Multi-disciplinary insights from the First European Forum on Visceral Myopathy 2022 Meeting

Visceral myopathy is a rare, life-threatening disease linked to identified genetic mutations in 60% of cases. Mostly due to the dearth of knowledge regarding its pathogenesis, effective treatments are lacking. The disease is most commonly diagnosed in children with recurrent or persistent disabling episodes of functional intestinal obstruction, which can be life threatening, often requiring long-term parenteral or specialized enteral nutritional support. Although these interventions are undisputedly life-saving as they allow affected individuals to avoid malnutrition and related complications, they also seriously compromise their quality of life and can carry the risk of sepsis and thrombosis. Animal models for visceral myopathy, which could be crucial for advancing the scientific knowledge of this condition, are scarce. Clearly, a collaborative network is needed to develop research plans to clarify genotype–phenotype correlations and unravel molecular mechanisms to provide targeted therapeutic strategies. This paper represents a summary report of the first ‘European Forum on Visceral Myopathy’. This forum was attended by an international interdisciplinary working group that met to better understand visceral myopathy and foster interaction among scientists actively involved in the field and clinicians who specialize in care of people with visceral myopathy

Single Nucleus Sequencing of Human Colon Myenteric Plexus–Associated Visceral Smooth Muscle Cells, Platelet Derived Growth Factor Receptor Alpha Cells, and Interstitial Cells of Cajal

Background and Aims: Smooth muscle cells (SMCs), interstitial cells of Cajal (ICCs), and platelet-derived growth factor receptor alpha (PDGFRα+) cells (PαCs) form a functional syncytium in the bowel known as the “SIP syncytium.” The SIP syncytium works in concert with the enteric nervous system (ENS) to coordinate bowel motility. However, our understanding of individual cell types that form this syncytium and how they interact with each other remains limited, with no prior single-cell RNAseq analyses focused on human SIP syncytium cells. Methods: We analyzed single-nucleus RNA sequencing data from 10,749 human colon SIP syncytium cells (5572 SMC, 372 ICC, and 4805 PαC nuclei) derived from 15 individuals. Results: Consistent with critical contractile and pacemaker functions and with known enteric nervous system interactions, SIP syncytium cell types express many ion channels, including mechanosensitive channels in ICCs and PαCs. PαCs also prominently express extracellular matrix–associated genes and the inhibitory neurotransmitter receptor for vasoactive intestinal peptide (VIPR2), a novel finding. We identified 2 PαC clusters that differ in the expression of many ion channels and transcriptional regulators. Interestingly, SIP syncytium cells co-express 6 transcription factors (FOS, MEIS1, MEIS2, PBX1, SCMH1, and ZBTB16) that may be part of a combinatorial signature that specifies these cells. Bowel region–specific differences in SIP syncytium gene expression may correlate with regional differences in function, with right (ascending) colon SMCs and PαCs expressing more transcriptional regulators and ion channels than SMCs and PαCs in left (sigmoid) colon. Conclusion: These studies provide new insights into SIP syncytium biology that may be valuable for understanding bowel motility disorders and lead to future investigation of highlighted genes and pathways

Generation of CHOPi012-A iPSC line from a patient with visceral myopathy-related chronic intestinal pseudo-obstruction

Visceral myopathies are debilitating conditions characterized by dysfunction of smooth muscle in visceral organs (bowel, bladder, and uterus). Individuals affected by visceral myopathy experience feeding difficulties, growth failure, life-threatening abdominal distension, and may depend on intravenous nutrition for survival. Unfortunately, our limited understanding of the pathophysiology of visceral myopathies means that current therapies remain supportive, with no mechanism-based treatments. We developed a patient-derived iPSC line with a c.769C > T p.R257C/+ mutation, the most common genetic cause of visceral myopathy. This cell line will facilitate studies of how the ACTG2 R257C heterozygous variant affects smooth muscle development and function

The Variability of Lumbar Facet Joint Synovial Cyst Recurrence Requiring Revision Surgery After Decompression-only and Decompression/Fusion

