Fetal Valproate Syndrome

Albayrak, Hatice Mutlu; Bulut, Cahide; Çaksen, Hüseyîn

doi:10.1016/j.pedneo.2016.01.009

Cited by 31 publications

(36 citation statements)

References 21 publications

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“…The clinically healthy progenitors and siblings of the patients showed levels of these microRNAs intermediate between those of controls and the reduced expression of patients. The same pattern was observed in two mouse models, one generated via the injection of valproic acid (VPA), a drug known to induce autism in humans [11][12][13] and rodents 14,15 and another one resulting from heterozygosity of the Cc2d1a +/− locus, a gene of the ASD constellation encoding a transcriptional repressor of serotonin receptors 16,17 . Among more than one-hundred gene reported to exhibit an altered expression pattern in human ASD instances, mice with a Cc2d1a mutation were chosen because, the loss of the gene affects serotonin receptors involved in the normal and pathological brain development [18][19][20] and mutants were considered as valuable models of ASD.…”

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confidence: 52%

A heritable profile of six miRNAs in autistic patients and mouse models

Özkul

Taheri

Bayramov

et al. 2020

Sci Rep

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Autism spectrum disorder (ASD) is a group of developmental pathologies that impair social communication and cause repetitive behaviors. The suggested roles of noncoding RNAs in pathology led us to perform a comparative analysis of the microRNAs expressed in the serum of human ASD patients. The analysis of a cohort of 45 children with ASD revealed that six microRNAs (miR-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p, and miR-499a-5p) were expressed at low to very low levels compared to those in healthy controls. A similar but less pronounced decrease was registered in the clinically unaffected parents of the sick children and in their siblings but never in any genetically unrelated control. Results consistent with these observations were obtained in the blood, hypothalamus and sperm of two of the established mouse models of ASD: valproic acid-treated animals and Cc2d1a +/− heterozygotes. In both instances, the same characteristic miRNA profile was evidenced in the affected individuals and inherited together with disease symptoms in the progeny of crosses with healthy animals. The consistent association of these genetic regulatory changes with the disease provides a starting point for evaluating the changes in the activity of the target genes and, thus, the underlying mechanism(s). From the applied societal and medical perspectives, once properly confirmed in large cohorts, these observations provide tools for the very early identification of affected children and progenitors. Autism spectrum disorders (ASDs) encompass a range of disorders characterized by impaired social interactions and communications, together with repetitive stereotypic behaviors (refs. 1-5 for recent reviews). The genetic architecture underlying the range of ASD symptoms has been investigated (reviewed by Iakoucheva et al. 1). Mutations in more than 100 genes involved in brain development and neural activity have been identified in patients and are thought to confer a risk for ASD 2,3 , but a constant association that would suggest a causal relationship has not been observed. The same conclusion was recently reached from a large-scale exon sequencing analysis 4. Hence, mouse models that reproduce characteristic elements of the disease have been developed 5. As in other instances, attention has recently been focused on a peculiar class of regulatory alterations that modifies noncoding (nc) RNAs 6 with putative regulatory functions in the synthesis of proteins. One class of these alterations comprises the genes encoding 22 nt-long RNA (often abbreviated miRNAs) that regulate the expression of homologous target genes by blocking translation and inducing the degradation of the mRNAs 7. Among the miRNA genes in the mammalian genome (several hundred in the human genome), a large subset is expressed in the brain 8 , and dysfunctions of particular miRNAs have been tentatively associated with neuropathological conditions, including ASD 9,10 , with however diverging patterns of expression. They may reflect still unknown complexities of the dis...

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confidence: 52%

A heritable profile of six miRNAs in autistic patients and mouse models

Özkul

Taheri

Bayramov

et al. 2020

Sci Rep

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“…3). The IFNg-induced decline in the cutaneous production of Cer that bear VLC N-acyl fatty acids has been further ascribed to Th2-mediated down-regulation of two fatty acid elongases, ELOVL1 and 4 [73,82]. Because VPA-exposed brains and skin exhibited a comparable increase in IFNg levels, this mechanism could explain the presence of parallel AD-like lipid biochemical alterations in the brains of VPA-exposed animals.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic overlap between atopic dermatitis and autism

Shin

Crumrine

Kim

et al. 2020

Preprint

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Background: Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as Autism Spectrum Disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation.Methods: We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various post-natal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels.Results: AD-like changes in ceramide content occurred by day one post-partum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with the early appearance of Th2 markers (i.e., interleukin [IL]-4, 5, & 13, mast cells) in the skin and brain. The high levels of interferon (IFN)g not only in skin, but also in brain likely account for a significant decrease in very-long-chain N-acyl fatty acids in brain ceramides that again mimicked known IFNg-induced changes in AD. Conclusion: The baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both the epidermis and neural tissues originate from the embryonic neuroectoderm These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that ASD could be included within the atopic diathesis.

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“…We assessed here the potential basis for the baseline association of AD with ASD in neonatal offspring of pregnant mice, who had been exposed to the anti-seizure medication, valproic acid (VPA) at 12.5d of fetal age, a standard ASD animal model [4,[45][46][47][48]. Pertinently, exposure of pregnant and neonatal humans to potential neurotoxins, like VPA and gabapentin, has been linked to severe hypersensitivity reactions [50,71,72], and the subsequent development of ASD [4,73]. Although the neuropathology resulting from toxin exposure has been assessed in this mouse model (e.g., [47,74]), the likely presence of parallel cutaneous abnormalities has been missed, likely due to the animals' furry pélage.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Overlap between Atopic Dermatitis and Autism

Shin

Crumrine

Kim

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Though multifactorial in etiology, approximately 10% of autism spectrum disorders (ASD) are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in hairless mice.Methods: We performed our studies in valproic acid (VPA)-treated hairless mice. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5, and these mice were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various post-natal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels.Results: AD-like changes in ceramide content occurred by day one post-partum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with the early appearance of Th2 markers (i.e., interleukin [IL]-4, 5, & 13, mast cells) both in the skin and brain. The high levels of interferon (IFN)g not only in skin, but also in brain likely account for a significant decrease in very-long-chain N-acyl fatty acids in brain ceramides that again mimicked known IFNg-induced changes in AD.Conclusion: The baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both the epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, and suggest further that ASD could be included within the atopic diathesis.

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Fetal Valproate Syndrome

Abstract: In conclusion, there is a recognizable spectrum of abnormalities in some infants exposed to VPA without dose-depence and the common facial dysmorphic features and minor skeletal abnormalities that may occur within the both low and high dose VPA use.

Cited by 31 publications

References 21 publications

A heritable profile of six miRNAs in autistic patients and mouse models

A heritable profile of six miRNAs in autistic patients and mouse models

Phenotypic overlap between atopic dermatitis and autism

Phenotypic Overlap between Atopic Dermatitis and Autism

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