Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann-Pick disease, type C1.

Identifying meaningful predictors of therapeutic efficacy from preclinical studies is challenging. However, clinical manifestations occurring in both patients and mammalian models offer significant translational value. Many neurological disorders, including inherited, metabolic Niemann-Pick disease, type C (NPC), exhibit ataxia. Both individuals with NPC and murine models manifest ataxia, and investigational therapies impacting this phenotype in mice have been reported to slow disease progression in patients (e.g. miglustat, intrathecal 2-hydroxypropyl-beta-cyclodextrin, and acetyl-L-leucine). Reproducible phenotypic scoring of animal models can facilitate comparisons between genotypes, sexes, disease course, and therapies. Previously, other groups have developed a composite phenotypic scoring system (CPSS), which was subsequently used to distinguish strain-dependent phenotypes and, with modifications, to evaluate potential therapies. However, high inter-rater reliability is paramount to widespread use. We have created a comprehensive, easy-to-follow phenotypic assessment based on the CPSS and have verified its reproducibility using murine models of NPC disease. Application of this scoring system is not limited to NPC disease and may be applicable to other models of neurodegeneration exhibiting motor incoordination, thereby increasing its utility in translational studies.

Longitudinal growth curves for children with classical osteogenesis imperfecta (types III and IV) caused by structural pathogenic variants in type I collagen.

PURPOSE: Growth deficiency is a cardinal feature of osteogenesis imperfecta (OI) types III and IV, caused by pathogenic variants in type I collagen. OI-specific longitudinal growth charts are needed for patient care. METHODS: We compiled longitudinal length, weight, head circumference, and body mass index (BMI) data from 100 children with types III and IV OI and known type I collagen pathogenic variants. Effects of gender, OI type, and pathogenic variant were examined using multilevel modeling. OI-specific centile curves were constructed using generalized additive model for location, scale, and shape (GAMLSS). RESULTS: OI type and gender, but not the specific mutated collagen gene, significantly affect stature, but only OI type affects weight. Head circumference was not significantly different by gender, type, or mutated gene. In both genders, length curves for types III and IV OI overlap and the type IV 95th centile curve overlaps the lower US Centers for Disease Control and Prevention (CDC) curves for the general population. A pubertal growth spurt is generally absent or blunted in types III/IV OI. The body mass index 50th and 95th centile curves are distinctly shifted above respective US CDC curves in both genders. CONCLUSIONS: OI type is a stronger contributing factor than gender for OI growth, while curves do not differ for COL1A1 versus COL1A2 pathogenic variants. Types III and IV OI-specific growth curves are presented.

Effects of early and later family violence on children's behavior problems and depression: a longitudinal, multi-informant perspective.

OBJECTIVES: To examine the effects of different forms of family violence at two developmental stages by assessing a sample of 110 Israeli children, drawn from the case files of Israeli family service agencies, studied longitudinally in both middle childhood and adolescence. METHODS: Information about the children's adjustment was obtained from parents, teachers, and the children themselves when the children averaged 10.6 and 15.9 years of age using the Child Behavior Checklist (CBCL), Teacher Report Form (TRF), Youth Self-Report (YSR), and Children's Depression Inventory (CDI). Information about the history of family violence was obtained from the mothers, fathers, children, and social workers. RESULTS: The results paint a mixed picture of the effects of family violence on children and adolescents. The relationship between concurrent behavior problems and abuse group varied by informant and study phase, although they were strongest when children were the informants. Predictions regarding the relationship between early abuse and later adjustment were only partially confirmed. Different informants did not agree about which groups of children were most adversely affected, there was little stability over time in the pattern of reported effects, and children were more likely than other informants to report levels of maladjustment that varied depending on recent or concurrent exposure to family violence. Many families changed their abuse status over time, and children who were new victims at follow-up had the most internalizing problems. Girls were found to be at more risk for internalizing and externalizing behavior problems than boys. CONCLUSIONS: Multiple informants are necessary to evaluate and assess the effects of family violence on children's behavior. Younger children may be more susceptible to the effects of family violence than older children, but problems manifest by some children may not carry over to adolescence. Changes in family and parenting practices, as well as in children's capacity to appraise and cope with family violence may help mitigate the adverse effects of family violence.

Adolescents' perceptions of attachments to their mothers and fathers in families with histories of domestic violence: a longitudinal perspective.

OBJECTIVE: The effects of both childhood and teenage experiences of domestic violence on adolescent-parent attachments were examined. METHOD: Israeli adolescents (M = 15.9 years) who were either victims of physical abuse, witnesses of physical spouse abuse, victims and witnesses of abuse, or neither victims nor witnesses of abuse were questioned about attachments to their parents using the Inventory of Parent and Peer Attachment [IPPA; Armsden, G. C., & Greenberg, M. T. (1987). The inventory of parent and peer attachment: Individual differences and their relationship to psychological well-being in adolescence. Journal of Youth and Adolescence, 16, 427-454]. FINDINGS: Abuse status 5 years earlier was unrelated to the adolescents' current perceptions of their attachments whereas current abuse status predicted the adolescents' perceptions of attachment to their mothers. Adolescents who were victims of physical abuse reported weaker attachments to their parents than adolescents who were not abused or who had solely witnessed interparental physical abuse. Attachments to mothers were weaker whether or not mothers were the perpetrators of abuse. CONCLUSIONS: These findings suggest that victimization adversely affects children's perceptions of relationships with their parents, but that changes in the exposure to family violence are associated with changes in relationships with parents. These findings suggest that intervention can have positive effects on parent-child relationships despite violent histories.