Early disease progression of Hurler syndrome

Abstract Background Newborn screening for mucopolysaccharidosis type I (MPS I) shows promise to improve outcomes by facilitating early diagnosis and treatment. However, diagnostic tests for MPS I are of limited value in predicting whether a child will develop severe central nervous system disease associated with Hurler syndrome, or minimal or no central nervous system involvement associated with the attenuated phenotypes (Hurler–Scheie and Scheie syndromes). Given that the optimal treatment differs between Hurler syndrome and the attenuated MPS I phenotypes, the absence of a reliable prognostic biomarker complicates clinical decision making for infants diagnosed through newborn screening. Information about the natural history of Hurler syndrome may aid in the management of affected infants, contribute to treatment decisions, and facilitate evaluation of treatment effectiveness and prognosis. Thus, the aim of this study was to characterize the progression and timing of symptom onset in infants with Hurler syndrome. Results Clinical data from 55 patients evaluated at a single center were retrospectively reviewed. Information about each child’s medical history was obtained following a standardized protocol including a thorough parent interview and the review of previous medical records. All patients underwent systematic physical and neurodevelopmental evaluations by a multidisciplinary team. Nearly all patients (98%) showed signs of disease during the first 6 months of life. Common early disease manifestations included failed newborn hearing screen, respiratory symptoms, difficulty latching, and otitis media. Other symptoms such as kyphosis, corneal clouding, cardiac disease, joint restrictions, and enlarged head circumference typically appeared slightly later (median age, 8–10 months). During the first 12 months, gross motor development was the most severely affected area of functioning, and a significant number of patients also experienced language delays. Cognition was typically preserved during this period. Conclusions In this large cohort of patients with Hurler syndrome, the vast majority showed signs and symptoms of disease during the first months of life. More research is needed to determine the extent to which early clinical manifestations of MPS I can predict phenotype and treatment outcomes

Neuropsychological Profile of Autism and the Broad Autism Phenotype

Context: Multiple articles describe a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype (BAP) may provide a potentially important complementary approach for detecting the genes causing autism and defining associated neural circuitry by identifying more refined phenotypes that can be measured quantitatively in both affected and unaffected individuals and that are tied to functioning in particular regions of the brain. Objective: To gain insight into neuropsychological features that index genetic liability to autism. Design: Case-control study. Setting: The general community. Participants: Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (n = 83), as well as control individuals. Main Outcome Measures: A comprehensive battery of neuropsychological tasks assessing social cognition, executive function, and global vs local processing strategies (central coherence). Results: Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other 2 domains being more similar to controls. Conclusions: Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism and may ultimately provide insight into the genes involved in autism

Longitudinal Study of Amygdala Volume and Joint Attention in 2- to 4-Year-Old Children With Autism

CONTEXT: Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of subregions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism. OBJECTIVES: To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism. DESIGN: Longitudinal magnetic resonance imaging study. SETTING: University medical setting. PARTICIPANTS: Fifty autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age. MAIN OUTCOME MEASURES: Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response Scale; group comparisons including total tissue volume, sex, IQ, and age as covariates. RESULTS: Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, although the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism. CONCLUSIONS: The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism

To What Extent Do Joint Attention, Imitation, and Object Play Behaviors in Infancy Predict Later Communication and Intellectual Functioning in ASD?

The extent to which early social communication behaviors predict later communication and intellectual outcomes was investigated via retrospective video analysis. Joint attention, imitation, and complex object play behaviors were coded from edited home videos featuring scenes of 29 children with ASD at 9–12 and/or 15–18 months. A quantitative interval recording of behavior and a qualitative rating of the developmental level were applied. Social communication behaviors increased between 9–12 and 15–18 months. Their mean level during infancy, but not the rate of change, predicted both Vineland Communication scores and intellectual functioning at 3–7 years. The two methods of measurement yielded similar results. Thus, early social communicative behaviors may play pivotal roles in the development of subsequent communication and intellectual functioning

Longitudinal Study of Amygdala Volume and Joint Attention in 2- to 4-Year-Old Children With Autism

Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of sub-regions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism

