Testing SIPA1L2 as a modifier of CMT1A using mouse models.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.

Testing SIPA1L2 as a modifier of CMT1A using mouse models.

Charcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validate SIPA1L2 as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion in SIPA1L2 and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction between Sipa1l2 deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement of Sipa1l2 in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions between Sipa1l2 deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.

An allelic series of spontaneous Rorb mutant mice exhibit a gait phenotype, changes in retina morphology and behavior, and gene expression signatures associated with the unfolded protein response.

The Retinoid-related orphan receptor beta (RORß) gene encodes a developmental transcription factor and has 2 predominant isoforms created through alternative first exon usage; one specific to the retina and another present more broadly in the central nervous system, particularly regions involved in sensory processing. RORß belongs to the nuclear receptor family and plays important roles in cell fate specification in the retina and cortical layer formation. In mice, loss of RORß causes disorganized retina layers, postnatal degeneration, and production of immature cone photoreceptors. Hyperflexion or "high-stepping" of rear limbs caused by reduced presynaptic inhibition by Rorb-expressing inhibitory interneurons of the spinal cord is evident in RORß-deficient mice. RORß variants in patients are associated with susceptibility to various neurodevelopmental conditions, primarily generalized epilepsies, but including intellectual disability, bipolar, and autism spectrum disorders. The mechanisms by which RORß variants confer susceptibility to these neurodevelopmental disorders are unknown but may involve aberrant neural circuit formation and hyperexcitability during development. Here we report an allelic series in 5 strains of spontaneous Rorb mutant mice with a high-stepping gait phenotype. We show retinal abnormalities in a subset of these mutants and demonstrate significant differences in various behavioral phenotypes related to cognition. Gene expression analyses in all 5 mutants reveal a shared over-representation of the unfolded protein response and pathways related to endoplasmic reticulum stress, suggesting a possible mechanism of susceptibility relevant to patients.

The impact of COVID-19 restrictions in the United Kingdom on the positive behavioural support of people with an intellectual disability.

The way that people with an intellectual disability are supported is very important.The COVID-19 virus has changed the way that staff help people with an intellectual disability.We wanted to know about those changes and whether learning about positive behavioural support (PBS) helped staff to cope with them.The main changes were that people with an intellectual disability could not go out or see family and friends as often.Staff came up with new things to do for the people they supported, and PBS learning seemed to help staff to cope. Background: It has been suggested that COVID-19 and the associated restrictions are likely to have a negative impact on the provision of positive behavioural support (PBS) to people with an intellectual disability. Methods: Fifty-eight staff, who had recently completed an accredited positive behavioural support (PBS) programme, responded to an online questionnaire, which asked them to rate the impact of COVID-19 on factors related to PBS. Results: Participants reported a neutral or somewhat positive impact on all the areas measured, with the exception of the activities and quality of life of those they supported, which were somewhat negatively affected. The participants rated the learning from their PBS programme as helping them cope with COVID-19 to some extent. Examples of positive and negative effects and ways in which PBS helped staff to cope are presented. Conclusions: Many staff developed creative solutions that allowed them to provide PBS despite the COVID-19 restrictions. PBS learning appeared to help staff cope with the negative impact of the restrictions.

'It's been adapted rather than impacted': A qualitative evaluation of the impact of Covid-19 restrictions on the positive behavioural support of people with an intellectual disability and/or autism.

BACKGROUND: We used a qualitative approach to explore the experiences of social care staff regarding the provision of positive behavioural support (PBS) to people with an intellectual disability at the height of the Covid-19 restrictions. METHOD: We conducted semi-structured interviews with 19 staff who had recently completed a PBS workforce development programme. Data were analysed using thematic analysis. RESULTS: Three themes were identified in the context of the restrictions: The challenges to maintaining quality of life and PBS of the people being supported and staff attempts to overcome these; the ways in which PBS and behaviour support plans were implemented and the impact on behaviours that challenge; the ways in which PBS principles were applied at organisational levels to help to understand and address staff stress and distress. CONCLUSIONS: Overall, the staff identified many unexpected benefits of the restrictions. The results are discussed in the context of the study limitations.

