<i>ACTG2</i> Variants in Pediatric Chronic Intestinal Pseudo-obstruction With Megacystis

Hahn, Jong Woo; Moon, Soo Young; Kim, Min Soo; Woo, Min Hyung; Sohn, Min Ji; Kim, Sujeong; Seong, Moon-Woo; Park, Sung Sup; Moon, Jin Soo; Ko, Jae Sung

doi:10.5056/jnm20243

Cited by 15 publications

(8 citation statements)

References 34 publications

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“…The cohort included patients from 12 families: 10 unrelated patients, 1 pair of siblings (patients 6 and 7), and an affected father (patient 8) and his 3 affected children (patients [9][10][11]. For every proband (first affected family member), histopathological evaluation had preceded molecular genetic studies.…”

Section: Patient Cohortmentioning

confidence: 99%

“…Some investigators specifically noted an absence of histological abnormalities. [3][4][5][6][7] Others reported a variety of other putative alterations in the muscularis propria including thinning of one or both muscle layers, [8][9][10] "vacuolar change", 7,9,11 intestinal neuronal dysplasia type B, 12 aplastic desmosis, 12 "disorderly arranged intramyenteric neural tissue", 13 nuclear palisading, 9 haphazard arrangement of smooth muscle cells, 13,14 muscle degeneration and fibrosis, 15 intracellular inclusion bodies, 16,17 and cytoplasmic aggregates or clumps of ACTG2-immunoreactive material. 10,16 These divergent findings prompted us to conduct a light and electron microscopic and immunohistochemical study of intestinal specimens from a series of 16 patients with pathogenic ACTG2 variants, in an effort to identify potentially distinctive features for patients with this form of visceral myopathy.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature

et al. 2022

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Background Dominant gamma-smooth muscle actin gene ( ACTG2) variants cause clinically diverse forms of visceral myopathy. Many patients undergo intestinal resection or biopsy before identification of their genetic defect. The pathology of ACTG2-variant visceral myopathy has not been evaluated systematically. Methods Glass slides, ultrastructural images, molecular genetic reports, and clinical records from 16 patients with pathogenic (15) or likely pathogenic (1) ACTG2 variants were reviewed and compared with surgical specimens from controls (no evidence of a primary myopathy or pseudo-obstruction due to Hirschsprung disease) and published descriptions. Results The variable clinical manifestations in our cohort matched those in the literature. Only non-specific light and electron microscopic findings observed in non-myopathic controls were encountered in 13 of 16 patients. The remaining 3 patients harbored hyalinized cytoplasmic inclusions in smooth muscle cells and 1 of them had polyglucosan bodies in the muscularis propria. Conclusions Apart from hyalinized inclusions, which were only observed in 3/16 patients, intestinal pathology in the majority of patients with ACTG2 variants is not indicative of an underlying visceral myopathy. Molecular testing should be considered even when no diagnostic intestinal pathology is identified.

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Section: Patient Cohortmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature

et al. 2022

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“…Moreover, apart from UFS, functional bladder outflow obstruction can be inherited as a Mendelian trait and some such individuals carry variants in genes other than HPSE2 or LRIG2. These other genes are implicated in the biology of bladder innervation, neuro-muscular transmission, or LUT smooth muscle differentiation (Weber et al, 2011 ;Caubit et al, 2016Houweling et al, 2019 ;Mann et al, 2019 ;Beaman et al, 2019;Hahn et al, 2022 ). Genetic mouse models exist for several of these human diseases and, again, could be used as models for gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2024

Preprint

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Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2 , encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral ( AAV ) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG , was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2 , the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

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“…Moreover, apart from UFS, functional bladder outflow obstruction can be inherited as a Mendelian trait and some such individuals carry variants in genes other than HPSE2 or LRIG2 . These other genes are implicated in the biology of bladder innervation, neuro-muscular transmission, or LUT smooth muscle differentiation (Weber et al , 2011; Caubit et al , 2016, Woolf et al , 2019; Houweling et al , 2019; Mann et al , 2019; Beaman et al , 2019; Hahn et al , 2022). Genetic mouse models exist for several of these human diseases and, again, could be used as models for gene therapy.…”

Section: Discussionmentioning

confidence: 99%

HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2023

Preprint

View full text Add to dashboard Cite

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the transduced genome was detected in pelvic ganglia, where human HPSE2 was also expressed. Moreover, heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, untreated mutant mice had distended urinary bladders, consistent with bladder outflow obstruction, but AAV9/HPSE2-administered mice did not, thus resembling wild-type mice. AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly ameliorated by AAV9/HPSE2. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

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ACTG2 Variants in Pediatric Chronic Intestinal Pseudo-obstruction With Megacystis

Cited by 15 publications

References 34 publications

Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature

Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

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