Henna Haravuori

Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin

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.

Assignment of the Tibial Muscular Dystrophy Locus to Chromosome 2q31

Tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late adult onset. The phenotype is relatively mild: muscle weakness manifests in the patients early 40s and remains confined to the tibial anterior muscles. Histopathological changes in muscle are compatible with muscular dystrophy, with the exception that rimmed vacuoles are a rather common finding. We performed a genomewide scan, with 279 highly polymorphic Cooperative Human Linkage Center microsatellite markers, on 11 affected individuals of one Finnish TMD family. The only evidence for linkage emerged from markers in a 43-cM region on chromosome 2q. In further linkage analyses, which included three other Finnish TMD families and which used a denser set of markers, a maximum two-point LOD score of 10.14 (recombination fraction of .05) was obtained with marker D2S364. Multipoint likelihood calculations, combined with the haplotype and recombination analyses, restricted the TMD locus to an approximately 1-cM critical chromosomal region without any evidence of heterogeneity. Since all the affecteds share one core haplotype, the dominance of one ancestor mutation is obvious in the Finnish TMD families. The disease locus that was found represents a novel muscular dystrophy locus, providing evidence for the involvement of one additional gene in the distal myopathy group of muscle disorders.

Tibial muscular dystrophy – from clinical description to linkage on chromosome 2q31

A genome scan with highly polymorphic markers has established linkage for tibial muscular dystrophy (TMD), a recently described late onset distal myopathy, to a novel myopathy locus on chromosome 2q31. The mode of inheritance in TMD is autosomal dominant and the typical symptom of ankle dorsiflexion weakness appears in the fourth to seventh decade. Weakness of lower leg muscles is slowly progressive eventually causing a moderate foot drop. Overall disability usually remains mild even in elderly patients and walking ability is preserved throughout the patients lifetime. The main target of the disease, the tibial anterior muscle, shows progressive dystrophic changes with rimmed vacuoles at the early stages and complete replacement pathology at later stages of the disease. The linkage studies in four different TMD families revealed a common core haplotype with a set of markers on the chromosome 2q31 locus. This indicates one major ancient founder mutation for TMD in Finland. There is one superior candidate gene on the 2q31 locus, the gene encoding a giant protein titin, expressed in heart and skeletal muscle.

Effects of media exposure on adolescents traumatized in a school shooting

This study analyzes the impact of the media on adolescents traumatized in a school shooting. Participants were trauma-exposed students (n = 231) and comparison students (n = 526), aged 13-19 years. A questionnaire that included the Impact of Event Scale and a 36-item General Health Questionnaire was administered 4 months after the shooting. Being interviewed was associated with higher scores on the Impact of Event Scale (p = .005), but posttraumatic symptoms did not differ between those who refused to be interviewed and those not approached by reporters. Following a higher number of media outlets did not affect symptoms.

The first European family with tibial muscular dystrophy outside the Finnish population

We report the first European tibial muscular dystrophy (TMD) family outside the Finnish population. Clinical examination showed late onset distal leg myopathy similar to the description of TMD. A molecular genetic study was made owing to the very recent TMD linkage findings on chromosome 2q31. All five clinically affected patients segregated a specific haplotype for the locus, whereas two unaffected patients had different haplotype. The results of this family without Finnish ancestors show that TMD exists outside the Finnish population.

Adverse childhood experiences as risk factors for serious mental disorders and inpatient hospitalization among adolescents

Psychiatric hospitalization is an intense and powerful intervention for patients and is highly expensive for society. espite the individual and social costs of hospitalization, it is a common practice in the Finnish adolescent mental health are system (Fredriksson & Pelanteri, 2012). Hospitalized adolescents typically suffer from severe psychiatric disorders, ave faced several traumatic life events and experience psychosocial difficulties with their families and peer groups Gyllenberg et al., 2010; Sourander, Helenius, & Piha, 1995). Thus, it is important to identify the most prevalent and owerful childhood psychosocial risk factors for severe mental health disorders among high-risk adolescents to diminsh personal agony, prevent the aggravation of psychiatric problems and reduce hospitalization and high health care osts. Adolescence is a unique period of cognitive, emotional, social, and physical development. Adolescents are particularly ulnerable to the negative effects of exposure to adverse childhood experiences (ACEs, De Bellis, 2005), and many psychitrically hospitalized adolescents have a history of several ACEs. The most frequently examined ACEs are emotional, physical nd sexual abuse, neglect, being bullied and household dysfunction, including parental mental illness, alcohol or drug abuse, ivorce, death and criminality. In a recent Finnish study of 508 adolescent psychiatric inpatients, 34.6% of patients (29.3% ales and 38.3% females) reported being bullying victims (Mustanoja et al., 2011). The same research group reported that pproximately 25% of hospitalized adolescents had been exposed to physical abuse, approximately 23% of girls and 3% of oys had been exposed to sexual abuse and 31% of girls and 28% of boys had witnessed intimate partner violence. For

