The developmental dynamics of gait maturation with a focus on spatiotemporal measures.

Gait analysis is recognised as a powerful clinical tool for studying relationships between motor control and brain function. By drawing on the literature investigating gait in individuals with neurological disorders, this review provides insight into the neural processes that contribute to and regulate specific spatiotemporal sub-components of gait and how they may mature across early to late childhood. This review also discusses the roles of changing anthropomorphic characteristics, and maturing sensory and higher-order cognitive processes in differentiating the developmental trajectories of the sub-components of gait. Importantly, although studies have shown that cognitive-gait interference is larger in children compared to adults, the contributing neurocognitive mechanisms may vary across age groups who have different types of attentional or cognitive vulnerabilities. These findings have implications for current models of gait maturation by highlighting the need for a dynamic model that focuses on the integration of various factors that contribute to gait though experience and practice. This is essential to elucidating why gait and other motor deficits are often contiguous with cognitive neurodevelopmental disorders.

Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females.

DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.

Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors.

Photoreceptor replacement by transplantation is proposed as a treatment for blindness. Transplantation of healthy photoreceptor precursor cells into diseased murine eyes leads to the presence of functional photoreceptors within host retinae that express an array of donor-specific proteins. The resulting improvement in visual function was understood to be due to donor cells integrating within host retinae. Here, however, we show that while integration occurs the majority of donor-reporter-labelled cells in the host arises as a result of material transfer between donor and host photoreceptors. Material transfer does not involve permanent donor-host nuclear or cell-cell fusion, or the uptake of free protein or nucleic acid from the extracellular environment. Instead, RNA and/or protein are exchanged between donor and host cells in vivo. These data require a re-evaluation of the mechanisms underlying rescue by photoreceptor transplantation and raise the possibility of material transfer as a strategy for the treatment of retinal disorders.

ß-glucuronidase mRNA levels are correlated with gait and working memory in premutation females: understanding the role of FMR1 premutation alleles.

Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions). FXTAS is associated with elevated levels of FMR1 mRNA which are toxic. In this study, relationships between neurocognitive and intra-step gait variability measures with mRNA levels, measured in blood samples, were examined in 35 PM and 35 matched control females. The real-time PCR assays measured FMR1 mRNA, and previously used internal control genes: ß-Glucuronidase (GUS), Succinate Dehydrogenase 1 (SDHA) and Eukaryotic Translation Initiation Factor 4A (EI4A2). Although there was significant correlation of gait variability with FMR1 mRNA levels (p = 0.004) when normalized to GUS (FMR1/GUS), this was lost when FMR1 was normalized to SDHA and EI4A2 (2IC). In contrast, GUS mRNA level normalized to 2IC showed a strong correlation with gait variability measures (p < 0.007), working memory (p = 0.001) and verbal intelligence scores (p = 0.008). PM specific changes in GUS mRNA were not mediated by FMR1 mRNA. These results raise interest in the role of GUS in PM related disorders and emphasise the importance of using appropriate internal control genes, which have no significant association with PM phenotype, to normalize FMR1 mRNA levels.

Exploring factors related to the anger superiority effect in children with Autism Spectrum Disorder.

Despite face and emotion recognition deficits, individuals with Autism Spectrum Disorder (ASD) appear to experience the anger superiority effect, where an angry face in a crowd is detected faster than a neutral face. This study extended past research to examine the impacts of ecologically valid photographic stimuli, gender and anxiety symptoms on the anger superiority effect in children with and without ASD. Participants were 81, 7-12year old children, 42 with ASD matched on age, gender and perceptual IQ to 39 typically developing (TYP) children. The photographic stimuli did not impact on task performance in ASD with both groups exhibiting the anger superiority effect. There were no gender differences and no associations with anxiety. Age was associated with the effect in the TYP but not ASD group. These findings confirm a robust effect of speeded detection of threat in ASD which does not appear to be confounded by gender or anxiety, but may have different underlying age-associated mechanisms.

The emergence and stability of attention deficit hyperactivity disorder in boys with fragile X syndrome.

