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BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.
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Colestase Intra-Hepática , Prurido , Humanos , Método Duplo-Cego , Masculino , Feminino , Colestase Intra-Hepática/tratamento farmacológico , Colestase Intra-Hepática/sangue , Criança , Adolescente , Pré-Escolar , Lactente , Prurido/etiologia , Prurido/tratamento farmacológico , Resultado do Tratamento , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiênciaRESUMO
In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.
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Hepatite , Hepatopatias , Transplante de Fígado , Humanos , Criança , Fígado/patologia , Hepatite/patologia , Hepatopatias/patologia , BiópsiaRESUMO
BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.
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COVID-19 , Hepatite , Pré-Escolar , Feminino , Humanos , Masculino , Doença Aguda , Estudos de Casos e Controles , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
Background & Aims: Antibody-induced bile salt export pump deficiency (AIBD) is an acquired form of intrahepatic cholestasis, which may develop following orthotopic liver transplantation (OLT) for progressive familial intrahepatic cholestasis type 2 (PFIC-2). Approximately 8-33% of patients with PFIC-2 who underwent a transplant develop bile salt export pump (BSEP) antibodies, which trans-inhibit this bile salt transporter from the extracellular, biliary side. AIBD is diagnosed by demonstration of BSEP-reactive and BSEP-inhibitory antibodies in patient serum. We developed a cell-based test directly measuring BSEP trans-inhibition by antibodies in serum samples to confirm AIBD diagnosis. Methods: Sera from healthy controls and cholestatic non-AIBD or AIBD cases were tested (1) for anticanalicular reactivity by immunofluorescence staining of human liver cryosections, (2) for anti-BSEP reactivity by immunofluorescence staining of human embryonic kidney 293 (HEK293) cells expressing BSEP-enhanced yellow fluorescent protein (EYFP) and immunodetection of BSEP-EYFP on Western blot, and (3) for BSEP trans-inhibition using HEK293 cells stably expressing Na+/taurocholate cotransporting polypeptide (NTCP)-mCherry and BSEP-EYFP. The trans-inhibition test uses [3H]-taurocholate as substrate and is divided into an uptake phase dominated by NTCP followed by BSEP-mediated export. For functional analysis, sera were bile salt depleted. Results: We found BSEP trans-inhibition by seven sera containing anti-BSEP antibodies, but not by five cholestatic or nine control sera, all lacking BSEP reactivity. Prospective screening of a patient with PFIC-2 post OLT showed seroconversion to AIBD, and the novel test method allowed monitoring of treatment response. Notably, we identified a patient with PFIC-2 post OLT with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling. Conclusions: Our cell-based assay is the first direct functional test for AIBD and allows confirmation of diagnosis as well as monitoring under therapy. We propose an updated workflow for AIBD diagnosis including this functional assay. Impact and Implications: Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect patients with PFIC-2 after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using a patient's serum and propose an updated diagnostic algorithm for AIBD.
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BACKGROUND: Acute rejection is the leading cause of mortality and morbidity for children following intestinal transplantation. Rapid detection and prompt treatment are critical; however, the only reliable method of diagnosis and monitoring is endoscopic graft biopsies. The required regular anesthetics are particularly problematic in children, and non-invasive strategies are needed. METHODS: We describe the intestinal ultrasound findings of three children before and after treatment for rejection. Ultrasounds were performed within 24 h of endoscopically obtained biopsies which were used to establish a diagnosis of rejection and to define severity. A single sonographer performed the ultrasounds and was blinded to biopsy results at the time of the scanning. These findings are provided in the context of the ultrasound appearance of seven children who had no features of rejection on surveillance biopsies. RESULTS: Intestinal ultrasound demonstrated increased bowel wall thickness, vascularity, and mesenteric inflammation during moderate to severe rejection episodes. The submucosal layer was particularly thickened, which may represent a finding more specific for rejection. All patients demonstrated improvement in all quantitative ultrasound features correlating with the resolution of acute cellular rejection on histology. Patients with no evidence of rejection on biopsy had a bowel wall thickness range of 0.9-2.8 mm, suggesting a normal upper limit of 3 mm. CONCLUSION: Moderate and severe acute rejection may be detected and response to treatment can be monitored by intestinal ultrasound and, correlating with clinical improvement, can aid in follow-up.
