Familial Visceral Myopathy Research Articles

The Diverse Phenotype of Intestinal Dysmotility Secondary to ACTG2-related Disorders.

The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease. Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored. One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores. Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.

Hollow Visceral Myopathy: Diagnosis and Management

Abstract: The aetiology of hollow visceral myopathy remains poorly understood despite the review of histology and is often misdiagnosed. It is characterized by impaired intestinal function and motility in absence of mechanical obstruction, which may be familial (transmitted by a dominant or recessive gene) or sporadic. Familial visceral myopathy is a rare hereditary myopathic degeneration of both gastrointestinal (and urinary tracts) that causes chronic intestinal obstruction. Typically, it presents after the first decade of life with symptoms of abdominal distension, abdominal pain, vomiting, constipation, and diarrhoea. It is, therefore, a rare cause of chronic intestinal pseudo-obstruction. Secondary chronic intestinal pseudo-obstruction is typically managed by treating the underlying condition, however, decompression by colostomy or tube gastrostomy/enterostomy/caecostomy may be performed; this also allows for feeding and irrigation of the alimentary tract. This case study emphasizes the atypical presentation of hollow visceral myopathy and the importance of thorough investigations, the various findings during surgery (including a para-duodenal volvulus), and the different approaches to decompression of the intestinal tract that may be considered for such a patient.

Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution.

Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin γ-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

Familial visceral myopathy diagnosed by exome sequencing of a patient with chronic intestinal pseudo-obstruction

A 55-year-old woman with a history of bowel dysmotility presented with abdominal distension and peritonitis. Family history included premature deaths with intestinal symptomatology, suggesting autosomal dominant inheritance. Computed tomography showed a distended small bowel. Symptoms were alleviated by enterocutaneous stomas. Initial ileal biopsy suggested neuropathy; however, exome sequencing revealed an Arg148Ser mutation in the enteric smooth muscle actin gamma 2 (ACTG2) gene. Histological reassessment showed abnormal muscularis propria and smooth muscle actin, with the same findings in sibling, confirming familial visceral myopathy. Thus, noninvasive genomic analysis can provide early and specific diagnosis of familial visceral myopathy, which may help to avoid inappropriate surgery.

Covering the Cover

Covering the Cover

Segregation of a Missense Variant in Enteric Smooth Muscle Actin γ-2 With Autosomal Dominant Familial Visceral Myopathy

Familial visceral myopathy (FVM) is a rare inherited form of myopathic pseudo-obstruction; little is known about the genetic factors that cause this disorder. FVM is characterized by impaired functions of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. We searched for genetic factors that might cause this disorder. We performed whole-exome sequence analysis of blood samples from 2 individuals in a family that had 7 members diagnosed with FVM. Sanger sequencing was used to analyze additional family members and 280 individuals without this disorder (controls). Intestinal tissue samples from 4 patients and 2 controls were analyzed by immunohistochemistry. Functional studies, including immunofluorescence, cell contractility, and actomyosin structure analyses, were performed using CRL-1976 and U2OS sarcoma cell lines. Whole-exome sequence analysis of DNA from 2 siblings identified 83 gene variants that were shared between the siblings and considered as possible disease-causing changes. A heterozygous variant, R148S in enteric smooth muscle actin γ-2 (ACTG2), segregated with disease phenotype. Intestinal smooth muscle (muscularis propria) from individuals with FVM had reduced levels of cytoplasmic ACTG2 and abnormal accumulation of the protein into intracellular inclusions compared with controls. Sarcoma cells that expressed exogenous ACTG2(R148S) incorporated reduced amounts of this protein into actin filaments compared with cells expressing ACTG2(wt) (P < .001). ACTG2(R148S) also interfered with actin cytoskeleton organization and the contractile activities of the cells, indicating a dominant-negative effect. These findings, along with the site of the variation in the protein, indicate that ACTG2 R148S interferes with actin filament assembly. We identified the R148S variant in ACTG2 as a cause of FVM in one family. The altered ACTG2 protein appears to aggregate, rather than form actin filaments, in intestinal smooth muscle tissue. This defect could impair contraction of the visceral smooth muscle cells and reduce bowel motility.

An adult case of midgut volvulus in familial visceral myopathy

We report an adult case of midgut volvulus in familial visceral myopathy (FVM) that had affected family members over three generations. The patient was a Japanese woman in her fifties, who had chronic intestinal pseudo-obstruction (CIPO) since the age of about 40 years and had been treated chronically with conservative therapies. Her abdominal symptoms suddenly worsened and surgery became necessary. Surgery revealed a midgut volvulus secondary to intestinal malrotation and the twisted intestine was resected. Histology revealed diffuse damage of myocytes confined to the muscularis propria throughout the resected intestine. The myocytes were irregulary arranged, contained cytoplasmic inclusions, and had mild and focal vacuolar changes. The mucsularis propria showed hypertrophy with delicate interstitial fibrosis. A diagnosis of FVM was made on the basis of this characteristic myopathy. Intestinal malrotation is known to be a complication of CIPO in children, but is rare in adults. Although midgut volvulus appears to be extremely rare, it can occur after a relatively stable chronic phase in adult CIPO patients, who should be monitored carefully to assess the risk of such complications.

