Preclinical testing of the ketogenic diet in fragile X mice

Westmark, Pamela R.; Gutierrez, Alejandra; Gholston, Aaron; Wilmer, Taralyn M.; Westmark, Cara J.

doi:10.1016/j.neuint.2020.104687

Cited by 18 publications

(38 citation statements)

References 96 publications

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“…There is a paucity of studies examining the effects of diet in FXS [ 11 , 14 , 15 , 19 , 20 , 21 , 22 , 23 , 24 ]. Herein, diet-responsive autistic behaviors in FXS included three behaviors in girls within the Language category (talk, speak in 3-word sentences and use words to request things), one behavior in girls within the Parent Thought Problem category (learning problem), and one behavior in boys within the Autistic Behaviors category (injure self) in association with soy-based infant formula.…”

Section: Discussionmentioning

confidence: 99%

Parental Reports on Early Autism Behaviors in Their Children with Fragile X Syndrome as a Function of Infant Feeding

Westmark

2021

Nutrients

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This study evaluates the prevalence of autistic behaviors in fragile X syndrome as a function of infant diet. Retrospective survey data from the Fragile X Syndrome Nutrition Study, which included data on infant feeding and caregiver-reported developmental milestones for 190 children with fragile X syndrome enrolled in the Fragile X Online Registry with Accessible Database (FORWARD), were analyzed. Exploratory, sex-specific associations were found linking the use of soy-based infant formula with worse autistic behaviors related to language in females and self-injurious behavior in males. These findings prompt prospective evaluation of the effects of soy-based infant formula on disease comorbidities in fragile X syndrome, a rare disorder for which newborn screening could be implemented if there was an intervention. Gastrointestinal problems were the most common reason cited for switching to soy-based infant formula. Thus, these findings also support the study of early gastrointestinal problems in fragile X syndrome, which may underly the development and severity of disease comorbidities. In conjunction with comorbidity data from the previous analyses of the Fragile X Syndrome Nutrition Study, the findings indicate that premutation fragile X mothers should be encouraged to breastfeed.

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Section: Discussionmentioning

confidence: 99%

Parental Reports on Early Autism Behaviors in Their Children with Fragile X Syndrome as a Function of Infant Feeding

Westmark

2021

Nutrients

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“…The number of trinucleotide cytosine-guanine-guanine (CGG) repeats in premutation carriers correlates with multiple plasma metabolite levels including lower levels of fatty acids and the ketone body 3-hydroxybutyrate, as well as the ratio of n -3 to n -6 fatty acids [ 51 ]. Omega-3 fatty acids are essential for brain development, and a high fat ketogenic diet is highly effective in reducing seizures and hyperactivity in Fmr1 KO mice [ 52 ]. Fmr1 KO mice exhibit reduced triglycerides, total cholesterol, carnitine, leptin and insulin, and increased levels of free fatty acid and the ketone bodies acetone and acetoacetate [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome

Westmark

2021

Nutrients

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Breastfeeding is associated with numerous health benefits, but early life nutrition has not been specifically studied in the neurodevelopmental disorder fragile X syndrome (FXS). Herein, I evaluate associations between the consumption of breast milk during infancy and the prevalence of autism, allergies, diabetes, gastrointestinal (GI) problems and seizures in FXS. The study design was a retrospective survey of families enrolled in the Fragile X Online Registry and Accessible Research Database (FORWARD). There was a 1.7-fold reduction in the prevalence of autism in FXS participants who were fed breast milk for 12 months or longer. There were strong negative correlations between increased time the infant was fed breast milk and the prevalence of autism and seizures and moderate negative correlations with the prevalence of GI problems and allergies. However, participants reporting GI problems or allergies commenced these comorbidities significantly earlier than those not fed breast milk. Parsing the data by sex indicated that males exclusively fed breast milk exhibited decreased prevalence of GI problems and allergies. These data suggest that long-term or exclusive use of breast milk is associated with reduced prevalence of key comorbidities in FXS, although breast milk is associated with the earlier development of GI problems and allergies.

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“…The sex differences in the behavioral indices is not surprising. Although until recently the consensus in animal studies was the use of only males to avoid the effect of the estrus-cycle of females, it became obvious that sex differences exist on multiple levels including the phenotype of diseases 52 and the response to treatment 53,54 . In particular, sex differences are well established in the autism field.…”

Section: Discussionmentioning

confidence: 99%

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

et al. 2020

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Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/− genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/− mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/− mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

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Preclinical testing of the ketogenic diet in fragile X mice

Cited by 18 publications

References 96 publications

Parental Reports on Early Autism Behaviors in Their Children with Fragile X Syndrome as a Function of Infant Feeding

Parental Reports on Early Autism Behaviors in Their Children with Fragile X Syndrome as a Function of Infant Feeding

Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice

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