The role of attachment in recovery after a school-shooting trauma

Background Survivors of life-endangering trauma use varying resources that help them to recover. Attachment system activates in the times of distress, and is expected to associate with stress responses, arousal regulation, and mental health. Objective We examined the associations of attachment style with posttraumatic stress disorders (PTSD) symptoms and dissociative symptoms, and posttraumatic growth (PTG) among students exposed to a school shooting in Finland in a three-wave follow-up setting. Method Participants were students (M age=24.9 years; 95% female) who were followed 4 (T1, N=236), 16 (T2, N=180), and 28 months (T3, N=137) after the shooting. The assessments included the Attachment Style Questionnaire, the Impact of Event Scale, part of the Adolescent Dissociative Experiences Scale and the Posttraumatic Growth Inventory. Results Securely attached survivors had lower levels of posttraumatic stress and dissociative symptoms than preoccupied at T1 and T2 as hypothesized. At T3 survivors with avoidant attachment style had higher levels of intrusive and hyperarousal symptoms than those with secure style. Concerning PTG, survivors with avoidant attachment style scored lower in PTG at T3 than survivors with both secure and preoccupied style. Conclusion Secure attachment style was beneficial in trauma recovery. A challenge to the health care systems is to acknowledge that survivors with preoccupied and avoidant attachment styles react uniquely to trauma, and thus need help in different doses, modalities, and timings.

Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)

We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.

Framework of the outreach after a school shooting and the students perceptions of the provided support

Background A large number of bereaved family members, surviving students, and their relatives as well as school staff and the wider community were in need of psychosocial support as a result of a school shooting in Kauhajoki, Finland, 2008. A multilevel outreach project provided psychosocial care to the trauma-affected families, students, schools staff, and wider community for 2 years and 4 months. Objective This article is twofold. First, it presents the theoretical rationale behind the psychosocial support and describes the multimodal elements of the services. Second, it analyzes the trauma-exposed students’ help-seeking behavior and perceptions of the usefulness of the support they were offered in different phases of recovery. Method Information of students’ help-seeking and perceptions of support is based on a follow-up data from 4 months (T1, N=236), 16 months (T2, N=180), and 28 months (T3, N=137) after the shootings. Mean age of students was 24.9 (SD=10.2; 95% women). Their perceptions of the offered psychosocial support were collected with structured and open questions constructed for the study. Results The results confirmed the importance of enhancing the natural networks after a major trauma and offering additional professional support for those in greatest need. The students’ perceptions of the provided care confirmed that the model of the acute and long-term outreach can be used after major tragedies in diverse situations and in other countries as well.

Mediators between adverse childhood experiences and suicidality

We investigated whether psychiatric symptomatology, impulsivity, family and social dysfunction, and alcohol use mediate the relationship between adverse childhood experiences (ACEs) and suicidality. The study population comprised 206 adolescent psychiatric inpatients and 203 age- and gender-matched adolescents from the community. ACEs and suicidality were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime version, the Life Events Checklist, and a structured background data collection sheet. Psychiatric symptomatology was measured using the Symptom Checklist -90. Impulsivity, social dysfunction, and family dysfunction were measured using the Offer Self-Image Questionnaire, and alcohol use was assessed with the Alcohol Use Disorders Identification Test. A simple mediation test and multiple mediation analyses were conducted. A positive direct effect of ACEs on suicidality was observed. Also seen was a positive indirect effect of ACEs on suicidality through psychiatric symptomatology, impulsivity, and family and social dysfunctions. Alcohol misuse did not, however, mediate the relationship between ACEs and suicidality. According to the multiple mediation analyses, psychiatric symptomatology was the most significant mediator, followed by impulsivity. Psychiatric symptoms, impulsivity, and family and social dysfunctions are factors that should be taken into consideration when assessing suicidality in adolescents.