BACKGROUND: Children with fragile X syndrome (FXS) are at high risk for developing a range of behavioural disorders, including attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). However, very few studies have investigated the comorbid profile of FXS and ADHD and the possible dissociation from the FXS and ASD profile. The present study examined the relationship of childhood temperament characteristics of the Surgency facet (activity level, impulsivity, approach, shyness, and smiling and laughter) and the severity of ADHD and ASD features at two measurement time points in childhood, preschool (ages 3-4) and at school entry (ages 5-6). METHODS: The study consisted of males with FXS measured at each time point (preschool and school entry), as well as comparison of typically developing (TD) boys at the preschool measurement time point. Parent reported measures of temperament and behavioural symptoms were collected at each time point. Multiple regression analyses were used to analyse obtained data. RESULTS: Elevated activity level scores are associated with ADHD scores at preschool age and elevated shyness and decreased smiling and laughter are strongly associated with ADHD scores upon school entry. Impulsivity emerges as a strong indicator of elevated ADHD scores around school age, but even preschool impulsivity scores demonstrate some predictive value for higher ADHD scores later in school. Finally, no Surgency characteristic was significantly related to ASD scores at any age. CONCLUSIONS: Impulsivity serves as an indicator of elevated ADHD symptoms across development periods in boys with FXS, while activity level is just indicative of higher ADHD scores at the preschool age. The Surgency facet of temperament at either age does not predict strong relationships of comorbid pathologies of ADHD and ASD in FXS. However, Surgency characteristics may serve as informative discriminative factors when studying behavioural outcomes in boys with FXS.

Parent-Child Agreement Using the Spence Children's Anxiety Scale and a Thermometer in Children with Autism Spectrum Disorder.

Children with Autism Spectrum Disorder (ASD) experience high anxiety which often prompts clinical referral and requires intervention. This study aimed to compare parent and child reports on the Spence Children's Anxiety Scale (SCAS) and a child-reported "worry thermometer" in 88 children aged 8-13 years, 44 with ASD and 44 age, gender, and perceptual IQ matched typically developing children. There were no gender differences in child report on the SCAS and worry thermometers. Results indicated generally good correlations between parent and child self-reported SCAS symptoms for typically developing children but poor agreement in parent-child ASD dyads. The worry thermometer child-report did not reflect child or parent reports on the SCAS. Findings suggest 8-13-year-old children with ASD may have difficulties accurately reporting their anxiety levels. The clinical implications were discussed.

Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males.

Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X-associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26-80) and 24 matched controls (ages 26-77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat-mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline.

Cognitive training as a resolution for early executive function difficulties in children with intellectual disabilities.

Core executive functions (EF) such as attention, and working memory have been strongly associated with academic achievement, language development and behavioral stability. In the case of children who are vulnerable to cognitive and learning problems because of an underlying intellectual disability, EF difficulties will likely exacerbate an already compromised cognitive system. The current review examines cognitive training programs that aim to improve EF, specifically focusing on the potential of this type of intervention for children who have intellectual disabilities. We conclude that despite considerable discrepancies regarding reported intervention effects, these inconsistencies can be attributed to flaws in both program and study design. We discuss the steps needed to address these limitations and to facilitate the advancement of non-pharmaceutical interventions for children with intellectual disabilities.

Understanding the neuropsychiatric phenotype of fragile X-associated tremor ataxia syndrome: a systematic review.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a recently identified X-linked neurodegenerative disorder affecting a proportion of premutation carriers of the Fragile X Mental Retardation 1 (FMR1) gene. Previous research suggests that cognitive and psychiatric features of FXTAS may include primary impairments in executive function and increased vulnerability to mood and anxiety disorders. A number of these reports, however, are based on overlapping cohorts or have produced inconsistent findings. A systematic review was therefore conducted to further elucidate the neuropsychiatric features characteristic of FXTAS. Fourteen papers met inclusion criteria for the review and were considered to represent nine independent FXTAS cohorts. Findings from the review suggest that the neuropsychiatric phenotype of FXTAS is characterised primarily by poorer performance on measures of executive function, working memory, information processing speed, and fine motor control when compared to matched comparison groups. Two studies were identified in which psychiatric symptoms in FXTAS were compared with controls, and these yielded mixed results. Overall the results of this review support previous reports that the neuropsychiatric profile of FXTAS is consistent with a dysexecutive fronto-subcortical syndrome. However, additional controlled studies are required to progress our understanding of FXTAS and how the neuropsychiatric profile relates to underlying pathological mechanisms.

Symbolic sequence learning is associated with cognitive-affective profiles in female FMR1 premutation carriers.

