Neurodevelopmental disorders in children with macrocephaly: A prevalence study and PTEN gene analysis

Kurata, Hiroyuki; Shirai, Kentaro; Saito, Yoshiaki; Okazaki, Taro; Ohno, Kiyotaka; Oguri, Masayoshi; Adachi, Kaori; Nanba, Eiji; Maegaki, Yoshihiro

doi:10.1016/j.braindev.2017.07.005

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…Interestingly, the mTOR pathway is significantly over-represented among DAGs from multiple comparisons of our idiopathic cases and sibling controls (Tables 1–3 and 5). This pathway is highly relevant to ASD, not only because it involves a number of genes that are directly responsible for several genetically defined syndromic forms of autism, such as Fragile X and tuberous sclerosis (Persico & Bourgeron, 2006), but also because inherited mutations in PTEN , a component of the mTOR signaling pathway, can lead to an autism phenotype (Butler et al, 2005; Kurata et al, 2018; Leslie & Longy, 2016; Rademacher & Eickholt, 2019; Spinelli et al, 2015). In fact, the PTEN signaling pathway is the most significant over-represented canonical pathway among DAGs identified in the case–control analysis of the combined group of 21 sib pairs (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Yang

et al. 2020

Autism

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Although differences in DNA methylation have been associated with both syndromic and idiopathic autism, differential methylation has not been examined previously with respect to sex differences. The goals of this study were to (1) identify differences in the DNA methylation profiles of lymphoblastoid cell lines derived from a subgroup of severely affected individuals with idiopathic autism and their respective sex-matched siblings, (2) describe autism spectrum disorder–relevant pathways and functions that may be impacted by differentially methylated genes, and (3) investigate sex-dependent differences in methylation patterns and signaling pathways. Our results revealed significant differences in DNA methylation in cells from individuals with idiopathic autism spectrum disorders and from their unaffected sex-matched siblings. The samples were divided either by sex or by separation into discovery and validation groups. The genes in differentially methylated regions were statistically enriched in autism susceptibility genes and canonical pathways commonly associated with autism spectrum disorders, including synaptogenesis, semaphorin, and mammalian target of rapamycin signaling pathways. Differentially methylated region–associated genes in females were additionally associated with pathways that implicate mitochondrial dysfunction and metabolic disorders that may offer some protection against autism spectrum disorders. Further investigations of sex differences are required to develop a fuller understanding of the pathobiology, gene regulatory mechanisms, and differential susceptibility of males and females toward autism spectrum disorders. Lay abstract This study investigates altered DNA methylation that may contribute to autism spectrum disorders. DNA methylation is an epigenetic mechanism for regulating the level at which genes are expressed, and is thus complementary to genetics and gene expression analyses which look at the variations in gene structure and gene products in cells. Here, we identify DNA methylation differences between autistic and sex-matched non-autistic siblings, focusing on a subgroup of severely affected individuals with language impairment to reduce the clinical heterogeneity among the cases. Our results show significant differentially methylated genes between the sibling groups that are enriched in autism risk genes as well as in signaling and biochemical pathways previously associated with the pathobiology of autism spectrum disorders. Moreover, we show for the first time that these differences are in part sex dependent, with differentially methylated genes in females associated with pathways that implicate mitochondrial dysfunction and metabolic disorders that may offer some protection to females against autism spectrum disorders. Further investigations of sex differences are required to develop a fuller understanding of the pathobiology, gene regulatory mechanisms, and differential susceptibility of males and females toward autism spectrum disorders.

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Section: Discussionmentioning

confidence: 99%

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Yang

et al. 2020

Autism

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“…Although PHTS is recognized mainly as a hereditary cancer syndrome, numerous clinical case reports indicate a high rate of comorbidities such as macrocephaly (measured with head circumference) (43–100%) (Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ), autism spectrum disorder (ASD) (14–50%) (Balci et al, ; Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ), and intellectual dysfunction/developmental delay (31–67%) (Hansen‐Kiss et al, ; Kato et al, ; Kurata et al, ).…”

Section: Introductionmentioning

confidence: 99%

Brain morphological analysis in PTEN hamartoma tumor syndrome

Shiohama

Levman

Vasung

et al. 2020

American J of Med Genetics Pt A

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PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Megacorpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS. K E Y W O R D SHARDI, mega corpus callosum, megalencephaly, PTEN hamartoma tumor syndrome, structural brain MRI

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“…"The diversity of phenotypes now observed in PTEN mutation carriers and the numerous organs and cell types affected provide important evidence for the multiple actions of the P13K/PTEN signalling network in the regulation of many celular processes (…)" (Leslie y Longue, 2016: 30) Entre los síntomas neurológicos que afectan a más de la mitad de los afectados, cabe destacar hipotonía, retraso mental de leve a grave, dispraxia en el desarrollo, TDAH y crisis convulsivas (Martín Fernández-Mayoralas 2007: 520). Por otra parte, es común en la bibliografía la asociación de gran parte de los casos con macrocefalia a trastornos del espectro autista (Butler et al 2005;Kurata et al 2018). En menor medida y más recientemente se ha vinculado estos últimos casos con alteraciones de los tractos de sustancia blanca 20 que pueden explicar ciertos trastornos neuropsiquiátricos (Balci et al, 2017).…”

Section: A Propósito De Un Caso Pediátrico: El Síndrome De Bannayan Runclassified

El lenguaje como marco de abordaje de cromosomopatías de baja prevalencia

Varo¹

2020

Pragmalinguistica

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Neurodevelopmental disorders in children with macrocephaly: A prevalence study and PTEN gene analysis

Cited by 13 publications

References 27 publications

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Brain morphological analysis in PTEN hamartoma tumor syndrome

El lenguaje como marco de abordaje de cromosomopatías de baja prevalencia

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