Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

PurposePathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.MethodsWe perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.ResultsOur data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.ConclusionInsights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.     

The emerging role of exosomes in Alzheimer’s disease

Alzheimer’s disease (AD), manifested by memory loss and a decline in cognitive functions, is the most prevalent neurodegenerative disease accounting for 60–80 % of dementia cases. But, to-date, there is no effective treatment available to slow or stop the progression of AD. Exosomes are small extracellular vesicles that carry constituents, such as functional messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive substances of their source cells. In the brain, exosomes are likely to be sourced by almost all cell types and involve in cell communication to regulate cellular functions. The yet, accumulated evidence on the roles of exosomes and their constituents in the AD pathological process suggests their significance as additional biomarkers and therapeutic targets for AD. This review summarizes the current reported research findings on exosomes roles in the pathogenesis, diagnosis, and treatment of AD.     

Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three‐nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.     

Position of Glycine Substitutions in the Triple Helix of COL6A1, COL6A2, and COL6A3 is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies

Glycine substitutions in the conserved Gly‐X‐Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N‐terminal to the 17th Gly‐X‐Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly‐X‐Y triplets 10–15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N‐terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

1 + 1 = 3? The systematic development of a theoretical and evidence-based tailored multimedia intervention to improve medication adherence

ObjectiveTo describe the development of a theoretical and evidence-based tailored multimedia intervention to improve medication intake behavior in patients with inflammatory bowel disease (IBD). The intervention integrates interpersonal and technology-mediated strategies with the expectation that this will work synergistically.MethodsThe development followed the Medical Research Council's framework. Three literature reviews and three pre-tests among 84 IBD patients and eight nurses were conducted to guide the development of the intervention. A feasibility study was carried out among four nurses and 29 patients.ResultsThe components include: (1) an online preparatory assessment (OPA); (2) tailored interpersonal communication; and (3) tailored text messaging. To support the development, the feasibility was tested. Results indicated that the OPA was comprehensive and could be a helpful tool for both patients and nurses to prepare for the consultation. The training was evaluated as being instructive and applicable with a mean mark of 8.5. Of the developed messages, 65.6% received positive evaluations and were used in the intervention.ConclusionBy applying the framework, we were able to describe the logic behind the development of a tailored multimedia intervention to improve medication intake behavior.Practice implicationsThis study could serve as a guide for the development of other health interventions.     

Mapping Different Intra-Hemispheric Parietal-Motor Networks Using Twin Coil TMS

BackgroundAccumulating evidence suggests anatomical and functional differences in connectivity between the anterior and posterior parts of the inferior-parietal lobule (IPL) and the frontal motor areas.Objective/HypothesisThis study investigates whether different intra-hemispheric parietal-motor interactions can be observed along the anterior–posterior axis of the IPL in the resting human brain.MethodsWe use a twin coil transcranial magnetic stimulation technique to test intra-hemispheric interactions between three points adjacent to the intra-parietal sulcus (anterior, central, posterior) and the ipsilateral primary motor cortex (M1) at rest in both hemispheres.ResultsWe found that stimulation of the anterior IPL resulted in an inhibition of the ipsilateral M1 in both hemispheres. Stimulation of the central and posterior IPL resulted in a facilitatory effect on ipsilateral M1 in the left but not for the right hemisphere. Additionally we show that there is considerable inter-subject variability concerning the optimal parietal facilitatory and inhibitory position.ConclusionsThe IPL has distinct inhibitory and facilitatory connections to the ipsilateral M1. Whereas inhibitory connections are observed in both hemispheres, facilitatory connections are asymmetric. These parietal-motor networks may represent the basis for the functional differences between these regions in reaching and grasping tasks and mirror the functional asymmetry observed in the motor system. From a practical point of view, we note that the inter-subject variability means that future TMS studies of the parietal area might consider a hot-spot localization similar to the procedures commonly used for M1.