This study examines implicit sequence learning impairments that may indicate at-risk cerebellar profiles proposed to underlie some aspects of subtle cognitive and affective dysfunctions found among female fragile X mental retardation 1 (FMR1) premutation (PM)-carriers. A total of 34 female PM-carriers and 33 age- and intelligence-matched controls completed an implicit symbolically primed serial reaction time task (SRTT) previously shown to be sensitive to cerebellar involvement. Implicit learning scores indicated a preservation of learning in both groups; however, PM-carriers demonstrated poorer learning through significantly elevated response latencies overall and at each specific block within the symbolic SRTT. Group comparisons also revealed a core deficit in response inhibition, alongside elevated inattentive symptoms in female PM-carriers. Finally, strong and significant associations were observed between poor symbolic SRTT performance and executive, visuospatial and affective deficits in the PM-carrier group. These associations remained strong even after controlling motor speed, and were not observed in age- and intelligence quotient-matched participants. The findings implicate cerebellar non-motor networks subserving the implicit sequencing of responses in cognitive-affective phenotypes previously observed in female PM-carriers. We contend that symbolic SRTT performance may offer clinical utility in future pharmaceutical interventions in female PM-carriers.

Attention deficits predict phenotypic outcomes in syndrome-specific and domain-specific ways.

Attentional difficulties, both at home and in the classroom, are reported across a number of neurodevelopmental disorders. However, exactly how attention influences early socio-cognitive learning remains unclear. We addressed this question both concurrently and longitudinally in a cross-syndrome design, with respect to the communicative domain of vocabulary and to the cognitive domain of early literacy, and then extended the analysis to social behavior. Participants were young children (aged 4-9 years at Time 1) with either Williams syndrome (WS, N = 26) or Down syndrome (DS, N = 26) and typically developing controls (N = 103). Children with WS displayed significantly greater attentional deficits (as indexed by teacher report of behavior typical of attention deficit hyperactivity disorder (ADHD) than children with DS, but both groups had greater attentional problems than the controls. Despite their attention differences, children with DS and those with WS were equivalent in their cognitive abilities of reading single words, both at Time 1 and 12 months later, at Time 2, although they differed in their early communicative abilities in terms of vocabulary. Greater ADHD-like behaviors predicted poorer subsequent literacy for children with DS, but not for children with WS, pointing to syndrome-specific attentional constraints on specific aspects of early development. Overall, our findings highlight the need to investigate more precisely whether and, if so, how, syndrome-specific profiles of behavioral difficulties constrain learning and socio-cognitive outcomes across different domains.

The use of propranolol in the management of periocular capillary haemangioma--a systematic review.

Capillary haemangioma or infantile haemangioma (IH) is the most common congenital vascular tumour in the periocular region. Several treatment modalities have been documented, with variable degree of success. Propranolol has recently been reported to be an effective and safe alternative. The aim of this systematic review is to examine the evidence base for the use of propranolol administered orally in the management of periocular capillary haemangioma, and use this information to guide future research. A systematic review of literature was carried out by two independent reviewers using the search strategies highlighted below. A total of 100 cases of oral propranolol use in periorbital or orbital capillary haemangiomas have been documented in the literature. Of the 85 cases that had details of previous treatment, it was used as first-line treatment in 50 (58.8%). The commonest dose used was 2 mg/kg/day. Adverse events were documented in one-third of cases; in most cases these were minor. Improvement or complete resolution of the lesions occurred in 96% of cases. Recurrence was noted in one-fifth of cases. Propranolol has shown a lot of promise in the therapy of IH and further research in the form of properly designed randomized trials is certainly warranted. Treatment guidelines based on literature available to date is included in this review.

An unusual case of pediatric painless ophthalmoplegia.

Acquired unilateral ophthalmoplegia in childhood has many potential causes. Tolosa-Hunt Syndrome is characterized by painful ophthalmoplegia caused by nonspecific inflammation of cavernous sinus or superior orbital fissure. It is rarely present in children. Corticosteroid treatment is the current mainstay of treatment but cases of THS that failed to respond to steroids have been reported. We report a case of cavernous sinus pseudotumour presenting as a painless ophthalmoplegia in a child, in which complete resolution was spontaneous. To our knowledge, such a case has never been reported in the literature.

Deep anterior lamellar keratoplasty on a previously failed full-thickness graft.

PURPOSE: To report a case of deep anterior lamellar keratoplasty (DALK) on a previously failed full-thickness graft in a case of herpetic keratitis. METHODS: A 70-year-old patient with a history of penetrating keratoplasty for herpetic keratitis performed 30 years ago presented with blurry vision in her left eye. She had corneal stromal scarring secondary to herpetic keratitis. The endothelium was spared. We performed a DALK with big-bubble technique. RESULTS: Postoperatively, corneal edema was noticed initially, which resolved in 3 months. Her best-corrected visual acuity is 6/12 in her left eye. CONCLUSION: DALK on a previous penetrating keratoplasty is a technical possibility when there is a functioning endothelium.

