Hirschsprung disease

Montalva, Louise; Cheng, Lily S.; Kapur, Raj; Langer, Jacob C.; Berrebi, Dominique; Kyrklund, Kristiina; Pakarinen, Mikko; de Blaauw, Ivo; Bonnard, Arnaud; Gosain, Ankush

doi:10.1038/s41572-023-00465-y

Cited by 20 publications

(13 citation statements)

References 227 publications

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“…Defective ENCC migration is linked to Hirschsprung's disease (HSCR), an intestinal motility disorder leading to severe intestinal obstruction in infancy. The disease is characterized by the absence of ENCs in the distal colon 4 . Previous studies have shown that genetic predispositions (such as variants of RET, SOX10, and EDNRB) and nutritional factors (such as retinoic acid deficiency) contribute to HSCR by impairing ENCC migration [4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…The disease is characterized by the absence of ENCs in the distal colon 4 . Previous studies have shown that genetic predispositions (such as variants of RET, SOX10, and EDNRB) and nutritional factors (such as retinoic acid deficiency) contribute to HSCR by impairing ENCC migration [4][5][6][7][8][9][10] . However, HSCR does not follow simple mendelian inheritance 5 10 , and extensive ENCC-derived enteric glial cells have been observed in aganglionic colons in HSCR 11 12 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Postnatal herpes simplex virus 1 infection promotes neutrophil-mediated destruction of the ENCs and HSCR-like megacolon in mice 16 . Given that the intestinal microenvironment changes dramatically after birth 4 , it is essential to determine whether abnormal intestinal factors contribute to disease aggregation postnatally. Currently, the cellular heterogeneity of human ENCs have been studied by spatial and single-cell transcriptomic sequencing 17–20 , but definitive characterization of ENCs in HSCR is lacking.…”

Section: Introductionmentioning

confidence: 99%

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Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease

Xu,

Liang,

Lan

et al. 2024

Preprint

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Objective: Enteric nervous system dysfunction is linked to digestive and neurological disorders. Hirschsprung's disease (HSCR) is characterized by the loss of enteric neuron cells (ENCs) in the distal colon. Embryonic enteric neural crest cell (ENCC) migration defects contribute to HSCR development in some infants, but postnatal factors that regulate ENC fate are undetermined. We sought to establish how postnatal changes contribute to HSCR by profiling the colonic microenvironment of HSCR infants. Design: In this study, we recruited infants with HSCR, infants with anorectal malformations but normal ENC development (CT), and an group of age-matched healthy control subjects. Laboratory findings and clinical manifestations were recorded. Single-cell and spatial transcriptome sequencing were applied to colonic tissues from a sub-cohort of CT and HSCR infants. Patient specimens, a mouse model of neonatal ischemic enterocolitis, and Sox10 knockdown mouse (Sox10WT/MUT) were used to reveal the factors that leads to ENC loss in HSCR infants. Results: We discover that intestinal ischemia promotes CLDN1+ hypertrophic nerve trunk formation and ENC death. Mechanistically, ischemia leads to defective nitric oxide (NO) signaling in ENCs, which aggravates mitochondria damage and caspase-mediated apoptosis that can be ameliorated by a NO donor drug. Conclusion: We show that ischemia contributes to postnatal ENC loss in HSCR infants and suggest that NO donor drugs may alleviate ischemia-related ENC death.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease

Xu,

Liang,

Lan

et al. 2024

Preprint

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“…Hirschsprung disease is a disorder of the enteric nervous system characterized by the absence of ganglia in the intestinal plexuses. It is a rare genetic condition, with an incidence rate typically around one out of every 5000 individuals [1]. Familial and isolated forms of Hirschsprung disease have been associated with various genetic factors, although mutations in the EDNRB and RET proto-oncogenes are commonly reported.…”

Section: Introductionmentioning

confidence: 99%

Chronic Constipation Unmasking as Hirschsprung Disease in a Preadolescent: Delayed Presentation or Delayed Diagnosis?

Bhargava,

Khedkar

2024

Cureus

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Hirschsprung disease, a rare genetic disorder affecting the enteric nervous system, is characterized by the absence of ganglion cells in the myenteric plexus. Typically identified in neonates due to the failure to pass meconium, diagnosis beyond the first year of life is considered delayed. Common clinical manifestations in children with late-onset Hirschsprung disease include abdominal distension, abdominal pain, vomiting, fever, and abnormal bowel sounds. Sigmoid volvulus, though uncommon, can complicate Hirschsprung disease, potentially leading to misdiagnosis and severe complications such as intestinal perforation, hemorrhage, sepsis, and even mortality. Non-surgical interventions such as antibiotic therapy, intestinal decompression, and fluid resuscitation are preferred initial treatments to stabilize the patient. This case involves a 9-year-old boy who has presented with abdominal distension since birth and a lengthy history of irregular bowel habits. The diagnosis of Hirschsprung disease was confirmed at our institution, and the patient underwent a two-stage repair procedure, which was completed without any intraoperative or postoperative complications. The patient experienced an uneventful recovery, was discharged with stable vital signs, and regained normal bowel function. This case highlights the challenges of delayed diagnosis at nine years and underscores the importance of prompt management.

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H3K36 methyltransferase SMYD2 affects cell proliferation and migration in Hirschsprung's disease by regulating METTL3

Hou,

Yang,

Wang

et al. 2024

Journal Cellular Physiology

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The pathogenesis of Hirschsprung's disease (HSCR) is complex. Recently, it has been found that histone modifications can alter genetic susceptibility and play important roles in the proliferation, differentiation and migration of neural crest cells. H3K36 methylation plays a significant role in gene transcriptional activation and expression, but its pathogenic mechanism in HSCR has not yet been studied. This study aimed to elucidate its role and molecular mechanism in HSCR. Western blot analysis, immunohistochemistry (IHC) and reverse transcription‐quantitative PCR (RT‒qPCR) were used to investigate H3K36 methylation and methyltransferase levels in dilated and stenotic colon tissue sections from children with. We confirm that SMYD2 is the primary cause of differential H3K36 methylation and influences cell proliferation and migration in HSCR. Subsequently, quantitative detection of m6A RNA methylation revealed that SMYD2 can alter m6A methylation levels. Western blot analysis, RT‐qPCR, co‐immunoprecipitation (co‐IP), and immunofluorescence colocalization were utilized to confirm that SMYD2 can regulate METTL3 expression and affect m6A methylation, affecting cell proliferation and migration. These results confirm that the H3K36 methyltransferase SMYD2 can affect cell proliferation and migration in Hirschsprung's disease by regulating METTL3. Our study suggested that H3K36 methylation plays an important role in HSCR, confirming that the methyltransferase SMYD2 can affect m6A methylation levels and intestinal nervous system development by regulating METTL3 expression.

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Hirschsprung disease

Cited by 20 publications

References 227 publications

Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease

Ischemia promotes hypertrophic nerve trunk formation and enteric neuron cell death in Hirschsprung’s disease

Chronic Constipation Unmasking as Hirschsprung Disease in a Preadolescent: Delayed Presentation or Delayed Diagnosis?

H3K36 methyltransferase SMYD2 affects cell proliferation and migration in Hirschsprung's disease by regulating METTL3

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