Macrocephaly in Children and Adults With Autism

University of Utah, Salt Lake City 84108, USA.
Journal of the American Academy of Child & Adolescent Psychiatry (Impact Factor: 7.26). 03/1997; 36(2):282-90. DOI: 10.1097/00004583-199702000-00019
Source: PubMed


To explore the frequency and onset of macrocephaly in autism and its relationship to clinical features.
Head circumferences at birth, during early childhood, and at the time of examination were studied in a community-based sample of autistic children and adults. The authors investigated whether head circumference at the time of examination was associated with clinical features.
Fourteen percent of the autistic subjects had macrocephaly: 11% of males and 24% of females. In most, the macrocephaly was not present at birth; in some it became apparent in early and middle childhood as a result of increased rate of head growth. A small relationship was noted between head circumference percentile and less severe core features of autism. Neither macrocephaly nor head circumference percentile was associated with nonverbal IQ, verbal status, seizure disorder, neurological soft signs or minor physical anomalies in the autistic subjects.
Macrocephaly is common in autism and usually is not present at birth. Rates of head growth may be abnormal in early and middle childhood in some (37%) children with autism. Macrocephaly does not define a homogeneous subgroup of autistic individuals according to clinical features.

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    • "Our findings, like those of previous (Seifert et al. 2010) and more recent studies (Edmonson et al. 2014; Zeidán-Chuliá et al. 2014), indicate a role for astrocyte–neuron interaction in the pathogenesis of ASD and epilepsies and suggest that astroglial dysfunction deserves additional investigation in AEP. Interestingly , phenotypic dissection in over 200 patients (Valvo et al. 2013) has also suggested that macrocephaly (defined as head circumference [HC] greater than the 97th percentile ), together with generalized somatic overgrowth, predisposes to early-onset seizures in idiopathic ASD (Lainhart et al. 1997). It is tempting to hypothesize that shared pathogenic mechanisms might explain the concurrence of brain/cranial overgrowth, seizures (or paroxysmal EEG activity), and the neurobehavioral dysfunction characterizing ASD and thus allow the definition of an even more selective endophenotype (namely, the macrocephaly autism–epilepsy phenotype, MAEP). "
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    ABSTRACT: The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism–epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron–glia communication. Macrocephaly is also often comorbid with autism–epilepsy (autism–epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte–neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This “endophenotype-oriented” study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders.
    No preview · Article · Nov 2015 · Neuromolecular medicine
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    • "Both white matter and grey matter exhibit markedly slowed rates of growth during this stage (Courchesne et al., 2001). By late childhood, adolescence, or young adulthood, depending on the study, mean brain volumes in autism and normal control samples do not differ, even though mean head circumference and rates of macrocephaly remain increased in the autism groups (Lainhart et al., 1997; Courchesne et al., 2001; Hardan et al., 2001; Aylward et al., 2002). In contrast with typical development, however, adolescence and young adulthood in autism are often periods when cognitive and behavioural functioning plateaus or deteriorates. "
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    ABSTRACT: The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross-sectional and longitudinal sample of autistic subjects and age- and gender-matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3-36 years) and 60 males with typical development (mean age = 18 years; range 4-39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood.
    Full-text · Article · Apr 2014 · Brain
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    • "Of relevance to autism, the low activity allele has been associated with increased severity of a range of social and behavioral difficulties, including sensory behaviors, arousal regulation, aggression, social communication skills [54,55], a lower IQ [54], and, through our previous work, cerebral cortical enlargement [9]. This association with brain structure is noteworthy because increased head circumference and enlargement of the cerebral cortex are highly replicable biological correlates of autism [16,56]. "
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    ABSTRACT: Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS. Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles. MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10. The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.
    Full-text · Article · Mar 2014 · Journal of Neurodevelopmental Disorders
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