An evaluation of the distribution properties, factor structure, and item response profile of an assessment of emotion recognition.

Many people with developmental disabilities, such as autism spectrum disorder and intellectual disability have emotion recognition (ER) difficulties compared with typically developing (TD) peers. Accurate assessment of the extent and nature of differences in ER requires an understanding of the response profiles to ER assessment stimuli. We analysed data from 504 TD individuals in response to an ER assessment in respect of distribution properties, factor structure, and item response profile. Eighteen emotion items discriminated better at lower levels of ER ability in TD participants. Neutral expressions were the hardest to interpret; surprise, anger, happy, and bored were easiest. The amount of contextual information in combination with the emotion being depicted also appeared to influence level of difficulty. Similar psychometric research is needed with people with developmental disabilities.

Assessing the accuracy of the WISC-IV seven-subtest short form and the child and adolescent intellectual disability screening questionnaire in identifying intellectual disability in children.

Little research has been conducted into the accuracy of abbreviated assessments in identifying children and young people with an intellectual disability (ID). The present study compared two such methods in a clinical population of individuals with (n = 106) and without (n = 170) ID: a 7-subtest short form of the Wechsler Adult Intelligence Scales for Children--fourth edition (WISC-IV) proposed by Crawford and colleagues and the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q). Both the CAIDS-Q and the WISC-IV short form had high and comparable levels of predicting group classification (88% and 91% correct classification, respectively). Both methods would appear to offer clinicians and researchers an efficient and accurate means of identifying those who are likely to have ID. The WISC-IV short form was slightly more accurate, but the CAIDS-Q may offer the advantages of being shorter to administer and having no requirement for the user to have a particular qualification or training.

Towards a functional model of mental disorders incorporating the laws of thermodynamics.

The current paper presents the hypothesis that the understanding of mental disorders can be advanced by incorporating the laws of thermodynamics, specifically relating to energy conservation and energy transfer. These ideas, along with the introduction of the notion that entropic activities are symptomatic of inefficient energy transfer or disorder, were used to propose a model of understanding mental ill health as resulting from the interaction of entropy, capacity and work (environmental demands). The model was applied to Attention Deficit Hyperactivity Disorder, and was shown to be compatible with current thinking about this condition, as well as emerging models of mental disorders as complex networks. A key implication of the proposed model is that it argues that all mental disorders require a systemic functional approach, with the advantage that it offers a number of routes into the assessment, formulation and treatment for mental health problems.

The postnatal support needs of mothers with an intellectual disability.

OBJECTIVE: there is growing evidence that many parents with intellectual disabilities can parent successfully when given adequate support. This paper aims to explore the postnatal care experiences of mothers with an intellectual disability. DESIGN: a qualitative design was used and data were collected using a semi-structured interview format and analysed using Interpretative Phenomenological Analysis. SETTING: the study took place in community settings in Scotland. PARTICIPANTS: six mothers with intellectual disabilities were interviewed about their experiences. MEASUREMENTS AND FINDINGS: two super-ordinate themes are discussed with accompanying subthemes: challenges of providing support and how support was delivered. KEY CONCLUSIONS: the mothers valued formal postnatal care, but this was secondary to informal support. How mothers perceived the support impacted on its effectiveness and building effective relationships with professionals presented challenges. IMPLICATIONS FOR PRACTICE: the study suggests the structure and quality of the wider support networks of mothers with an intellectual disability are central and should be taken account of by professionals. Providing information and advice in ways that validates the mother's role is also important, particularly as the mother's perception of how help is given can impact on the degree to which mothers engage with professionals.

An examination of the effects of stimulant medication on response inhibition: a comparison between children with and without attention deficit hyperactivity disorder.

This study investigated whether methylphenidate is effective in improving response inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD). Children with ADHD were compared with normally developing children on measures of response inhibition. Participants with ADHD were compared across two conditions--medicated and unmedicated. There was no significant difference between the inhibitory control of children with and without ADHD. Children with ADHD showed significant improvements in inhibitory control following methylphenidate. The findings of the present study contrast with previous studies which document reduced inhibitory control in ADHD, compared with normally developing children. Reports of methylphenidate improving functioning in children with ADHD are supported. Limitation and implications of the study are discussed.