck and shoulder muscle pain has clinically been conceptualized as myofascial trigger points (mTrPs). However, concepts remain controversial, and the identification of mTrPs is mostly restricted to manual palpation in clinical routine. This study investigates a more objective, quantitative assessment of mTrPs by means of magnetic resonance imaging (MRI) with T2 mapping. METHODS: Ten subjects (nine females, 25.6 ± 5.2 years) with a diagnosis of migraine according to ICHD-3 underwent bilateral manual palpation of the upper trapezius muscles to localize mTrPs. Capsules were attached to the skin adjacent to the palpated mTrPs for marking. MRI of the neck and shoulder region was performed at 3 T, including a T2-prepared, three-dimensional (3D) turbo spin echo (TSE) sequence. The T2-prepared 3D TSE sequence was used to generate T2 maps, followed by manual placement of regions of interest (ROIs) covering the trapezius muscles of both sides and signal alterations attributable to mTrPs. RESULTS: The trapezius muscles showed an average T2 value of 27.7 ± 1.4 ms for the right and an average T2 value of 28.7 ± 1.0 ms for the left side (p = 0.1055). Concerning signal alterations in T2 maps attributed to mTrPs, nine values were obtained for the right (32.3 ± 2.5 ms) and left side (33.0 ± 1.5 ms), respectively (p = 0.0781). When comparing the T2 values of the trapezius muscles to the T2 values extracted from the signal alterations attributed to the mTrPs of the ipsilateral side, we observed a statistically significant difference (p = 0.0039). T2 hyperintensities according to visual image inspection were only reported in four subjects for the right and in two subjects for the left side. CONCLUSIONS: Our approach enables the identification of mTrPs and their quantification in terms of T2 mapping even in the absence of qualitative signal alterations. Thus, it (1) might potentially challenge the current gold-standard method of physical examination of mTrPs, (2) could allow for more targeted and objectively verifiable interventions, and (3) could add valuable models to understand better central-peripheral mechanisms in migraine.

Six-minute walk test versus two-minute walk test in children with Duchenne muscular dystrophy: Is more time more information?

BACKGROUND/PURPOSE: The six minute walk test is a widely accepted primary outcome parameter in most studies in Duchenne muscular dystrophy (DMD). To compare information obtained by the six minute walk distance (6MWD) test and the two minute walk distance (2MWD) in patients with DMD, a cohort of 13 voluntary DMD boys did a repeated six minute walking test. METHODS: Patients had to be ambulatory with a physical disability according to Levels 1-3 on the Vignos-Scale for lower extremity. Measurements were taken at one minute intervals. Reliability was measured by intraclass correlation. RESULTS: Test-retest reliability for 6MWD and 2MWD in two different age classes was very good for both subgroups. Test-retest-reliability was lower in patients with more advanced disability in both tests. Walking speed remained completely stable from time points 1-6 minutes in the whole study patient collective, which indicates that physical exhaustion is not reached after six minutes even in more disabled patients. CONCLUSION: Thus the 6MWD in DMD patients does not give additional information as compared to a 2MWD.

Does hip displacement influence health-related quality of life in children with cerebral palsy?

OBJECTIVE: To evaluate the association of hip lateralisation with health-related quality of life (HRQL) in children with cerebral palsy (CP) using the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD(®)) questionnaire. METHODS: We assessed n = 34 patients (mean age: 10.2 years, SD: 4.7 years; female: n = 16) with bilateral CP and Gross Motor Function Classification System (GMFCS) Level III-V using the CPCHILD(®) questionnaire. Hip lateralisation was measured by Reimer`s migration percentage (MP). RESULTS: There was an association between both, MP and GMFCS with CPCHILD(®) total score. Stratified analyses did not suggest interaction of the association between MP and CPCHILD(®) total score by GMFCS level. After adjustment for GMFCS level, we found a significant linear decrease of CPCHILD(®) total score of -0.188 points by 1% increment in MP. CONCLUSIONS: There was an association between MP and HRQL, which could not be explained by the GMFCS level.