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Rejeição de Enxerto , Intestinos , Criança , Humanos , Intestinos/diagnóstico por imagem , Ultrassonografia , Biópsia , Rejeição de Enxerto/diagnóstico por imagem , Rejeição de Enxerto/patologiaRESUMO
BACKGROUND: Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents. METHODS: We conducted a retrospective study involving children referred to a single pediatric liver-transplantation center in the United Kingdom between January 1 and April 11, 2022. These children were 10 years of age or younger and had hepatitis that met the case definition of the U.K. Health Security Agency for confirmed acute hepatitis that was not hepatitis A through E and did not have a metabolic, inherited or genetic, congenital, or mechanical cause, in the context of a serum aminotransferase level greater than 500 IU per liter. We reviewed medical records and documented demographic characteristics, clinical features, and results of liver biochemical, serologic, and molecular tests for hepatotropic and other viruses, as well as radiologic and clinical outcomes. The outcomes were classified as an improving condition, liver transplantation, or death. RESULTS: A total of 44 children had hepatitis that met the confirmed case definition, and most were previously healthy. The median age was 4 years (range, 1 to 7). Common presenting features were jaundice (in 93% of the children), vomiting (in 54%), and diarrhea (in 32%). Among the 30 patients who underwent molecular testing for human adenovirus, 27 (90%) were positive. Fulminant liver failure developed in 6 patients (14%), all of whom received a liver transplant. None of the patients died. All the children, including the 6 who received liver transplants, were discharged home. CONCLUSIONS: In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.
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Hepatite , Falência Hepática Aguda , Transplante de Fígado , Doença Aguda , Criança , Pré-Escolar , Hepatite/etiologia , Hepatite/cirurgia , Humanos , Lactente , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/cirurgia , Transplante de Fígado/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Higher incidence of posttransplant lymphoproliferative disorder (PTLD) is reported in the pediatric small bowel transplant (SBTx) population, which may be associated with more aggressive disease and poorer outcome as compared to liver transplant (LTx) recipients. We aim to compare the characteristics and outcome of PTLD in pediatric SBTx against LTx patients at a single center. METHODS: Retrospective review of pediatric SBTx and LTx patients diagnosed with PTLD from 1989 to 2016 was conducted. Diagnosis of PTLD was biopsy-proven based on World Health Organization histologic criteria. Treatment protocol consisted of reduction of immunosuppression (RIS), rituximab (from 2000), cytotoxic T-lymphocyte (CTL) therapy (available in 1999-2004 and from 2011), and chemotherapy. RESULTS: Thirty-seven PTLD patients were included following LTx (n = 23, incidence = 2.8%) and SBTx (n = 14, incidence = 14.9%). Monomorphic PTLD made up 64% of SBTx and 43% of LTx cases. RIS alone resulted in remission in 50% of LTx patients but none of the SBTx patients (P = 0.002). Poorer overall remission (57% versus 96%, P = 0.004), 2-year (46% versus 91%, P = 0.003), and 5-year survival rates (39% versus 90%, P = 0.002) were observed in the SBTx group. Risk factors associated with mortality following PTLD were SBTx (odds ratio [OR], 12.00; 95% confidence interval [CI], 2.34-61.45; P = 0.003), monomorphic histology (OR, 10.63; 95% CI, 1.88-60.25; P = 0.008), multisite involvement (OR, 6.38; 95% CI, 1.35-30.14; P = 0.019), and tumor involvement of allograft (OR, 5.33; 95% CI, 1.14-24.90; P = 0.033). Introduction of CTL therapy was associated with improved survival. CONCLUSIONS: Majority of PTLD following pediatric SBTx are of monomorphic subtype and associated with poorer outcome as compared to LTx patients. RIS is inadequate as a single strategy in managing PTLD in SBTx and prompt escalation to rituximab and CTL is recommended.
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Infecções por Vírus Epstein-Barr/epidemiologia , Terapia de Imunossupressão/efeitos adversos , Intestino Delgado/transplante , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/epidemiologia , Adolescente , Linfócitos B/imunologia , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Masculino , Complicações Pós-Operatórias , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Linfócitos T Citotóxicos/imunologia , Transplante Homólogo/efeitos adversosRESUMO
Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.
