Background: Tibial muscular dystrophy (TMD), a late-onset dominant distal myopathy, is caused by yet unknown mutations on chromosome 2q, whereas MD with myositis (MDM) is a muscular dystrophy of the mouse, also progressing with age and linked to mouse chromosome 2. For both disorders, linkage studies have implicated titin as a potential candidate gene. Methods: The authors analyzed major candidate regions in the titin gene by sequencing and Southern blot hybridization, and performed titin immunohistochemistry on TMD patient material to identify the underlying mutation. Western blot studies were performed on the known titin ligands in muscle samples of both disorders and controls, and analysis of apoptosis was also performed. Results: The authors identified almost complete loss of calpain3, a ligand of titin, in the patient with limb-girdle MD (LGMD) with a homozygous state of TMD haplotype when primary calpain3 gene defect was excluded. Apoptotic myonuclei with altered distribution of transcription factor NF-kB and its inhibitor IkBα were encountered in muscle samples of patients with either heterozygous or homozygous TMD haplotype. Similar findings were confirmed in the MDM mouse. Conclusions: These results imply that titin mutations may be responsible for TMD, and that the pathophysiologic pathway following calpain3 deficiency may overlap with LGMD2A. The loss of calpain3 could be a downstream effect of the deficient TMD gene product. The significance of the secondary calpain3 defect for the pathogenesis of TMD was emphasized by similar calpain3 deficiency in the MDM mouse, which is suggested to be a mouse model for TMD. Homozygous mutation at the 2q locus may thus be capable of producing yet another LGMD.

Distal myopathies have been associated with mutations in titin, dysferlin, GNE, desmin and myosin. Of these, only titin mutations were previously known to cause dominant late-onset distal myopathy. Recent findings, however, have indicated that patients affected with myofibrillar myopathy have a more distal than proximal muscle phenotype and a proportion of these may have mutations in myotilin, ZASP or filamin C, besides previously known desmin and αB-crystallin. Here we report that the disorder in one of the well-characterized autosomal dominant distal myopathy families, the Markesbery et al. family, first reported in 1974, is caused by ZASP mutation A165V. Previous linkage to the titin locus 2q31 proved incorrect. ZASP expression by immunoblotting shows normal presence of the main 32 and 78 kDa bands and immunohistochemistry in patients reveals normal Z-disc localization except for moderate accumulations together with myotilin, desmin αB-crystallin and α-actinin. Muscle imaging reveals involvement in both the posterior and anterior compartments of the lower leg and considerable affection of proximal leg muscles at later stages. Haplotype studies in this family and in five other unrelated families with European ancestry carrying the identical A165V mutation share common markers at the locus suggesting the existence of a founder mutation.

The Symptom Checklist-90 (SCL-90) is a questionnaire that is widely used to measure subjective psychopathology. In this study we investigated the psychometric properties of the SCL-90 among adolescent inpatients and community youth matched on age and gender. The final SCL-90 respondents comprised three subsets: 201 inpatients at admission, of whom 152 also completed the instrument at discharge, and 197 controls. The mean age at baseline was 15.0 years (SD 1.2), and 73 % were female. Differential SCL-90 item functioning between the three subsets was assessed with an iterative algorithm, and the presence of multidimensionality was assessed with a number of methods. Confirmatory factor analyses for ordinal items compared three latent factor models: one dimension, nine correlated dimensions, and a one-plus-nine bifactor model. Sensitivity to change was assessed with the bifactor model’s general factor scores at admission and discharge. The accuracy of this factor in detecting the need for treatment used, as a gold standard, psychiatric diagnoses based on clinical records and the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime (K-SADS-PL) interview. Item measurement properties were largely invariant across subsets under the unidimensional model, with standardized factor scores at admission being 0.04 higher than at discharge and 0.06 higher than those of controls. Determination of the empirical number of factors was inconclusive, reflecting a strong main factor and some multidimensionality. The unidimensional factor model had very good fit, but the bifactor model offered an overall improvement, though subfactors accounted for little item variance. The SCL-90s ability to identify those with and without a psychiatric disorder was good (AUC = 83 %, Glass’s Δ = 1.4, Cohen’s d = 1.1, diagnostic odds ratio 12.5). Scores were also fairly sensitive to change between admission and discharge (AUC 72 %, Cohen’s d = 0.8). The SCL-90 proved mostly unidimensional and showed sufficient item measurement invariance, and is thus a useful tool for screening overall psychopathology in adolescents. It is also applicable as an outcome measure for adolescent psychiatric patients. SCL-90 revealed significant gender differences in subjective psychopathology among both inpatients and community youth.