Arthrogryposis-renal Dysfunction-cholestasis Research Articles

Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia.

Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.

Arthrogryposis Renal Dysfunction Cholestasis Syndrome: An Uncommon Presentation in a Newborn

A preterm baby born at 35 weeks of gestation was noted to have severe limb deformities suggestive of arthrogryposis along with dysmorphic facies and developed seizures, renal dysfunction in addition to cholestasis. MRI brain showed corpus callosum agenesis. Although there are several isolated cases of arthrogryposis, the association with other congenital anomalies are rarely seen. The constellation of anomalies noted in this case along with renal tubular dysfunction and direct hyperbilirubinemia with normal GGT is suggestive of Arthrogryposis renal dysfunction Cholestasis (ARC) syndrome. It is a very rare autosomal recessive multisystem disorder resulting from mutations in the vacuolar protein sorting 33B (VPS33B) or VPS33B-interacting protein, and apical-basolateral polarity regulator (VIPAR) genes. This disorder is associated with a very poor prognosis with children seldom surviving beyond 1 year of age necessitating a detailed genetic evaluation to identify the various mutations and appropriate genetic counselling.

Laparoscopic partial internal biliary diversion through a cholecystojejunocolonic anastomosis in children: Report of a case series with a novel simplified approach

BackgroundBiliary diversion techniques have been described as an alternative for the treatment of intractable pruritus due to chronic cholestasis. The aim of this study was to describe a simplified partial internal biliary diversion by laparoscopy and to evaluate the results in these patients. MethodsBetween 2017 and 2021, three children with chronic cholestasis disease underwent Laparoscopic partial internal biliary diversion (Lapin-PIBD). The etiologies were: Alagille Syndrome, Arthrogryposis-Renal dysfunction-Cholestasis and cholestatic liver disease associated with KMT2D mutation. Laparoscopic procedure included: mobilization of the ascending colon, jejunal bowel exteriorization through the umbilical incision and creation of an isoperistaltic jejunal segment. Jejuno-jejunal anastomosis and jejuno-colonic anastomosis were performed extracorporeally. Proximal jejunum was anastomosed to the fundus of the gallbladder using intracorporeal interrupted sutures. In one case Indocyanine green (ICG) fluorescence was used to evaluate the passage of the bile through the conduit and the bowel vascularization. ResultsThree patients underwent Lapin-PIBD successfully. The median weight was 10.8 kg (5.6–16). All patients showed reduction of pruritus and liver enzymes levels at three months postoperatively. Mean follow-up was 28 months and none of the children had complications. ConclusionsLapin-BD through cholecystojejunocolonic anastomosis is an effective treatment of severe pruritus in patients with chronic cholestasis improving their quality of life. It offers the advantages of minimally invasive surgery and reduces the abdominal adhesions in patients who may require a liver transplant in the future.Level of Evidence:IV

One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype

BackgroundArthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare disease with a high mortality rate caused by VPS33B or VIPAS39 mutations. ARC syndrome typically presents with arthrogryposis, renal tubular leak and neonatal cholestatic jaundice, and most patients with this disease do not survive beyond one year.Case presentationHere, we report the case of a 13-year-old girl with ARC featuring an incomplete and mild phenotype with novel compound heterozygous mutations of VPS33B. The patient presented with arthrogryposis (claw-shaped limbs), ichthyosis, jaundice, and pruritus. Laboratory tests revealed highly evaluated levels of total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA) as well as normal levels of gamma-glutamyltransferase (GGT). However, signs of renal dysfunction, as well as other manifestations of ARC syndrome, including nervous system abnormalities, deafness, and failure to thrive, were not observed. The patient’s clinical symptoms of jaundice and pruritus were significantly alleviated by administration of ursodeoxycholic acid. Whole-exome sequencing (WES) revealed novel compound heterozygous mutations of VPS33B, c.1081 C > T (p.Q361X,257)/c.244 T > C (p.C82R). Both variants were predicted to be pathogenic in silico and have never been reported previously. To date, the patients’ cholestatic jaundice has been well controlled with continuous treatment of ursodeoxycholic acid.ConclusionsWe report the case of a Chinese female with ARC including novel compound heterozygous mutations of VPS33B and an incomplete and mild phenotype. Early diagnosis and suitable symptomatic therapies are critical for the management of ARC patients with mild manifestations and prolonged lifespan.

