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Atypical habituation to repetitive information has been commonly reported in Autism Spectrum Disorder (ASD) but it is not yet clear whether similar abnormalities are present in Neurofibromatosis Type 1 (NF1). We employed a cross-syndrome design using a novel eye tracking paradigm to measure habituation in preschoolers with NF1, children with idiopathic ASD and typically developing (TD) children. Eye movements were recorded to examine fixation duration to simultaneously presented repeating and novel stimuli. Children with NF1 showed a bias for longer look durations to repeating stimuli at the expense of novel stimuli, and slower habituation in NF1 was associated with elevated ASD traits. These findings could indicate aberrant modulation of bottom-up attentional networks that interact with the emergence of ASD phenotypes. [ABSTRACT FROM AUTHOR]

This study investigated sex and age differences in autistic behaviours in children with neurofibromatosis type 1 (NF1) who scored within the clinical range on the Social Responsiveness Scale - Second Edition (T score ≥ 60). Thirty-four males and 28 females (3–16 years) were assessed with the Autism Diagnostic Observation Schedule - Second Edition and Autism Diagnostic Interview - Revised. Across both measures, males exhibited greater social communication deficits relative to females. Age-related abatement of social communication difficulties was observed for males but not females. Conversely, no sex differences were found for restricted/repetitive behaviours, which were stable over time for both males and females. The findings are discussed within the context of broader neurodevelopmental considerations that are common in NF1. [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. Methods: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7–17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. Results: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). Discussion: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. Conclusion: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1. [ABSTRACT FROM AUTHOR]

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis. Immune cells are important regulators of adipose tissue function, including adaptive thermogenesis. Here the authors show that mice with Krüppel-like factor 3 (KLF3) deficiency in bone marrow-derived cells have increased adipose tissue beiging which may at least in part be due to altered eosinophil paracrine signaling. [ABSTRACT FROM AUTHOR]

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. This Review describes progress in the study of human genetics, in which rapid advances in technology, foundational genomic resources and analytical tools have contributed to the understanding of the mechanisms responsible for many rare and common diseases and to preventative and therapeutic strategies for many of these conditions. [ABSTRACT FROM AUTHOR]

In light of the proliferation of recent research into social function in neurofibromatosis type 1 (NF1), a systematic review and meta-analysis is required to synthesise data and place findings within the context of a theoretical framework. This paper reviews findings from research into social function and autism spectrum disorder (ASD) in children and adults with NF1 and integrates these findings with the Socio-Cognitive Integration Abilities Model (SOCIAL). It also critically appraises links between social outcomes, internal and external factors moderating social functioning, cognitive domains implicated in social functioning, and underlying neural pathology in NF1. A systematic literature search conducted in MedLine (Ovid), PsycINFO (Ovid), Embase (Ovid), and PubMed electronic databases yielded 35 papers that met inclusion criteria for the systematic review. Out of these papers, 22 papers provided sufficient data for meta-analysis. Findings from this review and meta-analysis provide evidence that children and adults with NF1 exhibit significantly higher prevalence and severity of social dysfunction and ASD symptomatology. To date, very few studies have examined social cognition in NF1 but results indicate the presence of both perceptual and higher-level impairments in this population. The results of this review also provide support for age, gender, and comorbid ADHD as moderating factors for social outcomes in NF1. Suggestions for future research are offered to further our understanding of the social phenotype in NF1 and to facilitate the development of targeted interventions. [ABSTRACT FROM AUTHOR]

Individuals with neurofibromatosis type 1 (NF1) exhibit significant impairments in attention across multiple domains. Very little is known about the contributing neural networks. We used task-based functional magnetic resonance imaging (fMRI) to examine dorsal and ventral attention networks during auditory oddball processing in children and adolescents with NF1 and typically developing controls. Significant differences in neural activation patterns were identified within brain regions supporting the ventral attention system. Children with NF1 demonstrated hypoactivation in the temporoparietal junction and the anterior cingulate cortex compared to typically developing children. Hypoactivation in the anterior cingulate cortex was associated with poorer selective attention and attentional control in children with NF1. Results indicate an abnormality in bottom-up attention networks in NF1 that may lead to inefficient and faulty suppression of stimulus-driven information outside the current attentional set that play a significant role in the NF1 behavioral phenotype. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether in-the-moment diary reports of daily experience, taken collectively, are a valid representation of health-related quality of life (HRQL).Methods: A total of 35 boys with Duchenne muscular dystrophy (DMD) were recruited through four neuromuscular care providers across Australia. Participants completed the PedsQL™ Generic Core scales and one week of experience-sampling diary reporting on a personal digital assistant. Rasch analysis was undertaken on the diary data to derive a single valid measure score. The resulting measure score for each participant was correlated with the summary score from the PedsQL™ Generic Core scales to examine whether daily experience was representative of HRQL.Results: The daily diary method showed good metric properties, with adequate goodness of fit for data from items and participants suggesting unidimensionality of the construct: quality of everyday experience. The correlation of the daily diary measure score with overall PedsQL™ summary score showed moderate agreement (r = .60, p = 0.001).Conclusions: The benefits of measuring daily quality of life include detailed descriptions of day-to-day experiences of children without the need for retrospective recall. Diary methods on an electronic platform or software application for personal devices may be a useful tool to understand HRQL as the repeated measures data provide a detailed experience directly from the child and the platform makes data completion highly motivating. [ABSTRACT FROM AUTHOR]

Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression. [ABSTRACT FROM AUTHOR]

Transmembrane water transport is mediated by aquaporins (AQPs), of which AQP1 and AQP4 are expressed in skeletal muscle. AQP4 expression is reduced in Duchenne muscular dystrophy (DMD) patients, and is reported to correlate with decreased α1-syntrophin and altered osmotic permeability. In this study, we assessed the relationship between AQP1, AQP4, dystrophin and α1-syntrophin in dystrophinopathy and dysferlinopathy patients. Muscle biopsies of patients with DMD ( n = 8) and limb–girdle muscular dystrophy type 2B (LGMD2B; n = 5) were screened for AQP1 and AQP4 expression by real-time quantitative RT-PCR or Western blot and immunohistochemistry. AQP expression was further analyzed in primary myotubes derived from DMD and LGMD2B patients by cell culture and immunohistochemistry. AQP1 transcript and protein expression was significantly elevated in DMD biopsies, and was localized to the sarcolemma of muscle fibers and endothelia of muscle capillaries. AQP4 was significantly reduced despite normal dystrophin and α1-syntrophin in dysferlinopathy patients, while expression of AQP1 was variably upregulated. Expression of AQP1 and AQP4 was normal in patient-derived primary myotubes, suggesting that altered AQPs observed in biopsies are likely secondary to the dystrophic process. Our study shows that AQP4 downregulation can occur in muscular dystrophies with either normal or disrupted expression of dystrophin-associated proteins, and that this might be associated with upregulation of AQP1. [ABSTRACT FROM AUTHOR]

More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein α-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that α-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of α-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism. [ABSTRACT FROM AUTHOR]

Background: T2 hyperintensities (T2H) on MRI are the most common CNS lesions in individuals with neurofibromatosis type 1 (NF1).Objectives: The aim was to determine the frequency, signal characteristics and localization of T2H at different ages. In addition, we examined the sensitivity of different MR imaging sequences in detecting these lesions.Materials and Methods: We studied prospectively a cohort of children, adolescents and young adults with NF1 using T2-volume (T2-V) and conventional MRI sequences. Lesions were designated as either discrete or diffuse, and the region of signal abnormality was recorded. A total of 103 patients were studied (age range 8.0-25.4 years, mean 13.9 years).Results: The frequency, size, and intensity of T2H decreased with age in the basal ganglia (BG) and the cerebellum/brainstem (CB/BS). The majority of thalamic and CB/BS lesions were diffuse. Of the total cohort, 80% had diffuse bilateral hippocampal hyperintensities and 18.4% had hemispheric lesions best demonstrated on FLAIR; there was no significant difference in the frequency or signal intensity of hemispheric lesions with age.Conclusion: Lesions in the cerebral hemispheres and hippocampus imaged by MR do not change in prevalence over time, suggesting a different pathological basis from the lesions in the in BG and CB/BS that resolve with age. FLAIR and T2-V sequences are more sensitive in detecting lesions than standard T2-weighted sequences. [ABSTRACT FROM AUTHOR]

Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding α-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant α-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type α-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage. [ABSTRACT FROM AUTHOR]

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle α-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA. [ABSTRACT FROM AUTHOR]

The article discusses the study by Wein, N. and colleagues to demonstrate that initiation of Duchenne muscular dystrophy (DMD) exon 6 translation is driven by an internal ribosome entry site (IRES) in exon 5 nucleic acid sequence and this allows translation of truncated form of dystrophin protein. It states that mass spectrometry on muscle biopsy tissue of an asymptomatic individual was carried out and a form of dystrophin was detected and therapeutic use of IRES modulation was established.

Reports on the absence of actin-binding proteins in muscle biopsies of patients with muscular dystrophy. Identification of actinin deficiency by immunocytochemistry; Determination of the frequency and ethnic distribution in the general population; Reevaluation of previous studies on the loss actinin in patients with Duchenne muscular dystrophy.