Twenty years of ambient observations of nitrogen oxides and specified hydrocarbons in air masses dominated by traffic emissions in Germany.

The analysis of the individual composition of hydrocarbon (VOC) mixtures enables us to transform observed VOC-concentrations into their respective total VOC-reactivity versus OH radicals (RVOC = Σ(kOH+VOCi × [VOCi])). This is particularly useful because local ozone production essentially depends on this single parameter rather than on the details of the underlying hydrocarbon mixture (Klemp et al., Schriften des Forschungszentrums Jülich, Energy & Environment, 2012, 21). The VOC composition also enables us to pin down the major emission source of hydrocarbons in urban areas to be petrol cars with temporarily reduced catalyst efficiency (the so-called cold-start situation) whereas the source of nitrogen oxides (NOx = NO + NO2) is expected to be nowadays dominated by diesel cars. The observations in the vicinity of main roads in German cities show a decrease in the ratio of OH reactivities of VOC and NO2 (RVOC/RNO2) by a factor of 7.5 over the time period 1994-2014. This is larger than the expected decrease of a factor of 2.9 taking estimated trends of VOC and NOx traffic emissions in Germany (Umweltbundesamt Deutschland, National Trend Tables for the German Atmospheric Emission Reporting, 2015), during this time period. The observed reduction in the RVOC/RNO2 ratio leads to a drastic decrease in local ozone production driven by the reduction in hydrocarbons. The analysis reveals that the overall reduction of ozone production benefits from the low decrease of NOx emissions from road traffic which is a consequence of the eventual absence of catalytic converters for nitrogen oxide removal in diesel cars up to now.

Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.

Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.

A unique case of female pseudohermaphroditism with 21-hydroxylase deficiency and small supernumerary marker chromosome 7.

Small supernumerary marker chromosomes (sSMCs) are present in ~2.6x106 individuals worldwide. Concerning their clinical consequences as well as their chromosomal origin and shape, sSMCs are a heterogeneous group of derivative chromosomes; 70% of sSMC carriers are clinically normal. In the present study, we report on a female with mosaicism (45%) of a de novo sSMC derived from chromosome 7, in which the observed clinical signs do not correspond to comparable cases in the literature. She is clinically normal apart from problems in gender determination, a uterus without ovaries and an external penis, pointing overall towards an adrenogenital syndrome (AGS). 21-Hydroxylase deficiency (21-OHD) is the most common cause of AGS. A corresponding analysis for underlying mutations in the CYP21A2 gene revealed a homozygous mutation c.518T>A (p.Ile173Asn) inherited from both non-related parents. Overall, in this study, we report a unique case of female pseudohermaphroditism, classified as a simple virilization form of 21-OHD having an additional minute-shaped chromosome 7 [min(7)(:p11.1->q11.23:)]. Notably, AGS was due to a mutation in the CYP21A2 gene located on chromosome 6. This is a further example that detection of an sSMC does not always resolve the clinical case.

Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.

OBJECTIVE: To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation. RESEARCH DESIGN AND METHODS: The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS: WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P<0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P=0.049). Mean duration of remission in WSD was 2.3±2.4 vs. 1.6±2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P<0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c>7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028). CONCLUSIONS: Endoplasmic reticulum stress-mediated decline of ß-cells in WSD occurs earlier in life than autoimmune-mediated ß-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.