Development of a clinical algorithm for the early diagnosis of mucopolysaccharidosis III

Mucopolysaccharidosis III (MPS III) is a rare inherited metabolic disease primarily affecting the central nervous system, leading to developmental and/or speech regression. Early diagnosis of the disease is important to introduce appropriate management measures and to optimize therapeutic outcomes. The diagnosis of MPS III is often significantly delayed due to the rarity of the disease, the more attenuated somatic presentation compared to other MPS types, and the symptom overlap with other developmental disorders. To shorten the time to diagnosis, a list of eight early signs and symptoms was identified through an expert system approach by a global, multidisciplinary working group of 13 specialists with expertise in various aspects of MPS and developmental disorders and three parents of MPS III patients. Coarse facial features and persistent hirsutism or prominent, thick eyebrows were identified as the most important MPS III early signs. The list of eight early MPS III signs and symptoms is the first step towards the development of a clinical algorithm aiming to identify neonates and infants with MPS III before the onset of neurocognitive damage, ultimately shortening the diagnostic journey of MPS III patients

Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy

ObjectiveThe diagnosis of autism spectrum disorder (ASD) has been found to be remarkably stable but few studies have followed children not initially diagnosed with ASD beyond 3 years of age to examine late or delayed diagnoses. The present study used a prospective familial-risk design to identify children who had undergone multiple comprehensive assessments in preschool and were determined to be negative for ASD only to meet criteria for ASD when tested in middle childhood.MethodData were pooled across 3 research teams studying later-born siblings of children with ASD. Fourteen children met inclusion criteria for the late-diagnosed group and were compared with a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at 3 years of age.ResultsAs a group, the late-diagnosed children scored between the TD and ASD groups on most measures administered at 3 years and differed significantly from the ASD group on most measures. However, there was significant heterogeneity among the late-diagnosed cases. Seven showed very little evidence of ASD in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology.ConclusionSome children with ASD might present with a subtle phenotype early in life or show a prolonged time course of symptom development. This emphasizes the need for screening and surveillance schedules that extend past 36 months and continued evaluation of any child who presents with atypical early development and/or high-risk status. The findings also shed light on reasons why the mean age of ASD diagnosis remains older than 4 years

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically

Disengagement of visual attention in infancy is associated with emerging autism in toddlerhood

Background: Early emerging characteristics of visual orienting have been associated with a wide range of typical and atypical developmental outcomes. In the current study, we examined the development of visual disengagement in infants at risk for autism. Methods: We measured the efficiency of disengaging from a central visual stimulus to orient to a peripheral one in a cohort of 104 infants with and without familial risk for autism by virtue of having an older sibling with autism. Results: At 7 months of age, disengagement was not robustly associated with later diagnostic outcomes. However, by 14 months, longer latencies to disengage in the subset of the risk group later diagnosed with autism was observed relative to other infants at risk and the low-risk control group. Moreover, between 7 months and 14 months, infants who were later diagnosed with autism at 36 months showed no consistent increases in the speed and flexibility of visual orienting. However, the latter developmental effect also characterized those infants who exhibited some form of developmental concerns (but not meeting criteria for autism) at 36 months. Conclusions: Infants who develop autism or other developmental concerns show atypicality in the development of visual attention skills from the first year of life

The prodrome of autism: early behavioral and biological signs, regression, peri- and post-natal development and genetics

Autism is one of the most heritable neurodevelopmental conditions and has an early onset, with symptoms being required to be present in the first 3 years of life in order to meet criteria for the ‘core’ disorder in the classification systems. As such, the focus on identifying a prodrome over the past 20 years has been on pre-clinical signs or indicators that will be present very early in life, certainly in infancy. A number of novel lines of investigation have been used to this end, including retrospective coding of home videos, prospective population screening and ‘high risk’ sibling studies; as well as the investigation of pre- and peri-natal, brain developmental and other biological factors. Whilst no single prodromal sign is expected to be present in all cases, a picture is emerging of indicative prodromal signs in infancy and initial studies are being undertaken to attempt to ameliorate the early presentation and even ‘prevent’ emergence of the full syndrome

Infant EEG activity as a biomarker for autism: a promising approach or a false promise?

The ability to determine an infant's likelihood of developing autism via a relatively simple neurological measure would constitute an important scientific breakthrough. In their recent publication in this journal, Bosl and colleagues claim that a measure of EEG complexity can be used to detect, with very high accuracy, infants at high risk for autism (HRA). On the surface, this appears to be that very scientific breakthrough and as such the paper has received widespread media attention. But a close look at how these high accuracy rates were derived tells a very different story. This stems from a conflation between "high risk" as a population-level property and "high risk" as a property of an individual. We describe the approach of Bosl et al. and examine their results with respect to baseline prevalence rates, the inclusion of which is necessary to distinguish infants with a biological risk of autism from typically developing infants with a sibling with autism. This is an important distinction that should not be overlooked

GOLIAH: A Gaming Platform for Home-Based Intervention in Autism – Principles and Design

Meeting the required intensive intervention hour for treating children with autism is challenging in terms of trained manpower needed and costs. Advances in Information Communication Technology and computer gaming may help in this respect by creating a nomadically deployable closed loop intervention system involving the child and active participation of parents and therapists.An automated serious gaming platform enabling intensive intervention in nomadic settings has been developed by mapping two pivotal skills in autism spectrum disorder: Imitation and Joint Attention (JA). Eleven games – seven Imitation and four JA – were derived from the Early Start Denver Model. The games involved application of visual and audio stimuli with multiple difficulty levels and a wide variety of tasks and actions pertaining to the Imitation and JA. The platform runs on mobile devices and allows the therapist to (1) characterize the child’s initial difficulties/strengths, ensuring tailored and adapted intervention by choosing appropriate games and (2) investigate and track the temporal evolution of the child’s progress through a set of automatically extracted quantitative performance metrics. The platform allows the therapist to change the game or its difficulty levels during the intervention depending on the child’s progress. Performance of the platform was assessed in a 3-month open trial with 10 children with autism. The children and the parents participated in 80% of the sessions both at home (77.5%) and at hospital (90%). All children went through all games but, given the diversity of the games and the heterogeneity of children profiles and abilities, for a given game the number of sessions dedicated to the game varied and could be tailored through automatic scoring. Parents (N = 10) highlighted enhancement in the child’s concentration, flexibility and self-esteem in 78%, 89% and 44% of the cases respectively and 56% observed an enhanced parents-child relationship. This pilot study shows the feasibility of using the developed gaming platform for home-based intensive intervention. However, the overall capability of the platform in delivering intervention needs to be assessed in a bigger open trial

Diagnostic stability in young children at risk for autism spectrum disorder:A baby siblings research consortium study

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across 7 sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis

Do imitation problems reflect a core characteristic in autism? Evidence from a literature review

A

From early markers to neuro-developmental mechanisms of autism

A fast growing field, the study of infants at risk because of having an older sibling with autism (i.e. infant sibs) aims to identify the earliest signs of this disorder, which would allow for earlier diagnosis and intervention. More importantly, we argue, these studies offer the opportunity to validate existing neuro-developmental models of autism against experimental evidence. Although autism is mainly seen as a disorder of social interaction and communication, emerging early markers do not exclusively reflect impairments of the “social brain”. Evidence for atypical development of sensory and attentional systems highlight the need to move away from localized deficits to models suggesting brain-wide involvement in autism pathology. We discuss the implications infant sibs findings have for future work into the biology of autism and the development of interventions