Study design: This is a retrospective study. Objective: The objective of this study was to evaluate lumbar spine synovial cyst recurrence rates of decompression-alone versus decompression/fusion procedures. Background: Improvements in imaging modalities allow for increased diagnosis and surgical treatment of symptomatic spinal juxtafacet synovial cysts. Conservative management may be used as a first-line management strategy, however rarely provides durable, effective relief of symptoms. Surgical treatment of spinal synovial cysts ranges from decompression and cyst excision to decompression with fusion procedures. Decompression procedures alone have a higher risk of recurrence of spinal synovial cysts. Methods: We retrospectively reviewed 87 patients undergoing surgical treatment of lumbar spinal juxtafacet synovial cysts as a single institution over 20 years. Surgical treatment consisted of either decompression versus decompression/fusion procedures. Preoperative symptoms included back pain, radiculopathy, motor deficits, or sensory deficits. The incidence of recurrence of spinal synovial cysts at the same-site or differing sites was compared between 2 categories of surgical treatment. Revision surgical procedure rates were also evaluated. Results: A total of 55 (63%) patients were treated with an index decompression-only procedure for the lumbar spinal synovial cyst compared with 32 (37%) patients treated with an index decompression and fusion procedure. Fifty-eight (68%) of the lumbar spinal cysts occurred at the L4-L5 level. There were 10 (11.5%) spinal synovial cyst recurrences in the decompression-only group, and 0 recurrences in the decompression/fusion group. Revision decompression procedures were performed in 4 of the 10 (4.6%) recurrences, and 6 of 10 (6.9%) recurrences had subsequent decompression and fusion surgery. The mean time to recurrence was 23.9±17.3 months. The mean length of follow-up was 65.1±48.6 months. Both recurrence and nonrecurrence cohorts had significant symptomatic improvement using Odom criteria. Conclusions: Decompression and cyst excision was the more common surgical treatment of lumbar spinal synovial cysts compared with decompression/fusion procedure in our study. The rate of synovial cyst recurrence and revision surgery in patients undergoing index decompression was relatively low and comparable to current literature. Symptomatic improvement of patients undergoing decompression versus decompression/fusion was similar in our study. Although the fusion may be required for the extent of pathology or coexisting instability, decompression and excision of spinal synovial cysts provide durable, effective treatment with a known, appropriate risk of recurrence and subsequent revision surgery

Generation of CHOPe003-A ESC line to study an ACTG2 variant affecting smooth muscle development and function

Dysfunction of visceral smooth muscle (“visceral myopathy”) impairs bowel, bladder, and uterine function. Symptoms of this life-threatening condition include massive intestinal distension with slow transit, vomiting, feeding intolerance, growth failure, poor bladder emptying, and difficult vaginal delivery. The most common genetic cause of visceral myopathy is a heterozygous point mutation (R257C) in gamma smooth muscle actin (ACTG2). We genetically modified the WAe0009-A human embryonic stem cell line to carry the c.769C>T p.R257C/+ mutation. This cell line will facilitate studies of how the ACTG2 R257C heterozygous variant affects smooth muscle development and function

Anatomic Considerations in the Lateral Transpsoas Interbody Fusion

Study design: This is a retrospective case series. Objective: Define the anatomic variations and the risk factors for such within the operative corridor of the transpsoas lateral interbody fusion. Summary of background data: The lateral interbody fusion approach has recently been associated with devastating complications such as injury to the lumbosacral plexus, surrounding vasculature, and bowel. A more comprehensive understanding of anatomic structures in relation to this approach using preoperative imaging would help surgeons identify high-risk patients potentially minimizing these complications. Materials and methods: Age-sex distributed, naive lumbar spine magnetic resonance imagings (n=180) were used to identify the corridor for the lateral lumbar interbody approach using axial images. Bilateral measurements were taken from L1-S1 to determine the locations of critical vascular, intraperitoneal, and muscular structures. In addition, a subcohort of scoliosis patients (n=39) with a Cobb angle \u3e10 degrees were identified and compared. Results: Right-sided vascular anatomy was significantly more variant than left (9.9% vs. 5.7%; P=0.001). There were 9 instances of at-risk vasculature on the right side compared with 0 on the left (P=0.004). Age increased vascular anatomy variance bilaterally, particularly in the more caudal levels (P≤0.001). A rising-psoas sign was observed in 26.1% of patients. Bowel was identified within the corridor in 30.5% of patients and correlated positively with body mass index (P Conclusions: Given the risks and complications associated with this approach, careful planning must be taken with an understanding of vulnerable anatomic structures. Our analysis suggests that approaching the intervertebral space from the patient\u27s left may reduce the risk of encountering critical vascular structures. Similarly, in the setting of scoliosis, an approach toward the concave side may have a more predictable course for surrounding anatomy. Level of evidence: Level 3-study