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RNA Helicases DEAD-box/imunologia , Diarreia Infantil/imunologia , Endorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo , Retardo do Crescimento Fetal/imunologia , Doenças do Cabelo/imunologia , Imunidade Inata/imunologia , Proteínas Nucleares/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Helicases/imunologia , Proteínas de Ligação a RNA/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Proteína DEAD-box 58 , Fácies , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I/imunologia , Camundongos Endogâmicos C57BL , Proteínas/imunologiaRESUMO
We present the case of a young boy with Dent's disease, identified as having a mutation in the kidney-specific chloride-proton antitransporter CLCN5 during investigation for nephrotic-range proteinuria. He went on to develop growth hormone deficiency and was treated with recombinant growth hormone. He later presented acutely with hepatorenal failure and thrombotic occlusion of the middle and right hepatic veins consistent with a diagnosis of Budd-Chiari syndrome, which required a prolonged period of intensive care. The diagnosis of Dent's disease should be considered early in boys with nephrotic-range proteinuria in the absence of clinical oedema and hypoalbuminaemia to allow for the timely introduction of strategies, such as a high-citrate diet, to preserve renal function. The measurement of urinary ß-2 microglobulin has been shown by this case to be a more reliable and specific marker of tubular dysfunction than the urinary retinol-binding protein.
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Síndrome de Budd-Chiari/complicações , Doença de Dent/complicações , Biópsia , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/terapia , Criança , Pré-Escolar , Canais de Cloreto/genética , Terapia Combinada , Análise Mutacional de DNA , Doença de Dent/diagnóstico , Doença de Dent/genética , Doença de Dent/terapia , Nanismo Hipofisário/complicações , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/genética , Diagnóstico Precoce , Seguimentos , Hemofiltração , Humanos , Rim/patologia , Testes de Função Renal , Testes de Função Hepática , Masculino , Derivação Portossistêmica Transjugular Intra-Hepática , Microglobulina beta-2/urinaRESUMO
Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.
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Ataxia Cerebelar/genética , Síndrome de Ellis-Van Creveld/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Retinose Pigmentar/genética , Alelos , Sequência de Aminoácidos , Animais , Povo Asiático/genética , Osso e Ossos/anormalidades , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Ataxia Cerebelar/patologia , Craniossinostoses/genética , Craniossinostoses/patologia , Dineínas do Citoplasma/genética , Dineínas do Citoplasma/metabolismo , Dineínas/genética , Dineínas/metabolismo , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Síndrome de Ellis-Van Creveld/patologia , Epistasia Genética , Feminino , Fibroblastos/patologia , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Dados de Sequência Molecular , Mutação , Fenótipo , Retinose Pigmentar/patologia , População Branca/genética , Peixe-Zebra/genéticaRESUMO
Neonatal conjugated jaundice is a common presentation of hereditary liver diseases, which, although rare, are important to recognize early. Developments in molecular genetic techniques have enabled the identification of causative genes, which has improved diagnostic accuracy for patients and has led to a greater understanding of the molecular pathways involved in liver biology and pathogenesis of liver diseases. This review provides an update of the current understanding of clinical and molecular features of the inherited liver diseases that cause neonatal conjugated jaundice.
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Síndrome de Alagille/complicações , Colestase/etiologia , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/tratamento farmacológico , Síndrome de Alagille/genética , Colestase/genética , Humanos , PrognósticoRESUMO
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.
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Transporte Biológico/genética , Cílios/metabolismo , Nefropatias/genética , Mutação , Animais , Ataxia Cerebelar/genética , Criança , Estudos de Coortes , Progressão da Doença , Exoma , Humanos , Nefropatias/patologia , Masculino , Camundongos , Retinose Pigmentar/genéticaRESUMO
We report a young man presenting with jaundice and severe debilitating intrahepatic cholestasis 7 months before the diagnosis of Hodgkin's lymphoma. Serum gamma-glutamyl transferase (GGT) activity was not raised. Liver biopsy demonstrated deficiency of canalicular GGT and bile salt export pump expression, which suggested "benign" recurrent intrahepatic cholestasis. Direct sequencing of genomic DNA was therefore undertaken to look for mutations in ATP8B1 and ABCB11. Cholestasis and pruritus are well recognized presenting features of Hodgkin's lymphoma. However, striking in this case is that the intrahepatic cholestasis presented and resolved 7 months before the diagnosis. Furthermore, 4 polymorphisms were identified in ATP8B1 in this patient-c.696T > C (rs319438), c.811A > C (rs319438), c.2855G > A (rs1296811) and c.3454G > A (rs222581)-and two polymorphisms in ABCB11-c.1331T > C (rs2287622) and c.3084A > G (rs497692); 2 of which have been associated with intrahepatic cholestasis of pregnancy. We therefore postulate that these polymorphisms predisposed this patient to the development of intrahepatic cholestasis within the abnormal pro-inflammatory cytokine milieu typical for Hodgkin's lymphoma. This case shows for the first time that some polymorphisms in ABCB11 and ATP8B1 may predispose to the development of intrahepatic cholestasis in Hodgkin's lymphoma. It also demonstrates the importance of close clinical surveillance for the development of Hodgkin's lymphoma in patients presenting with unexplained intrahepatic cholestasis.
