Detailed Analysis of <em>ITPR1 </em>Missense Variants Guides Diagnostics and Therapeutic Design

\ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Background: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Methods: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3-binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. \ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Heterothermy and seasonal patterns of metabolic rate in the southern African hedgehog (Atelerix frontalis)

Animals that inhabit unfavourable habitats and experience seasons where the cost of maintenance exceeds the available energy resources have over time developed behavioural and physiological mechanisms to survive. These adaptations include changes in activity, improvement of cold tolerance by using nonshivering thermogenesis (NST), improvement of thermal conductance, reduction of body mass, or acclimation to colder temperatures (reduction of metabolic requirement). In addition some species exhibit heterothermy, in the form of either daily torpor or longer-term hibernation. The southern African hedgehog (Atelerix frontalis) is an excellent candidate to investigate the phenomenon of heterothermy because it is a small insectivore (summer body mass ca. 300 to 400g), burrows, inhabits harsh habitats and is not easy to find during the winter months. In this study I aimed to investigate whether A. frontalis exhibits seasonal differences in metabolic rate and furthermore if this species exhibits heterothermy. The study was carried out in the Northern Cape Province, South Africa. Hedgehogs were hand captured and their metabolic rates were measured using indirect calorimetry. Individuals were implanted with temperature dataloggers for a summer period (November 2009-January 2010) and a winter period (May-August 2009). The summer BMR of adult A. frontalis (0.448 ±0.035 mlO2/g/h, n=4) was significantly lower than their winter BMR (0.811 ±0.073 mlO2/g/h, n=4) and statistical analyses revealed that this was an affect caused by seasonal changes in the ambient environment. Individuals spent up to 84 percent of time during the measurement period torpid (-8°C <Ta<21°C). Body mass appears to be an important factor in determining the pattern of heterothermy (daily torpor versus hibernation) used in this species. To my knowledge the extremely low body temperature (Tb min) of 1.0°C recorded for A. frontalis is the lowest Tb min recorded for a mainland Afrotropical mammal. This species displays classic up-regulation in metabolic rate during winter, resulting in an increase in the energetic requirements of the species. As a result, heterothermy appears to play a significant role in the energy balance of this species during winter, contributing to energy saving. Heterothermy may enable this species to survive in the face of global climate change

The dynamic relationship between cognitive function and walking speed:The English Longitudinal Study of Ageing

Cross-sectional studies show that older people with better cognition tend to walk faster. Whether this association reflects an influence of fluid cognition upon walking speed, vice versa, a bidirectional relationship or the effect of common causes is unclear. We used linear mixed effects models to examine the dynamic relationship between usual walking speed and fluid cognition, as measured by executive function, verbal memory and processing speed, in 2,654 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. There was a bidirectional relationship between walking speed and fluid cognition. After adjusting for age and sex, better performance on executive function, memory and processing speed was associated with less yearly decline in walking speed over the 6-year follow-up period; faster walking speed was associated with less yearly decline in each cognitive domain; and less yearly decline in each cognitive domain was associated with less yearly decline in walking speed. Effect sizes were small. After further adjustment for other covariates, effect sizes were attenuated but most remained statistically significant. We found some evidence that walking speed and the fluid cognitive domains of executive function and processing speed may change in parallel with increasing age. Investigation of the association between walking speed and cognition earlier in life is needed to better understand the origins of this relation and inform the development and timing of interventions.<br/

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Educational Inequalities in Health Behaviors at Midlife: Is There a Role for Early-life Cognition?

Education is a fundamental cause of social inequalities in health because it influences the distribution of resources, including money, knowledge, power, prestige, and beneficial social connections, that can be used in situ to influence health. Recent studies have highlighted early-life cognition as commonly indicating the propensity for educational attainment and determining health and age of mortality. Health behaviors provide a plausible mechanism linking both education and cognition to later-life health and mortality. We examine the role of education and cognition in predicting smoking, heavy drinking, and physical inactivity at midlife using data from the Wisconsin Longitudinal Study (N = 10,317), National Survey of Health and Development (N = 5,362), and National Childhood Development Study (N = 16,782). Adolescent cognition was associated with education but was inconsistently associated with health behaviors. Education, however, was robustly associated with improved health behaviors after adjusting for cognition. Analyses highlight structural inequalities over individual capabilities when studying health behaviors