Type I Familial Visceral Myopathy Presenting with CT Findings of Superior Mesenteric Artery Syndrome in an Adolescent

Type I Familial Visceral Myopathy Presenting with CT Findings of Superior Mesenteric Artery Syndrome in an Adolescent

Three-generation Familial Visceral Myopathy With α-actin–positive Inclusion Bodies in Intestinal Smooth Muscle

We report the clinical and histopathologic findings of a family with 7 affected members in 3 generations suffering from autosomal dominant visceral myopathy. All patients presented with chronic intestinal pseudo-obstruction affecting especially the entire small bowel. Histologic abnormalities involved intestinal smooth muscle, with degeneration and fibrosis of the muscularis propria. In addition, the inner circular layer of the muscularis propria contained alpha-smooth muscle actin-positive and, in more advanced disease, also periodic acid-Schiff-positive inclusion bodies. The inclusions were invisible in routine hematoxylin-eosin-stained sections, but were visible in immunohistochemical stainings for alpha-smooth muscle actin. No abnormality was evident in muscularis mucosae or in blood vessels, and the findings remained unidentified in mucosal biopsy specimens. To our knowledge, this is the first reported alpha-actin-positive inclusion body finding in familial visceral myopathy.

Mitochondrial Neurogastrointestinal Encephalomyopathy: Evidence of Mitochondrial DNA Depletion in the Small Intestine

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE. By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls. The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA. Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient.

Chronic Intestinal Pseudo‐Obstruction in a Cat Caused by Visceral Myopathy

Chronic Intestinal Pseudo‐Obstruction in a Cat Caused by Visceral Myopathy

Familial visceral myopathy with pseudo-obstruction, megaduodenum, Barrett's esophagus, and cardiac abnormalities

This report describes a new subgroup of familial visceral myopathy. Three patients from within this family were admitted to the hospital with pseudo-obstruction. Barium x-ray, abdominal plain film, esophageal manometry, colonoscopy, gastroscopy, and echocardiography were performed in all siblings for diagnostic evaluation. Two of our patients had surgery because of suspicion of acute abdomen. In one of them, full-thickness biopsy, which was performed during laparotomy, revealed findings that were compatible with familial visceral myopathy. Three siblings from this family with visceral myopathy, in which the parents were consanguineous, had megaduodenum, long-segment Barrett's esophagus, and different cardiac abnormalities.

Familial hollow visceral myopathy in a pediatric patient presenting as SMA syndrome

Familial hollow visceral myopathy in a pediatric patient presenting as SMA syndrome

A very rare cause of intestinal pseudoobstruction: familial visceral myopathy type IV

A very rare cause of intestinal pseudoobstruction: familial visceral myopathy type IV

A First Report of Familial Visceral Myopathy with Additional Chylous Ascites in Two Siblings

Background: Familial visceral myopathy in two siblings, involving the intestine with concurrent chylous ascites and chylous pleural effusion, is reported. In this connection a review of the recent gastroenterologic literature was performed. Patients: In two siblings, admitted between 1992 and 1995 with increasing ascites, loss of weight, and attacks of subileus, the diagnosis of familial visceral myopathy was established. Case one: During the initial preoperative examination hepatogenous ascites was diagnosed. Visceral myopathy and chylous ascites were subsequently established by means of an explorative laparotomy in conjunction with histologic examination of specimens taken from the small-bowel wall. Case two: The patient's brother was admitted 3 years later with similar symptoms. Complaints of chylous ascites and chylous pieural effusion in connection with attacks of subileus are still present. Outcome: The female sibling was discharged from hospital with unchanged complaints and died only a few months later; the male sibling is still alive, but with unchanged complaints. Conclusions: Rare cases of familial and sporadic myopathy have been reported in the recent literature, but to our knowledge these are the first cases with concurrent chylous ascites and chylous pleural effusion in this uncommon disorder.

