Expanding the phenotypic spectrum of Chromosome 16p13.11 microduplication: A multicentric analysis of 206 patients.

INTRODUCTION: Recurrent chromosome 16p13.11 microduplication has been characterised in the literature as a cause of developmental delay, learning difficulties and behavioural abnormalities. It is a neurosusceptibility locus and has incomplete penetrance and variable expression. Other clinical features, such as cardiac abnormalities have also been reported. The duplicated region contains the MYH11 gene, which encodes the protein myosin-11 and is a component of the myosin heavy chain in smooth muscle. Recent literature has suggested 16p13.11 microduplication as one of the possible risk factors for thoracic aortic aneurysms and dissection (TAAD). Therefore, we studied the detailed phenotype of cases of chromosome 16p13.11 microduplication from seven centres in the United Kingdom (UK) to expand the phenotype, focusing on the cardiac abnormalities. METHODS: All individuals with a chromosome 16p13.11 microduplication seen in Clinical Genetics prior to June 2017 in 6 centres (prior to 2018 in the seventh centre) were identified through the regional genetics laboratory databases. A Microsoft Excel® proforma was created and clinical data was collected retrospectively from clinical genetics databases from the seven genetics services in the UK. The data was collated and analysed collectively. RESULTS: The majority of the individuals presented with (72%) developmental delay and (62%) behavioural abnormalities, in keeping with the published literature. 27% had some dysmorphic features, 14% had visual impairment and 8% had congenital cardiac abnormalities. Echocardiograms were performed in 50% of patients, and only 3.8% patients had aortic dilatation and no one had aortic dissection. 9.7% of patients were found to have a second genetic/chromosomal diagnosis, especially where there were additional phenotypic features. CONCLUSION: 16p13.11 microduplication is a neurosusceptibility locus and is associated with variable expression. It may be helpful to refer children with 16p13.11 microduplication for a cardiac review for congenital cardiac abnormalities and also for ophthalmological assessment. Further prospective studies with cardiac assessments are recommended in this cohort of patients to determine whether ongoing aortic surveillance is indicated. Guidelines about the frequency of surveillance are indicated, especially in individuals with normal cardiac findings. We also highlight the importance of considering a second diagnosis if the phenotype is inconsistent with that reported.

Short-term test-retest reliability of the ImPACT in healthy young athletes.

The present study examined the short-term test-retest reliability of the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) variables with healthy 11- to 14-year-old athletes. 53 young athletes (Mage = 12.4 years, 9 female) were administered the ImPACT on two separate occasions two weeks apart. Participants were instructed to complete the Post-Concussion Symptom Scale (PCSS) and the baseline computerized neurocognitive test during both the baseline and retest phases. Intraclass correlation (ICC), standard error of measurement (SEM), and reliable change index (RCI) were used as reliability metrics. PCSS Total Symptoms and Visual-Motor Speed were the only scores to reach clinical reliability standards (i.e., R > 0.7). None of the scores exceeded RCI cut-offs. Results indicate that the composite scores of the ImPACT are differentially reliable in a preadolescent sample across a two-week retest period, with only motor processing speed and self-reported symptoms exceeding clinical reliability standards. The findings support the view that neurocognitive testing should not be the sole determining factor in concussion assessment. This study highlights the importance of continuing research with younger athletes to assess the reliability of neurocognitive measures in concussion management programs. Future research should focus on a larger, heterogeneous sample, including children with learning disabilities and ADHD.

Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK).

Duchenne muscular dystrophy (DMD), a progressive X-linked neuromuscular disorder, has an estimated worldwide incidence of 1:3500 male births. Currently, there are no curative treatments and the mean age of diagnosis is 5 years. In addition, subsequent pregnancies frequently occur before a diagnosis is made in an index case. An 'opt in' screening programme was introduced in Wales in 1990 with the aim to: reduce the diagnostic delay, permit reproductive choice and allow planning of the care of the affected boy. Newborn bloodspots were collected routinely as part of the Wales newborn screening programme. Specific consent was obtained for this test separately from the other tests. During the 21-year period, 369,780 bloodspot cards were received from male infants, of these 343,170 (92.8%) were screened using a bloodspot creatine kinase (CK) assay following parental consent. A total of 145 cases had a raised CK activity (≥250 U/l) and at follow-up, at 6-8 weeks of age, 79 cases had a normal serum CK (false-positive rate 0.023%) and 66 cases had an elevated serum CK. DMD was confirmed in 56 cases by genotyping/muscle biopsy studies, Becker muscular dystrophy in 5 cases and other rarer forms of muscular dystrophy in 5 cases. This long-term study has so far identified 13 false-negative cases. The incidence of DMD in Wales of 1:5136 during this period is lower than that of 1:4046 before commencement of screening in Wales. Screening has reduced the diagnostic delay enabling reproductive choice for parents of affected boys and earlier administration of current therapies.

The motor phenotype of Parkinson's disease in relation to age at onset.

BACKGROUND: Parkinson's disease (PD) is heterogeneous and age at onset may define variation in clinical phenotype. Most previous studies have used various age cut-offs and have been based on clinical case series. METHODS: We have studied the association between clinical features and age of onset in 358 community-based and regional patients with PD. RESULTS: Tremor at presentation is twice as common in those with onset over 64 years as compared to those with onset under 45 (early onset PD - EOPD) and becomes more common with increasing age at onset (p values for trend ≤ 0.004). Dystonia affects 60% of those with EOPD, shows a curvilinear relationship with age at onset (cubic versus linear p=0.01) with highest risk in patients whose disease began before 48 years. In this study age at onset was a strong predictor of the development of dyskinesias, with younger age associated with a higher risk of dyskinesias. Following multivariable analysis, allowing for possibly confounding factors (disease duration, L-DOPA dosage, L-DOPA treatment duration) younger age at onset, (less than 55 years) predicted the development of L-DOPA induced dyskinesia (odds ratio <45 years 2.1, 95% CI 1.0, 4.8; odds ratio < 55 years 3.8, 95% CI 1.8, 8.0). Only 2/70 (2.9%) EOPD patients carried pathogenic parkin or PINK1 mutations and the clinical differences between early and late onset disease were not explained by the presence of mutations in these genes. DISCUSSION: This study highlights the clinical differences between early and late onset PD, which have important implications for diagnosis and management.