An infant with Cholestasis and Refractory Electrolyte Abnormalities

Arthrogryposis-renal dysfunction-cholestasis (ARC) is a rare multisystem disorder caused by mutations in the VPS33B gene, which in turn lead to a premature truncation of the gene product. This autosomal recessive disease has variations in phenotype. We report an infant girl who had severe presentation in the form of dysmorphic features, abnormal hearing assessment and refractory electrolytes disturbances. She was a product of consanguineous marriage with family history of similar presentation. The child passed away at age of 6 months due to aspiration pneumonia.

Arthrogryposis-renal Dysfunction-cholestasis Syndrome

Background: Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive disorder mostly affecting the liver, kidney, skin, as well as central nervous and musculoskeletal systems. This multisystemic disease results from mutations in the vacuolar protein sorting 33B (VPS33B) or VPS33B- interacting protein, and apical-basolateral polarity regulator (VIPAR) genes. This is a lethal disorder from which few patients can survive at the first year of their life. This syndrome exhibits a wide range of phenotypes, such as ichthyosis, hypothyroidism, agenesis of the corpus callosum, and congenital cardiovascular anomalies. Case report: Here, we present the case of a 32-day-old male neonate with respiratory distress admitted to Children's Medical Center Hospital in Tehran, Iran, in August 2019. He had ichthyosis, cholestasis with arthrogryposis as bilateral clubfeet, developmental dysplasia of the hip, and flexion contractures in upper limbs. During hospitalization, he received Shohl’s solution for metabolic acidosis, intravenous antibiotics, fat-soluble vitamins, and levothyroxine. Other presentations in our case included ichthyosis, failure to thrive, congenital heart disease, and hypothyroidism. Conclusion: Timely diagnosis, supportive care and genetic counseling should be provided for better outcome. Keywords:

Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase.

Loss of the arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome-linked Vps33B protein results in exaggerated inflammatory responses upon activation of receptors of the innate immune system in both vertebrates and flies. However, little is known about the signaling elements downstream of these receptors that are critical for the hypersensitivity of Vps33B mutants. Here, we show that p38b MAP kinase contributes to the enhanced inflammatory responses in flies lacking Vps33B. Loss of p38b mitogen-activated protein kinase (MAPK) reduces enhanced inflammatory responses and prolongs the survival of infected Vps33B deficient flies. The function of p38 MAPK is not limited to its proinflammatory effects downstream of the PGRP-LC receptor as p38 also modulates endosomal trafficking of PGRP-LC and phagocytosis of bacteria. Expression of constitutively active p38b MAPK, but not dominant negative p38b MAPK enhances accumulation of endocytosed PGRP-LC receptors or phagocytosed bacteria within cells. Moreover, p38 MAPK is required for induction of macropinocytosis, an alternate pathway for the downregulation of immune receptors. Together, our data indicate that p38 MAPK activates multiple pathways that can contribute to the dysregulation of innate immune signaling in ARC syndrome.

A 45-Day-Old Infant: A Case Report of Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) Syndrome

Introduction: Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare disorder that affects several organs. Case Presentation: In this case report, a 45-days-old infant with ARC is introduced. The findings revealed different anomalies in different organ systems. He received supportive treatment, including Shohl's solution or bicitra for treating acidosis, and fat-soluble vitamins (A, D, E, K), multivitamins and MCT oil. Conclusions: More attention must be paid to patients with arthrogryposis-renal dysfunction-cholestasis (ARC).

Identification of genes and signaling pathways associated with arthrogryposis‑renal dysfunction‑cholestasis syndrome using weighted correlation network analysis.

The present study aimed to identify the molecular basis of the arthrogryposis‑renal dysfunction‑cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co‑expression network analysis to construct a protein‑protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll‑like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix‑receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=‑0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets.

Novel VPS33B mutations of G514S gene cause an arthrogryposis, renal dysfunction and cholestasis syndrome

Introduction: Arthrogryposis-renal dysfunctioncholestasis (Arc) syndrome is a rare multisystem disorder first described in 1979 and recently attributed to mutation in VPs33b, whose product acts in intracellular trafficking. It shows wide clinical variability. the characteristic features of Arc core phenotype include arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia. In some patients, these features are sometimes accompanied by different manifestations, such as ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. Many patients with different associations of cholestasis, renal tubular acidosis, and dysmorphic morphology may be underdiagnosed. case report: We assessed the clinical characteristics of patients and investigated the VPs33b mutation in the gene G514s in a turkish patient with Arc syndrome. We reported one turkish patient with Arc syndrome, along with the presentations of renal tubular dysfunction, cholestasis, arthrogryposis, VPs33b Mutations in the gene G514s. conclusion: this case shows that the variability of different manifestations of Arc syndrome is well described.