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Atresia Biliar/patologia , Cílios/patologia , Fígado/patologia , Adolescente , Atresia Biliar/genética , Atresia Biliar/metabolismo , Atresia Biliar/cirurgia , Criança , Pré-Escolar , Cílios/metabolismo , Humanos , Lactente , Doenças Renais Císticas/complicações , Fígado/metabolismo , Transplante de Fígado/efeitos adversos , Mutação , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Sistema Respiratório/fisiopatologiaRESUMO
BACKGROUND & AIMS: Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. METHODS: Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. RESULTS: Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. CONCLUSIONS: THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.
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Proteínas de Transporte/genética , Diarreia Infantil/genética , Mutação , Adolescente , Plaquetas/ultraestrutura , Criança , Biologia Computacional , Diarreia Infantil/sangue , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/análise , SíndromeRESUMO
Biliary atresia is a rare disease of infancy, which has changed within 30 years from being fatal to being a disorder for which effective palliative surgery or curative liver transplantation, or both, are available. Good outcomes for infants depend on early referral and timely Kasai portoenterostomy, and thus a high index of suspicion is needed for investigation of infants with persistent jaundice. In centres with much experience of treating this disorder, up to 60% of children will achieve biliary drainage after Kasai portoenterostomy and will have serum bilirubin within the normal range within 6 months. 80% of children who attain satisfactory biliary drainage will reach adolescence with a good quality of life without undergoing liver transplantation. Although much is known about management of biliary atresia, many aspects are poorly understood, including its pathogenesis. Several hypotheses exist, implicating genetic predisposition and dysregulation of immunity, but the cause is probably multifactorial, with obliterative extrahepatic cholangiopathy as the common endpoint. Researchers are focused on identification of relevant genetic and immune factors and understanding serum and hepatic factors that drive liver fibrosis after Kasai portoenterostomy. These factors might become therapeutic targets to halt the inevitable development of cirrhosis and need for liver transplantation.
Assuntos
Atresia Biliar/diagnóstico , Atresia Biliar/cirurgia , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/genética , Algoritmos , Atresia Biliar/epidemiologia , Atresia Biliar/etiologia , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Recém-Nascido , Icterícia Neonatal/etiologia , Transplante de Fígado , Triagem Neonatal , Cuidados Paliativos , Seleção de Pacientes , Portoenterostomia Hepática , Prognóstico , Doenças Raras , Encaminhamento e Consulta , Fatores de Risco , Resultado do TratamentoRESUMO
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.
Assuntos
Asfixia/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Doenças Renais Císticas/genética , Mutação/genética , Tetrahymena thermophila/genética , Doenças Torácicas/genética , Peixe-Zebra/genética , Animais , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Polidactilia/genética , Tetrahymena thermophila/crescimento & desenvolvimento , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
BACKGROUND: Hyaluronic acid (HA) is removed by the liver via sinusoidal cell adhesion molecules. This is impeded in fibrosis, leading to a rise in serum HA. As a noninvasive marker of fibrosis, HA may obviate the need for liver biopsy. OBJECTIVE: To evaluate HA as a marker of hepatic fibrosis, in unselected children undergoing liver biopsy. METHODS: Ninety-three unselected consecutive children (median age, 7.5 years; range, 0.07-19 years) undergoing a liver biopsy between April 2003 and March 2004 were prospectively recruited. Liver biopsy and fasting HA levels were taken simultaneously. The Ishak score was used to stage fibrosis. Scores of 3 or greater were regarded as significant fibrosis. Hyaluronic acid levels were measured using an enzyme-linked binding protein assay (2002 Corgenix, Inc) (adult reference range, 0-75 ng/mL; pediatric reference range, 0-30 ng/mL). RESULTS: Twenty-three (25%) of 93 biopsies had significant fibrosis, and HA levels in this group were significantly higher than those with mild fibrosis (Ishak score, <3), (median level, 72 ng/mL vs 30 ng/mL; Mann-Whitney U test; P < 0.005). Hyaluronic acid level of 50 ng/mL had a positive predictive value 40% and negative predictive value 86% for significant fibrosis. An HA level 200 ng/mL has a sensitivity of 26% and specificity of 90%. CONCLUSIONS: Hyaluronic Acid is a valid noninvasive predictor of hepatic fibrosis in unselected children with liver disease. An HA level of 200 ng/mL strongly suggests significant fibrosis. Hyaluronic acid level of less than 50 ng/mL accurately identifies those who do not have significant fibrosis.