Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Dec 23

PMID 36551277

Authors

Francesca Bianco

Giulia Lattanzio

Luca Lorenzini

Maurizio Mazzoni

Paolo Clavenzani

Laura Calza

Luciana Giardino

Catia Sternini

Anna Costanzini

Elena Bonora

Roberto De Giorgio

Affiliations

Soon will be listed here.

Abstract

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility.

Citing Articles

Idiopathic chronic intestinal pseudo-obstruction syndrome is strongly associated with low serum levels of vitamin D.

Panarese A, Dajti E, Eusebi L, Vestito A, Zagari R Eur J Gastroenterol Hepatol. 2024; 36(5):584-587.

PMID: 38477850 PMC: 11060052. DOI: 10.1097/MEG.0000000000002757.

Hospital admissions from the emergency department of adult patients affected by myopathies.

Monforte M, Torchia E, Bortolani S, Ravera B, Ricci E, Silvestri G Eur J Neurol. 2024; 31(5):e16214.

PMID: 38226549 PMC: 11236034. DOI: 10.1111/ene.16214.

The Oxidative Stress and Nervous Distress Connection in Gastrointestinal Disorders.

Stavely R, Ott L, Rashidi N, Sakkal S, Nurgali K Biomolecules. 2023; 13(11).

PMID: 38002268 PMC: 10669114. DOI: 10.3390/biom13111586.

References

Bauerschmidt C, Arrichiello C, Burdak-Rothkamm S, Woodcock M, Hill M, Stevens D . Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin. Nucleic Acids Res. 2009; 38(2):477-87. PMC: 2811025. DOI: 10.1093/nar/gkp976. View

Gargiulo A, Auricchio R, Barone M, Cotugno G, Reardon W, Milla P . Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. Am J Hum Genet. 2007; 80(4):751-8. PMC: 1852717. DOI: 10.1086/513321. View

Nishino I, Spinazzola A, Hirano M . Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999; 283(5402):689-92. DOI: 10.1126/science.283.5402.689. View

Assia Batzir N, Kishor Bhagwat P, Larson A, Akdemir Z, Baglaj M, Bofferding L . Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum Mutat. 2019; 41(3):641-654. PMC: 7720429. DOI: 10.1002/humu.23960. View

De Giorgio R, Sarnelli G, Corinaldesi R, Stanghellini V . Advances in our understanding of the pathology of chronic intestinal pseudo-obstruction. Gut. 2004; 53(11):1549-52. PMC: 1774265. DOI: 10.1136/gut.2004.043968. View

Moreno C, Metze K, Lomazi E, Bertola D, Barbosa R, Cosentino V . Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am J Med Genet A. 2016; 170(11):2965-2974. PMC: 5590821. DOI: 10.1002/ajmg.a.37857. View

Antonucci A, Fronzoni L, Cogliandro L, Cogliandro R, Caputo C, De Giorgio R . Chronic intestinal pseudo-obstruction. World J Gastroenterol. 2008; 14(19):2953-61. PMC: 2712158. DOI: 10.3748/wjg.14.2953. View

Lu H, Fagnant P, Krementsova E, Trybus K . Severe Molecular Defects Exhibited by the R179H Mutation in Human Vascular Smooth Muscle α-Actin. J Biol Chem. 2016; 291(41):21729-21739. PMC: 5076841. DOI: 10.1074/jbc.M116.744011. View

Rahman S, Copeland W . POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2018; 15(1):40-52. PMC: 8796686. DOI: 10.1038/s41582-018-0101-0. View

10.

Thapar N, Saliakellis E, Benninga M, Borrelli O, Curry J, Faure C . Paediatric Intestinal Pseudo-obstruction: Evidence and Consensus-based Recommendations From an ESPGHAN-Led Expert Group. J Pediatr Gastroenterol Nutr. 2018; 66(6):991-1019. DOI: 10.1097/MPG.0000000000001982. View

11.

Giordano C, Sebastiani M, De Giorgio R, Travaglini C, Tancredi A, Valentino M . Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol. 2008; 173(4):1120-8. PMC: 2543079. DOI: 10.2353/ajpath.2008.080252. View

12.

Boschetti E, Malagelada C, Accarino A, Malagelada J, Cogliandro R, Gori A . Enteric neuron density correlates with clinical features of severe gut dysmotility. Am J Physiol Gastrointest Liver Physiol. 2019; 317(6):G793-G801. PMC: 6962493. DOI: 10.1152/ajpgi.00199.2019. View

13.

Bianco F, Lattanzio G, Lorenzini L, Diquigiovanni C, Mazzoni M, Clavenzani P . Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility. Eur J Histochem. 2021; 65(s1). PMC: 8636838. DOI: 10.4081/ejh.2021.3289. View

14.

van der Werf C, Sribudiani Y, Verheij J, Carroll M, OLoughlin E, Chen C . Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations. Genet Med. 2012; 15(4):310-3. DOI: 10.1038/gim.2012.123. View

15.

Workman M, Mahe M, Trisno S, Poling H, Watson C, Sundaram N . Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med. 2016; 23(1):49-59. PMC: 5562951. DOI: 10.1038/nm.4233. View

16.

Granero Castro P, Fernandez Arias S, Moreno Gijon M, Alvarez Martinez P, Granero Trancon J, Alvarez Perez J . Emergency surgery in chronic intestinal pseudo-obstruction due to mitochondrial neurogastrointestinal encephalomyopathy: case reports. Int Arch Med. 2010; 3:35. PMC: 3018369. DOI: 10.1186/1755-7682-3-35. View

17.

Lehtonen H, Sipponen T, Tojkander S, Karikoski R, Jarvinen H, Laing N . Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy. Gastroenterology. 2012; 143(6):1482-1491.e3. DOI: 10.1053/j.gastro.2012.08.045. View

18.

Shaibani A, Shchelochkov O, Zhang S, Katsonis P, Lichtarge O, Wong L . Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol. 2009; 66(8):1028-32. PMC: 2747647. DOI: 10.1001/archneurol.2009.139. View

19.

Filosto M, Scarpelli M, Tonin P, Testi S, Cotelli M, Rossi M . Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy. J Inherit Metab Dis. 2011; 34(6):1199-203. DOI: 10.1007/s10545-011-9332-6. View

20.

Van Goethem G, Schwartz M, Lofgren A, Dermaut B, Van Broeckhoven C, Vissing J . Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet. 2003; 11(7):547-9. DOI: 10.1038/sj.ejhg.5201002. View