Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal α-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorder

Reliability and validity of the Adolescent Stress Questionnaire in a sample of European adolescents--the HELENA study

BACKGROUND: Since stress is hypothesized to play a role in the etiology of obesity during adolescence, research on associations between adolescent stress and obesity-related parameters and behaviours is essential. Due to lack of a well-established recent stress checklist for use in European adolescents, the study investigated the reliability and validity of the Adolescent Stress Questionnaire (ASQ) for assessing perceived stress in European adolescents. METHODS: The ASQ was translated into the languages of the participating cities (Ghent, Stockholm, Vienna, Zaragoza, Pecs and Athens) and was implemented within the HELENA cross-sectional study. A total of 1140 European adolescents provided a valid ASQ, comprising 10 component scales, used for internal reliability (Cronbach α) and construct validity (confirmatory factor analysis or CFA). Contributions of socio-demographic (gender, age, pubertal stage, socio-economic status) characteristics to the ASQ score variances were investigated. Two-hundred adolescents also provided valid saliva samples for cortisol analysis to compare with the ASQ scores (criterion validity). Test-retest reliability was investigated using two ASQ assessments from 37 adolescents. RESULTS: Cronbach α-values of the ASQ scales (0.57 to 0.88) demonstrated a moderate internal reliability of the ASQ, and intraclass correlation coefficients (0.45 to 0.84) established an insufficient test-retest reliability of the ASQ. The adolescents' gender (girls had higher stress scores than boys) and pubertal stage (those in a post-pubertal development had higher stress scores than others) significantly contributed to the variance in ASQ scores, while their age and socio-economic status did not. CFA results showed that the original scale construct fitted moderately with the data in our European adolescent population. Only in boys, four out of 10 ASQ scale scores were a significant positive predictor for baseline wake-up salivary cortisol, suggesting a rather poor criterion validity of the ASQ, especially in girls. CONCLUSIONS: In our European adolescent sample, the ASQ had an acceptable internal reliability and construct validity and the adolescents' gender and pubertal stage systematically contributed to the ASQ variance, but its test-retest reliability and criterion validity were rather poor. Overall, the utility of the ASQ for assessing perceived stress in adolescents across Europe is uncertain and some aspects require further examination.The HELENA Study takes place with the financial support of the European Community Sixth RTD Framework Programme (Contract FOOD-CT-2005-007034)

Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy

Charcot-Marie-Tooth type 2B (CMT2B) is clinically characterized by marked distal muscle weakness and wasting and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. CMT2B maps to chromosome 3q13-q22. We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. The alignment of RAB7 orthologs shows that both missense mutations target highly conserved amino acid residues. RAB7 is ubiquitously expressed, and we found expression in sensory and motor neurons