Feedback-Based Learning of Timing in Attention-Deficit/Hyperactivity Disorder and Neurofibromatosis Type 1.

OBJECTIVE: Patients with Neurofibromatosis Type 1 (NF1) frequently display symptoms resembling those of Attention Deficit/Hyperactivity Disorder (ADHD). Importantly, these disorders are characterised by distinct changes in the dopaminergic system, which plays an important role in timing performance and feedback-based adjustments in timing performance. In a transdiagnostic approach, we examine how far NF1 and ADHD show distinct or comparable profiles of timing performance and feedback-based adjustments in timing. METHOD: We examined time estimation and learning processes in healthy control children (HC), children with ADHD with predominantly inattentive symptoms and those with NF1 using a feedback-based time estimation paradigm. RESULTS: Healthy controls consistently responded closer to the correct time window than both patient groups, were less variable in their reaction times and displayed intact learning-based adjustments across time. The patient groups did not differ from each other regarding the number of in-time responses. In ADHD patients, the performance was rather unstable across time. No performance changes could be observed in patients with NF1 across the entire task. CONCLUSIONS: Children with ADHD and NF1 differ in feedback learning-based adjustments of time estimation processes. ADHD is characterised by behavioural fluctuations during the learning process. These are likely to be associated with inefficiencies in the dopaminergic system. NF1 is characterised by impairments of feedback learning which could be due to various neurotransmitter alterations occurring in addition to deficits in dopamine synthesis. Results show that despite the strong overlap in clinical phenotype and neuropsychological deficits between NF1 and ADHD, the underlying cognitive mechanisms are different.

Correction: Diagnostic value of partial exome sequencing in developmental disorders.

[This corrects the article DOI: 10.1371/journal.pone.0201041.].

Diagnostic value of partial exome sequencing in developmental disorders.

Although intellectual disability is one of the major indications for genetic counselling, there are no homogenous diagnostic algorithms for molecular testing. While whole exome sequencing is increasingly applied, we questioned whether analyzing a partial exome, enriched for genes associated with Mendelian disorders, might be a valid alternative approach that yields similar detection rates but requires less sequencing capacities. Within this context 106 patients with different intellectual disability forms were analyzed for mutations in 4.813 genes after pre-exclusion of copy number variations by array-CGH. Subsequent variant interpretation was performed in accordance with the ACMG guidelines. By this, a molecular diagnosis was established in 34% of cases and candidate mutations were identified in additional 24% of patients. Detection rates of causative mutations were above 30%, regardless of further symptoms, except for patients with seizures (23%). We did not detect an advantage from partial exome sequencing for patients with severe intellectual disability (36%) as compared to those with mild intellectual disability (44%). Specific clinical diagnoses pre-existed for 20 patients. Of these, 5 could be confirmed and an additional 6 cases could be solved, but showed mutations in other genes than initially suspected. In conclusion partial exome sequencing solved >30% of intellectual disability cases, which is similar to published rates obtained by whole exome sequencing. The approach therefore proved to be a valid alternative to whole exome sequencing for molecular diagnostics in this cohort. The method proved equally suitable for both syndromic and non-syndromic intellectual disability forms of all severity grades.

Executive Function Deficits in Seriously Ill Children-Emerging Challenges and Possibilities for Clinical Care.

The past years have seen an incredible increase in the quality and success rates of treatments in pediatric medicine. One of the resulting major challenges refers to the management of primary or secondary residual executive function deficits in affected children. These deficits lead to problems in the ability to acquire, understand, and apply abstract and complex knowledge and to plan, direct, and control actions. Executive functions deficits are important to consider because they are highly predictive of functioning in social and academic aspects of daily life. We argue that current clinical practice does not sufficiently account for the complex cognitive processes in this population. This is because widely applied pharmacological interventions only rarely account for the complexity of the underlying neuronal mechanisms and do not fit well into possibly powerful "individualized medicine" approaches. Novel treatment approaches targeting deficits in executive functions in seriously ill children could focus on neuronal oscillations, as these have some specific relations to different aspects of executive function. Importantly, such treatment approaches can be individually tailored to the individuals' deficits and can be transferred into home-treatment or e-health solutions. These approaches are easy-to-use, can be easily integrated into daily life, and are becoming increasingly cost-effective.

6q22.33 microdeletion in a family with intellectual disability, variable major anomalies, and behavioral abnormalities.

Interstitial deletions on the long arm of chromosome six have been described for several regions including 6q16, 6q22.1, and 6q21q22.1, and with variable phenotypes such as intellectual disability/developmental delay, growth retardation, major and minor facial anomalies. However, an isolated microdeletion of the sub-band 6q22.33 has not been reported so far and thus, no information about the specific phenotype associated with such a copy number variant is available. Here, we define the clinical picture of an isolated 6q22.33 microdeletion based on the phenotype of six members of one family with loss of approximately 1 Mb in this region. Main clinical features include mild intellectual disability and behavioral abnormalities as well as microcephaly, heart defect, and cleft lip and palate.