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Trafficking of cargo through the endosomal system depends on endosomal fusion events mediated by SNARE proteins, Rab-GTPases, and multisubunit tethering complexes. The CORVET and HOPS tethering complexes, respectively, regulate early and late endosomal tethering and have been characterized in detail in yeast where their sequential membrane targeting and assembly is well understood. Mammalian CORVET and HOPS subunits significantly differ from their yeast homologues, and novel proteins with high homology to CORVET/HOPS subunits have evolved. However, an analysis of the molecular interactions between these subunits in mammals is lacking. Here, we provide a detailed analysis of interactions within the mammalian CORVET and HOPS as well as an additional endosomal-targeting complex (VIPAS39-VPS33B) that does not exist in yeast. We show that core interactions within CORVET and HOPS are largely conserved but that the membrane-targeting module in HOPS has significantly changed to accommodate binding to mammalian-specific RAB7 interacting lysosomal protein (RILP). Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome-associated mutations in VPS33B selectively disrupt recruitment to late endosomes by RILP or binding to its partner VIPAS39. Within the shared core of CORVET/HOPS, we find that VPS11 acts as a molecular switch that binds either CORVET-specific TGFBRAP1 or HOPS-specific VPS39/RILP thereby allowing selective targeting of these tethering complexes to early or late endosomes to time fusion events in the endo/lysosomal pathway.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features.

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. Diagnosis of ARC syndrome relies on clinical features, organ biopsy, and mutational analysis. However, no specific treatment currently exists for this syndrome.ConclusionThis is an overview of the latest knowledge regarding the genetic features and clinical manifestations of ARC syndrome. Greater awareness and understanding of this syndrome should allow more timely intervention with potential for improving long-term outcome.

Liver Transplant in a Case of Arthrogryposis-Renal Tubular Dysfunction-Cholestasis Syndrome With Severe Intractable Pruritus

Arthrogryposis-renal tubular dysfunction-cholestasis syndrome (MIM No. 208085) is a rare multisystem disorder involving the liver, kidney, skin, and central nervous and musculoskeletal systems. The syndrome is an autosomal-recessive trait, associated with germ-line mutations in the VPS33B gene. We report an Iranian boy of consanguineous cousin parents who had congenital deformities of the upper and lower extremities, severe ichthyosis, cholestasis, intractable pruritus, metabolic acidosis, and failure to thrive. Owing to cholestasis, severe intractable pruritus, and poor quality of life, he underwent a living-related liver transplant from his mother, and his ichthyosis and pruritus dramatically improved. To the best of our knowledge, this is a first case of someone with arthrogryposis-renal tubular dysfunction-cholestasis syndrome who underwent a liver transplant and is in good condition more than 5 years after surgery.

Orthopaedic Manifestations of Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome

Arthrogryposis-Renal dysfunction-Cholestasis (ARC) syndrome (MIM♯208085) is a rare multisystem disorder, which involves the kidney, liver, skin, and central nervous and musculoskeletal systems. It is inherited as an autosomal-recessive trait, associated with germ-line mutations in the VPS33B gene. In this study, the authors reviewed the orthopaedic manifestations of ARC syndrome. Ten patients diagnosed as having ARC syndrome were the subjects of this study. ARC syndrome was confirmed by mutation analysis in 8 of the 10 patients. Medical records and radiographs were retrospectively reviewed with a focus on musculoskeletal manifestations. Seven patients either expired at 4 to 19 months of age or were presumed to have expired. The remaining 3 patients remained alive at the time of writing this manuscript and were aged from 7 to 23 months. All patients showed musculoskeletal symptoms and/or signs, which included vertical talus (7 feet, 4 patients), pes calcaneovalgus (4 feet, 3 patients), hip dislocation (6 hips, 3 patients), pathologic fractures (5 fractures in 5 patients), and rigid kyphosis (2 patients). No surgical intervention was performed. Orthopaedic treatments, other than fracture management, were abandoned soon after diagnoses were made. ARC syndrome should be included in the differential diagnosis of arthrogryposis. As there is no specific effective treatment for renal dysfunction and cholestasis, orthopaedic intervention should be postponed until long-term survival is expected, though this is unlikely. Level IV, diagnostic studies, case series.