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIP) is one of the four major categories into which diseases causing chronic benign intestinal failure can be classfied. 1 Patients with CIP constitute about 5% of those on home parenteral nutrition (HPN) in France, the UK and the USA. 2-5 In the Italian HPN register, 6 patients with intestinal obstruction represent about 12% of the total, but no distinction is made between organic obstruction and CIP. There are fewer data on home enteral nutrition (HEN). In a survey of 3708 HEN patients, Howard reported that 3.5% had motility disorders. 7 Comparable data from the Italian HEN register 8 indicate that motility disorders accounted for 1.5% of 829 patients with benign disease. CIP is caused by the failure of the intestine to propel its contents. This leads to signs and symptoms of bowel obstruction in the absence of a demonstrable occluding lesion. 9,1° The disordered propulsion may be due to dysfunction of either the smooth muscle or the enteric nerves or both. Primary or idiopathic CIP, is a heterogeneous group of diseases in which a primary alteration of smooth muscle or the myoenteric plexus has been demonstrated. Some of these diseases are familial, others are sporadic (familial visceral myopathy, familial visceral neuropathy, achalasia, Hirsprung's hypertrophic pyloric stenosis). CIP can also be secondary to a number of other circumstances. These include systemic diseases which involve smooth muscle (connective tissue diseases, mainly scleroderma, muscular dystrophies, amyloidosis, ceroidosis); neurological disorders (primary autonomic dysfunction, multiple sclerosis, Parkinson's disease, diabetic polyneuropathy, Chagas' disease); endocrine and metabolic disorders (hypothyroidism, hypoparathyroidism, uraemia, acute intermittent porphyria); drugs (opiates, anticholinergic agents, chemotherapy, anti-depressants, tranquillisers, antiParkinsonian, anthraquinones) and a variety of unclassifiable causes (post-operative pseudo-obstruction, jejunoileal bypass, organ transplant, paraneoplastic and radiation injury). When considering both primary and secondary CIP, more cases arise from visceral myopathies than from visceral neuropathy. T]he myopathy which accompanies scleroderma is the most frequent. CIP in children affects both sexes equally, whereas in adults a female:male ratio of 2:1 has been reported. The clinical manifestations of CIP depend on the site and extent of gastrointestinal tract involved and the cause and severity of the abnormal motility. Abdominal pain, distension and vomiting are the main clinical features. Involvement of the oesophagus may produce dysphagia, regurgitation and chest pain. Localisation to the stomach causes gastroparesis with epigastric bloating and pain, nausea and vomiting. Small intestinal involvement often causes bacterial overgrowth and the stagnant loop syndrome, which may lead to diarrhoea and steatorrhoea. Localisation to the colon leads to constipation. Signs and symptoms of malnutrition as consequence of reduced intake, malabsorption or intraluminal consumption of nutrients may also contribute to the clinical features. Diagnosis of CIP relies on techniques such as radiography, scintigraphy and tracer studies for gastrointestinal transit evaluation, and manometry and histopathology. Treatment of C1P involves drugs which act on gastrointestinal motility, antibiotics for bacterial overgrowth, surgery directed at specific problems, and home artificial nutrition. None of the treatments are curative or halt any of the disorders that cause CIP, except for some types of CIP which are secondary to systemic disease. For example, thyroid disease responds favourably to treatment, but scleroderma and diabetic enteropathy do not. Patients with extensive involvement of the small intestine have the most severe features of CIP and are those who may require HPN. In these patients the prokinetic agents metoclopramide and domperidone appear to be ineffective. The uncontrolled use of cisapride in 106 patients improved the symptoms in most of them, 11 however, in another study, although it decreased intestinal transit time in patients with CIP, a controlled trial of long-term therapy did not confirm its usefulness. 12 Erythromycin induces the migrating motor complex and has been used in a few patients, but its efficacy

Spontaneous chromosomal fragility in patients with familial visceral myopathy with megaduodenum

Spontaneous chromosomal fragility in patients with familial visceral myopathy with megaduodenum

Familial visceral myopathy associated with a mitochondrial myopathy.

A 27 year old man with intestinal pseudo-obstruction who developed parenteral nutrition induced hyperlipidaemia and who also had ophthalmoplegia and an undifferentiated myopathy is described. Histological examination of biopsy specimens and molecular analysis show that this patient had both familial visceral myopathy and a mitochondrial myopathy, suggesting that a mitochondrial DNA mutation is the molecular lesion in familial visceral myopathy.

Familial visceral myopathy

A family with the autosomal dominant form of familial visceral myopathy is described involving four generations. The members illustrate several different clinical presentations including severe constipation, diarrhea, alternating constipation and diarrhea, volvulus, urinary tract infection, and retention of urine. One patient's history suggested that the uterus may have been involved. Diagnosis of this rare disease requires an awareness of the variable presentation and a careful histological examination of full-thickness sections of bowel. The potential pitfalls in both histological and clinical diagnosis of this condition are demonstrated in this family's history. The extensive involvement of small and large bowel in at least two family members is unusual in the autosomal dominant form of the disease, but their course has so far been favorable, lending further evidence to the impression that prognosis is good. This is of importance for genetic counseling of families who have this very rare disease.

Small Intestinal Manometric Studies in Patients with Familial Visceral Myopathies

We studied jejunal manometry on 10 patients with type 1 familial visceral myopathy (FVM), and one patient each with types II and III. Two patients of type I and both patients of types II and III had intestinal pseudo‐obstruction syndrome. The record was obtained in each patient for 4 to 5 hours during fasting, and 1 hour after feeding. In type I FVM, migrating motor complexes were present in six and absent in four patients. In these four patients (two with intestinal pseudo‐obstruction syndrome) with absent migrating motor complexes, there was infrequent low‐amplitude contractions during fasting, and after feeding. In six patients with migrating motor complexes, the motility indices of phases 2, 3, and fed period were 59%, 49%, and 24% of those of control subjects, respectively, and the frequency of contractions of phases 2, 3 and the fed period were 70%, 79%, and 32% of those of control subjects, respectively. In both patients with types II and III FVM, only infrequent low‐amplitude contractions were recorded during fasting and after feeding. We concluded that intestinal contractions in patients with familial visceral myopathies were weak, and the weakness was more severe in patients with intestinal pseudo‐obstruction syndrome.