Tibial muscular dystrophy (TMD) is an autosomal dominant late-onset distal myopathy linked to chromosome 2q31. The linked region includes the giant TTN gene, which encodes the central sarcomeric protein, titin. We have previously shown a secondary calpain-3 defect to be associated with TMD, which further underscored that titin is the candidate. We now report the first mutations in TTN to cause a human skeletal-muscle disease, TMD. In Mex6, the last exon of TTN, a unique 11-bp deletion/insertion mutation, changing four amino acid residues, completely cosegregated with all tested 81 Finnish patients with TMD in 12 unrelated families. The mutation was not found in 216 Finnish control samples. In a French family with TMD, a Leu-->Pro mutation at position 293,357 in Mex6 was discovered. Mex6 is adjacent to the known calpain-3 binding site Mex5 of M-line titin. Immunohistochemical analysis using two exon-specific antibodies directed to the M-line region of titin demonstrated the specific loss of carboxy-terminal titin epitopes in the TMD muscle samples that we studied, thus implicating a functional defect of the M-line titin in the genesis of the TMD disease phenotype.

Symptoms of generalized anxiety disorder (GAD) are common among adolescents and can lead to severe psychosocial impairment, yet there is a lack of a good quality scale to measure symptoms of generalized anxiety in young people. The 7-item Generalized Anxiety Disorder Scale (GAD-7) is a self-report scale used to measure GAD symptoms and has been validated in adult populations, but the measure's psychometric properties regarding adolescents are unknown. The aim of this study was to investigate the reliability, factorial validity, and construct validity of the GAD-7 in adolescents in a nationally representative sample from a general population. Our study was based on Finnish survey data on 111,171 adolescents aged 14-18 years. Our results show that the GAD-7 demonstrates good psychometric properties in adolescents. The internal consistency of the GAD-7 was good (Cronbach's α = 0.91) and the instrument's unidimensional factor structure was supported. The associations of GAD-7 sum scores with self-report measures of depression and social anxiety supported construct validity. The psychometric properties of the GAD-7 in this sample of adolescents were similar to those reported among adults. However, studies in which diagnostic interviews are performed are needed to demonstrate the diagnostic efficacy of the measure in this age group.

The RECQL4 helicase gene is a member of the RECQL gene family, mutated in some Rothmund-Thomson syndrome (RTS) patients. Other members of this gene family are BLM mutated in Bloom syndrome, WRN mutated in Werner syndrome and RECQL and RECQL5. All polypeptides encoded by RECQL genes share a central region of seven helicase domains. The function of RECQL4 remains unknown, but based on the domain homology it possesses ATP-dependent DNA helicase activity such as BLM and WRN. Rothmund-Thomson, Bloom and Werner syndromes have overlapping clinical features, of which high predisposition to malignancies is the most remarkable feature. Here we report a fourth syndrome resulting in mutations in the RECQL genes. RAPADILINO syndrome is an autosomal recessive disorder characterized by short stature, radial ray defects and other malformations, as well as infantile diarrhoea, but not by a significant cancer risk. Four mutations in the RECQL4 gene were found in the Finnish patients, the most common mutation representing exon 7 in-frame deletion saving the helicase domain and showing dominant effect over other three nonsense mutations. The tissue expression of Recql4 in mouse well agrees with the tissue symptoms of RAPADILINO. The skeletal malformations in RAPADILINO and RTS patients as well as the high osteosarcoma risk in RTS propose a special role for RECQL4 in bone development.