Arc syndrome without arthrogryposis, with hip dislocation and renal glomerulocystic appearance: a case report

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare multisystem disorder first described in 1979 and recently ascribed to mutation in VPS33B whose product acts in intracellular trafficking. It exhibits wide clinical variability. Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype, in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. Many patients with different associations of cholestasis, renal tubular acidosis, and dysmorphic morphology may be underdiagnosed. We report the third patient of ARC syndrome from Turkey with an incomplete form with renal tubular dysfunction and cholestasis in the absence of arthrogryposis but exhibiting other rare features. Our case highlights that the variability of involvement of different systems in ARC syndrome is well described; however, the renal glomerulocystic appearance has not been reported previously. Knowledge of this rare condition can benefit the practitioner as well as the patient.

The zebrafish mutantlbk/vam6resembles human multisystemic disorders caused by aberrant trafficking of endosomal vesicles

The trafficking of intracellular vesicles is essential for a number of cellular processes and defects in this process have been implicated in a wide range of human diseases. We identify the zebrafish mutant lbk as a novel model for such disorders. lbk displays hypopigmentation of skin melanocytes and the retinal pigment epithelium (RPE), an absence of iridophore reflections, defects in internal organs (liver, intestine) as well as functional defects in vision and the innate immune system (macrophages). Positional cloning, an allele screen, rescue experiments and morpholino knock-down reveal a mutation in the zebrafish orthologue of the vam6/vps39 gene. Vam6p is part of the HOPS complex, which is essential for vesicle tethering and fusion. Affected cells in the lbk RPE, liver, intestine and macrophages display increased numbers and enlarged intracellular vesicles. Physiological and behavioural analyses reveal severe defects in visual ability in lbk mutants. The present study provides the first phenotypic description of a lack of vam6 gene function in a multicellular organism. lbk shares many of the characteristics of human diseases and suggests a novel disease gene for pathologies associated with defective vesicle transport, including the arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, the Hermansky-Pudlak syndrome, the Chediak-Higashi syndrome and the Griscelli syndrome.

VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: Incomplete ARC syndrome phenotype

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare multisystem disorder first described in 1979 and recently ascribed to mutation in VPS33B, whose product acts in intracellular trafficking. Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype, in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. We describe a patient with cholestasis, aminoaciduria, ichthyosis, partial callosal agenesis, and sensorineural deafness who, although homozygous for the novel VPS33B mutation 971delA/K324fs, predicted to abolish VPS33B function, did not exhibit arthrogryposis. The phenotypes associated with VPS33B mutation may include incomplete ARC.

A genetic screen in zebrafish identifies the mutantsvps18, nf2andfoie grasas models of liver disease

Hepatomegaly is a sign of many liver disorders. To identify zebrafish mutants to serve as models for hepatic pathologies, we screened for hepatomegaly at day 5 of embryogenesis in 297 zebrafish lines bearing mutations in genes that are essential for embryonic development. Seven mutants were identified, and three have phenotypes resembling different liver diseases. Mutation of the class C vacuolar protein sorting gene vps18 results in hepatomegaly associated with large, vesicle-filled hepatocytes, which we attribute to the failure of endosomal-lysosomal trafficking. Additionally, these mutants develop defects in the bile canaliculi and have marked biliary paucity, suggesting that vps18 also functions to traffic vesicles to the hepatocyte apical membrane and may play a role in the development of the intrahepatic biliary tree. Similar findings have been reported for individuals with arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, which is due to mutation of another class C vps gene. A second mutant, resulting from disruption of the tumor suppressor gene nf2, develops extrahepatic choledochal cysts in the common bile duct, suggesting that this gene regulates division of biliary cells during development and that nf2 may play a role in the hyperplastic tendencies observed in biliary cells in individuals with choledochal cysts. The third mutant is in the novel gene foie gras, which develops large, lipid-filled hepatocytes, resembling those in individuals with fatty liver disease. These mutants illustrate the utility of zebrafish as a model for studying liver development and disease, and provide valuable tools for investigating the molecular pathogenesis of congenital biliary disorders and fatty liver disease.

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.