Analysis of spectrum and frequencies of mutations in McArdle disease. Identification of 13 novel mutations.

BACKGROUND: McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and many rare mutations in the myophosphorylase gene. OBJECTIVES: To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease, to discuss diagnostic implications, and to analyse genotype-phenotype relationship. METHODS: Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35), UK (n = 13), and several other countries (n = 8) was performed using direct sequencing. RESULTS: Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected 26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T, IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed by R94W and G686R representing a frequency of 4% each. CONCLUSIONS: The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no genotype-phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular testing can avoid muscle biopsy.

Molecular and biochemical investigations in fumarase deficiency.

Fumarase (FH) deficiency is a rare autosomal recessive disease of the Krebs cycle causing severe neurological impairment in early childhood, characterized by encephalopathy with seizures and muscular hypotonia. Only a handful of patients with various recessive mutations in the FH gene have been described so far. Interestingly, autosomal dominant mutations in the same gene are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). We investigated a boy with developmental and growth delay, microcephaly, and muscular hypotonia recognized at the age of 3 months. No leiomyomatosis or renal cancer is known in the parents. Investigation of the patient's urine revealed massive fumarate excretion. FH activity was severely reduced in muscle and fibroblasts. Respirometric investigation of fibroblasts showed only modest changes indicating that fumarate mediated inhibition of enzymatic pathways other than oxidative phosphorylation might be more relevant in pathophysiology of FH deficiency. Molecular analysis revealed a known 435insK mutation on the paternal allele and a novel H275L mutation due to an A to T transversion of nucleotide 824 on the maternal allele. This mutation affects the same codon as a C to T transition of nucleotide 823, resulting in a H275Y mutation that was found in two families with HLRCC.

Traffic related air pollution in city districts near motorways.

Traffic related air pollution near major motorways was measured and results are presented.

Air pollution from truck traffic and lung function in children living near motorways.

The contribution of motorized traffic to air pollution is widely recognized, but relatively few studies have looked at the respiratory health status of subjects living near busy roads. We studied children in six areas located near major motorways in the Netherlands. We measured lung function in the children, and we assessed their exposure to traffic-related air pollution using separate traffic counts for automobiles and trucks. We also measured air pollution in the children's schools. Lung function was associated with truck traffic density but had a lesser association with automobile traffic density. The association was stronger in children living closest (< 300 m) to the motorways. Lung function was also associated with the concentration of black smoke, measured inside the schools, as a proxy for diesel exhaust particles. The associations were stronger in girls than in boys. The results indicate that exposure to traffic-related air pollution, in particular diesel exhaust particles, may lead to reduced lung function in children living near major motorways.

Motor vehicle exhaust and chronic respiratory symptoms in children living near freeways.

To examine whether motor vehicle exhaust from freeways has an effect on respiratory health of children, a cross-sectional study was conducted. Children attending schools situated less than 1000 m from major freeways in the Province of South Holland were asked to participate. The selected freeways carry between 80,000 and 150,000 vehicles per day. Separate counts for truck traffic indicated a range from 8000 to 17,500 trucks per day. At a total of 13 schools, 1498 children were asked to participate. From these children, 1068 usable questionnaires were obtained. Chronic respiratory symptoms reported in the questionnaire were analyzed with logistic regression. Distance from the freeway and (truck) traffic intensity were used as exposure variables. Cough, wheeze, runny nose, and doctor-diagnosed asthma were significantly more often reported for children living within 100 m from the freeway. Truck traffic intensity and the concentration of black smoke measured in schools were found to be significantly associated with chronic respiratory symptoms. These relationships were more pronounced in girls than in boys.

[Relationship between air pollution due to traffic, decreased lung function and airway symptoms in children]. / Samenhang tussen luchtverontreiniging door verkeer, vermindering van longfunctie en luchtwegsymptomen bij kinderen.

OBJECTIVE: To assess whether air pollution by traffic was related to lung function and chronic respiratory symptoms in children living. DESIGN: Descriptive. SETTING: The province of South Holland, the Netherlands. METHODS: In the period May through July of 1995 pulmonary function tests and questionnaires were obtained from 1,092 and 1,068 children respectively in six city districts near busy motorways in the province of South Holland. In the same period, indoor measurements were performed at 12 schools of NO2, black smoke and PM10 dust density. Lung function data were analysed by multiple linear regression and respiratory symptoms were analysed by multiple logistic regression. As independent variables, distance between motorway and home, passenger car traffic density and lorry traffic density on the motorway, and black smoke and NO2 concentrations in schools were taken. RESULTS: Significant differences in lung function and respiratory symptoms were found between children living in different city districts. Lung function as well as symptoms were associated with lorry traffic density on the motorway. The validity of these findings was supported by associations between black smoke concentrations (representative for diesel soot) and lung function as well as respiratory symptoms. In contrast, there was no association between passenger car traffic counts or NO2 and lung function or respiratory symptoms. CONCLUSION: The results suggest that air pollution by lorry traffic can lead to reduced lung function and to an increased prevalence of chronic respiratory symptoms in children living near major motorways.