Neuropsychological Profile of Autism and the Broad Autism Phenotype

Context: Multiple articles describe a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype (BAP) may provide a potentially important complementary approach for detecting the genes causing autism and defining associated neural circuitry by identifying more refined phenotypes that can be measured quantitatively in both affected and unaffected individuals and that are tied to functioning in particular regions of the brain. Objective: To gain insight into neuropsychological features that index genetic liability to autism. Design: Case-control study. Setting: The general community. Participants: Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (n = 83), as well as control individuals. Main Outcome Measures: A comprehensive battery of neuropsychological tasks assessing social cognition, executive function, and global vs local processing strategies (central coherence). Results: Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other 2 domains being more similar to controls. Conclusions: Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism and may ultimately provide insight into the genes involved in autism

Hyporesponsiveness to social and nonsocial sensory stimuli in children with autism, children with developmental delays, and typically developing children

This cross-sectional study seeks to (a) describe developmental correlates of sensory hyporesponsiveness to social and nonsocial stimuli, (b) determine whether hyporesponsiveness is generalized across contexts in children with autism relative to controls, and (c) test the associations between hyporesponsiveness and social communication outcomes. Three groups of children ages 11-105 months (N = 178; autism = 63, developmental delay = 47, typical development = 68) are given developmental and sensory measures including a behavioral orienting task (the Sensory Processing Assessment). Lab measures are significantly correlated with parental reports of sensory hyporesponsiveness. Censored regression models show that hyporesponsiveness decreased across groups with increasing mental age (MA). Group differences are significant but depend upon two-way interactions with MA and context (social and nonsocial). At a very young MA (e.g., 6 months), the autism group demonstrates more hyporesponsiveness to social and nonsocial stimuli (with larger effects for social) than developmental delay and typically developing groups, but at an older MA (e.g., 60 months) there are no significant differences. Hyporesponsiveness to social and nonsocial stimuli predicts lower levels of joint attention and language in children with autism. Generalized processes in attention disengagement and behavioral orienting may have relevance for identifying early risk factors of autism and for facilitating learning across contexts to support the development of joint attention and language

Sensory features and repetitive behaviors in children with autism and developmental delays

This study combined parent and observational measures to examine the association between aberrant sensory features and restricted, repetitive behaviors in children with autism (N = 67) and those with developmental delays (N = 42). Confirmatory factor analysis was used to empirically validate three sensory constructs of interest: hyperresponsiveness, hyporesponsiveness, and sensory seeking. Examining the association between the three derived sensory factor scores and scores on the Repetitive Behavior Scales—Revised revealed the co-occurrence of these behaviors in both clinical groups. Specifically, high levels of hyperresponsive behaviors predicted high levels of repetitive behaviors, and the relationship between these variables remained the same controlling for mental age. We primarily found non-significant associations between hyporesponsiveness or sensory seeking and repetitive behaviors, with the exception that sensory seeking was associated with ritualistic/sameness behaviors. These findings suggest that shared neurobiological mechanisms may underlie hyperresponsive sensory symptoms and repetitive behaviors and have implications for diagnostic classification as well as intervention

A Pilot Study: Coordination of Precision Grip in Children and Adolescents with High Functioning Autism

PURPOSE: This pilot study compared temporal coordination during a precision grip task between 13 children and adolescents with autism spectrum disorders (ASD) who were high functioning and 13 peers with typical development. METHODS: Temporal coordination between grip and load forces was measured using latency between onset of grip and load forces, grip force at onset of load force, peak grip force (PGF), and time to PGF. RESULTS: Compared with peers with typical development, participants with ASD demonstrated prolonged latency between grip and load forces, elevated grip force at onset of load force, and increased movement variability. PGF and time to PGF were not significantly different between the 2 groups. CONCLUSIONS: These findings indicate temporal dyscoordination in participants with ASD. The findings also enhance our understanding of motor coordination deficits in persons with ASD and have theoretical as well as clinical implications

Early Brain Overgrowth in Autism Associated With an Increase in Cortical Surface Area Before Age 2 Years

Brain enlargement has been observed in 2 year old children with autism but the underlying mechanisms are unknown. This longitudinal MRI study investigated early growth trajectories in brain volume and cortical thickness