The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified. METHODS AND RESULTS: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls. CONCLUSION: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.

Is the pediatric quality of life inventory valid for use in preschool children with refractive errors?

PURPOSE: To determine the psychometric validity of the pediatric quality of life inventory (PedsQL 4.0) in assessing the impact of refractive errors on health-related quality of life (HRQoL) in preschool children in Singapore. METHODS: Parents of toddlers (aged 25 to 48 months) and young children (49 to 72 months) completed the PedsQL 4.0, an HRQoL scale as part of population-based trial in Singapore. The outcome measures were the overall score, and the "physical"; "emotional"; "social"; and "school" functioning subscales. Rasch analysis was used to validate the PedsQL 4.0. RESULTS: Parents of 939 (48.9%) toddlers and 982 (51.1%) young children completed the PedsQL 4.0 survey. The overall mean (±standard deviation) spherical equivalence for the right eye was 0.47 ± 1.13 diopter (D) for toddlers and 0.74 ± 1.22 D for young children. One hundred forty-nine (15.9%) toddlers and 90 (9.2%) young children were considered myopic (≥-0.50 D). Most participants (n = 1286, 89.6%) had presenting visual acuity 6/9 or better. Rasch analysis showed evidence of disordered category thresholds and poor person-item targeting for both groups. The separation reliability was 0.00 for toddlers and 0.03 for young children, indicating there was no variance in both samples. The PedsQL 4.0 overall and subscale scores displayed substantial multidimensionality as the variance values explained by the measures was <25% in both groups. A minimum value of 60% is usually considering acceptable. CONCLUSIONS: The PedsQL 4.0 in its current state is not a valid psychometric scale to effectively evaluate the impact of refractive errors on HRQoL in preschool children in Singapore.