Is microbiological analysis of donor cornea transport culture media necessary?

PURPOSE: To investigate microbial contamination of the transport medium. Examination of corneoscleral rims is not included in this series. METHODS: Transport media of 63 consecutive grafts done at Tennent Institute of Ophthalmology, Glasgow, were collected for microbial examination. RESULTS: None of the culture plates showed any growth after prolonged culture, and microscopy was negative in 100% of cases. CONCLUSIONS: Routine culture of transport media may not be necessary.

A comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome.

BACKGROUND: Standardised neuropsychological and cognitive measures present some limitations in their applicability and generalisability to individuals with intellectual disability (ID). Alternative approaches to defining the cognitive signatures of various forms of ID are needed to advance our understanding of the profiles of strengths and weaknesses as well as the affected brain areas. AIM: To evaluate the utility and feasibility of six non-verbal comparative neuropsychological (CN) tasks administered in a modified version of the Wisconsin General Test Apparatus (WGTA) to confirm and extend our knowledge of unique cognitive signatures of Fragile X syndrome (FXS) and Down syndrome (DS). METHOD: A test battery of CN tasks adapted from the animal literature was administered in a modified WGTA. Tasks were selected that have established or emerging brain-behaviour relationships in the domains of visual-perceptual, visual-spatial, working memory and inhibition. RESULTS: Despite the fact that these tasks revealed cognitive signatures for the two ID groups, only some hypotheses were supported. Results suggest that whereas individuals with DS were relatively impaired on visual-perceptual and visual-spatial reversal learning tasks they showed strengths in egocentric spatial learning and object discrimination tasks. Individuals with FXS were relatively impaired on object discrimination learning and reversal tasks, which was attributable to side preferences. In contrast, these same individuals exhibited strengths in egocentric spatial learning and reversal tasks as well as on an object recognition memory task. Both ID groups demonstrated relatively poor performance for a visual-spatial working memory task. CONCLUSION: Performance on the modified WGTA tasks differentiated cognitive signatures between two of the most common forms of ID. Results are discussed in the context of the literature on the cognitive and neurobiological features of FXS and DS.

Intravitreal bevacizumab and augmented trabeculectomy for neovascular glaucoma in young diabetic patients.

PURPOSE: To report two cases of young diabetic patients with intractable neovascular glaucoma (NVG) who were successfully managed with bevacizumab and mitomycin C-augmented trabeculectomy. RESULTS: Two young patients present with severe NVG secondary to diabetic proliferative retinopathy. The glaucoma was unresponsive to conventional medical therapy and complete panretinal photocoagulation. Both patients underwent augmented trabeculectomy with MMC and intravitreal injection of bevacizumab. Iris rubeosis resolved within 48 h. Both patients have a follow-up period of 6 months and the intraocular pressure (IOP) remain between 10-15 mmHg. CONCLUSIONS: Controlling IOP due to NVG in young diabetic patients is difficult and augmented trabeculectomy has a very high failure rate. The addition of intravitreal bevacizumab in the management of NVG particularly in young diabetic patients may improve the success rate of IOP control. It is known that bevacizumab retards neovascularisation. It may also be modulating wound-healing response as well. Bevacizumab may have a potential role in the surgical management of NVG.

The fragile X continuum: new advances and perspectives.

Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X 'signature' or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic 'signatures' within the fragile X continuum.

Visual search performance in children rated as good or poor attenders: the differential impact of DAT1 genotype, IQ, and chronological age.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by poor attention to detail, poor attention maintenance, and variability throughout task performance. The authors used a quantitative trait loci approach to assess the association between the dopamine transporter (DAT1) high-risk genotype, cognitive performance (visual search and vigilance), and ADHD symptoms in a community sample of boys 6-11 years of age. The potential confounding effects of IQ and chronological age were also investigated. Results demonstrate that accuracy in target detection, not speed, distinguishes poor attenders from good attenders. The authors speculate that the measure of performance (e.g., time and false alarms) may be critical in detecting attentional weaknesses. In contrast, DAT1 gene, known to be associated with the behavioral symptoms of ADHD, was unrelated to visual search or vigilance performance, although it was related to ADHD symptoms.