Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

Depression has often been associated with increased negative affect reactivity to stress (Stress-Sensitivity) and reduced capacity to experience pleasure or positive affect (Reward Experience). To date, no studies have prospectively examined changes in StressSensitivity and Reward Experience following antidepressant treatment. The sample included 83 depressed patients and 22 healthy controls. A randomized controlled trial was carried out with patients receiving either imipramine or placebo for 6 weeks. At baseline and 6 weeks, patients and controls participated in an Experience Sampling procedure, prospectively measuring ecologically valid daily life appraisals of activities and mood states. The course of depression was assessed with the Hamilton Depression Rating Scale (HDRS). Multilevel linear regression analyses showed that patients had higher negative and lower positive appraisals of activities than controls. In addition, patients showed increased Stress-Sensitivity (negative affect reactivity to negatively appraised activities). Treatment with imipramine decreased Stress-Sensitivity and increased Reward Experience (positive affect reactivity to positively appraised activities). Changes in Stress-Sensitivity and Reward Experience were in part reducible to changes in the process of activity appraisal itself. However, increase in Reward Experience, but not decrease in Stress-Sensitivity, discriminated between patients who responded and those who did not, independent of changes in the process of activity appraisal itself. Response to treatment in depression may be conditional on restoration of hedonic capacity, the cerebral substrate of which requires further study in relation to antidepressant response. A search for (synergistic) antidepressant therapies specifically targeting ability to experience reward may be warranted.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients.

Knowledge on mechanisms involved in early prediction of response to antidepressant medication may help optimize clinical decision making. Recent studies regarding response to pharmacotherapy implicate resilience-like mechanisms and involvement of positive, rather than negative emotions. The aim of the current study is to examine the contribution of early change in positive affect to the prediction of response to pharmacotherapy. Positive and negative emotions were measured at baseline and during the first week of pharmacotherapy, using experience sampling techniques. The association between early change in positive and negative emotions and severity of depressive symptoms at week six was examined in a sample of 49 depressed patients. The added benefits of measuring early change in positive emotions compared to early Hamilton Depression Rating Scale (HDRS) change alone were evaluated through model comparisons. Early improvement in positive affect during the first week of treatment predicted the continuous HDRS score (β=-0.64, p<0.001), response (50% reduction; OR=4.32, p<0.01), and remission (HDRS≤7; OR=9.29, p<0.001) at week six with moderate to large effect sizes. Effects of early change in negative emotions were only half as large and disappeared when evaluated simultaneously with early change in positive emotions. When early change in positive emotions was added to the models including early HDRS change only, all three models improved significantly. In conclusion, early change in positive rather than negative emotions best predicted response to treatment, supporting the notion that antidepressants activate resilience-like mechanisms. Moreover, monitoring of positive emotions in early stages of treatment may improve clinical decision making.

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