The Fecal Microbiome and Metabolome of Pitt Hopkins Syndrome, a Severe Autism Spectrum Disorder

Dilmore, Amanda Hazel; McDonald, Daniel; Nguyen, Tanya; Adams, James B.; Krajmalnik‐Brown, Rosa; Elijah, Emmanuel O.; Dorrestein, Pieter C.; Knight, Rob

doi:10.1128/msystems.01006-21

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…There have also been reported cases of Hirschsprung’s disease in patients with Pitt-Hopkins syndrome 9. Another study has found an altered gut microbiome in patients with Pitt-Hopkins syndrome, as well as the presence of metabolites associated with inflammatory bowel disease 10…”

Section: Discussionmentioning

confidence: 99%

Complex visceral hyperalgesia in an adolescent with Pitt-Hopkins syndrome

Reaney,

Collins

2024

BMJ Case Rep

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An early-adolescent boy with a background of Pitt-Hopkins syndrome was transferred to a tertiary paediatric hospital with symptoms of a functional large bowel obstruction. He required extensive surgical intervention including a transverse colectomy, drainage of an abdominal abscess, laparotomy and adhesionolysis, and insertion of a gastrostomy and jejunostomy. He had significant ongoing issues with visceral hyperalgesia that was refractory to a wide range of pharmacological treatments and required admission to the intensive care unit on multiple occasions, and consultations with international experts in Pitt-Hopkins syndrome and pain specialists. An individualised pain plan was created and adjusted over time, with eventual good effect, and he was transferred back to his regional hospital and subsequently discharged home.

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Section: Discussionmentioning

confidence: 99%

Complex visceral hyperalgesia in an adolescent with Pitt-Hopkins syndrome

Reaney,

Collins

2024

BMJ Case Rep

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“…Clostridium bolteae has been investigated in the context of ASD and is consistently more abundant in these children compared to their NT counterparts 10 , 57 , 58 . Abundances are even higher in individuals with Pitt Hopkins syndrome 59 , a severe ASD with a high incidence of GI dysfunction. C. bolteae produces a conserved specific capsular polysaccharide which is immunogenic in rabbits and has been the focus of ASD vaccine efforts 60 , 61 .…”

Section: Discussionmentioning

confidence: 99%

Multi-angle meta-analysis of the gut microbiome in Autism Spectrum Disorder: a step toward understanding patient subgroups

West

Yin

Rutherford

et al. 2022

Sci Rep

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Observational studies have shown that the composition of the human gut microbiome in children diagnosed with Autism Spectrum Disorder (ASD) differs significantly from that of their neurotypical (NT) counterparts. Thus far, reported ASD-specific microbiome signatures have been inconsistent. To uncover reproducible signatures, we compiled 10 publicly available raw amplicon and metagenomic sequencing datasets alongside new data generated from an internal cohort (the largest ASD cohort to date), unified them with standardized pre-processing methods, and conducted a comprehensive meta-analysis of all taxa and variables detected across multiple studies. By screening metadata to test associations between the microbiome and 52 variables in multiple patient subsets and across multiple datasets, we determined that differentially abundant taxa in ASD versus NT children were dependent upon age, sex, and bowel function, thus marking these variables as potential confounders in case–control ASD studies. Several taxa, including the strains Bacteroides stercoris t__190463 and Clostridium M bolteae t__180407, and the species Granulicatella elegans and Massilioclostridium coli, exhibited differential abundance in ASD compared to NT children only after subjects with bowel dysfunction were removed. Adjusting for age, sex and bowel function resulted in adding or removing significantly differentially abundant taxa in ASD-diagnosed individuals, emphasizing the importance of collecting and controlling for these metadata. We have performed the largest (n = 690) and most comprehensive systematic analysis of ASD gut microbiome data to date. Our study demonstrated the importance of accounting for confounding variables when designing statistical comparative analyses of ASD- and NT-associated gut bacterial profiles. Mitigating these confounders identified robust microbial signatures across cohorts, signifying the importance of accounting for these factors in comparative analyses of ASD and NT-associated gut profiles. Such studies will advance the understanding of different patient groups to deliver appropriate therapeutics by identifying microbiome traits germane to the specific ASD phenotype.

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“…Homozygous CNTNAP2 deletions have been shown to cause a monogenic disease called Pitt-Hopkins-Like Syndrome 1 (PTHLS1) [ 115 , 116 , 117 ]. PTHLS1 is a rare Mendelian condition characterized by severe intellectual disability, behavioral abnormalities, psychomotor delay along with other symptoms of facial dysmorphism, stereotypic movements, breathing difficulties, and seizures [ 116 ]. Some of these patients also present autism-like behaviors.…”

Section: Discussionmentioning

confidence: 99%

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model

Memis

Mittal

Furar

et al. 2022

JCM

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2−/− rats. We observed that the BBB permeability was significantly increased in Cntnap2−/− rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2−/− rats, suggesting oxidative stress. Brain sections from Cntnap2−/− rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2−/− rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2−/− rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.

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The Fecal Microbiome and Metabolome of Pitt Hopkins Syndrome, a Severe Autism Spectrum Disorder

Abstract: GI disturbances in ASD such as severe constipation can be medically significant and often require medication. This is especially true for individuals with PTHS, suggesting that the gut microbiome may be involved in PTHS’s pathology.

Cited by 10 publications

References 26 publications

Complex visceral hyperalgesia in an adolescent with Pitt-Hopkins syndrome

Complex visceral hyperalgesia in an adolescent with Pitt-Hopkins syndrome

Multi-angle meta-analysis of the gut microbiome in Autism Spectrum Disorder: a step toward understanding patient subgroups

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model

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