Publications by authors named "Muriel Girard"

35 Publications

Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease.

Pediatr Nephrol 2021 May 9;36(5):1165-1173. Epub 2020 Nov 9.

Department of Gastroenterology-Hepatology-Nutrition, Reference Center for Biliary Atresia and Cholestatic Genetic Diseases, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood.

Methods: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study.

Results: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt.

Conclusions: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
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http://dx.doi.org/10.1007/s00467-020-04808-9DOI Listing
May 2021

Long term outcome of MPI-CDG patients on D-mannose therapy.

J Inherit Metab Dis 2020 11 9;43(6):1360-1369. Epub 2020 Aug 9.

Inserm U1151, Institut Necker Enfants-Malades, Paris, France.

Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.
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http://dx.doi.org/10.1002/jimd.12289DOI Listing
November 2020

Congenital portosystemic shunts: Vascular liver diseases: Position papers from the francophone network for vascular liver diseases, the French Association for the Study of the Liver (AFEF), and ERN-rare liver.

Clin Res Hepatol Gastroenterol 2020 09 9;44(4):452-459. Epub 2020 Apr 9.

French Network for Rare Liver Diseases (FILFOIE), European Reference Network (ERN) "Rare-Liver" Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; Department of Hepatology, DHU Unity, Beaujon Hospital, AP-HP, 100, boulevard du Général-Leclerc, 92118 Clichy, France.

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http://dx.doi.org/10.1016/j.clinre.2020.03.004DOI Listing
September 2020

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

J Inherit Metab Dis 2020 07 21;43(4):671-693. Epub 2020 Apr 21.

Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.
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http://dx.doi.org/10.1002/jimd.12241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574589PMC
July 2020

Early Bacterial Infections After Pediatric Liver Transplantation in the Era of Multidrug-resistant Bacteria: Nine-year Single-center Retrospective Experience.

Pediatr Infect Dis J 2020 08;39(8):e169-e175

From the Service de réanimation et surveillance continue médico-chirurgicales pédiatriques, Hôpital Necker Enfants Malades, AP-HP, Université de Paris, Paris, France.

Background: Early bacterial infection is a major and severe complication after liver transplantation (LT). The rise of antimicrobial resistance, especially extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), is a growing concern for these patients. This study aimed to assess the epidemiology of early bacterial infections in a pediatric population, including those caused by multidrug-resistant (MDR) pathogens, and to identify risk factors for infection.

Methods: We conducted a monocentric retrospective study including 142 consecutive LTs performed in 137 children between 2009 and 2017.

Results: Ninety-three bacterial infections occurred after 67 (47%) LTs. Among the 82 isolated pathogens, the most common was Klebsiella pneumoniae (n = 19, 23%). Independent risk factors for early bacterial infection were low weight [odds ratio (OR) = 0.96; 95% confidence interval (CI): 0.9-0.99; P = 0.03] and the presence of a prosthetic mesh (OR = 2.4; 95% CI: 1.1-5.4; P = 0.046). Sixty-one children (45%) carried MDR bacteria and 16 infections were caused by MDR pathogens, especially ESBL-producing K. pneumoniae (n = 12). ESBL-PE stool carriage was associated with ESBL-PE infection (OR = 4.5; 95% CI: 1.4-17.4; P = 0.02). Four children died from an infection, three due to ESBL-producing K. pneumoniae.

Conclusions: This study confirmed a shift toward a predominance of Gram-negative early bacterial infections after pediatric LT. The risk factors for infection were low weight and the presence of a prosthetic mesh. ESBL-PE stool carriage was associated with ESBL-PE infection. Adapted antimicrobial prophylaxis and personalized antibiotherapy are mandatory to reduce infection prevalence and mortality.
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http://dx.doi.org/10.1097/INF.0000000000002662DOI Listing
August 2020

Hepatic manifestations of cystic fibrosis.

Curr Opin Gastroenterol 2020 05;36(3):192-198

Pediatric Hepatology Unit, Reference center for Biliary Atresia and Cholestatic Genetic Diseases, APHP-Hôpital Necker.

Purpose Of Review: Liver disease in cystic fibrosis (CF) usually develops before puberty, is often asymptomatic and slowly progressive. Multilobular cirrhosis develops in approximately 5-10% of patients by the age of 18, and is a significant contributor to the morbidity and mortality. No therapy, including ursodeoxycholic acid and cystic fibrosis transmembrane conductance regulator correctors or potentiators, has proven effective to prevent or halt the progression of liver disease towards cirrhosis and portal hypertension. This review provides the current knowledge in the epidemiology of CF liver disease and development of noninvasive tools to assess liver disease severity and progression overtime in order to optimize clinical management and therapeutic options.

Recent Findings: Liver disease not only develops during childhood but also later in the lifetime of patients with CF; the incidence of cirrhosis with portal hypertension increases progressively reaching 10% by age 30. Several noninvasive tools to measure liver stiffness as an indirect measure of fibrosis are being investigated, and show promising results for the assessment of early stages of liver fibrosis and disease progression.

Summary: Identifying noninvasive biomarkers is fundamental to improving early diagnosis, monitoring disease evolution and measuring treatment effects. A prerequisite is the use of consistent definitions for CF- liver disease (LD) in clinical trials.
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http://dx.doi.org/10.1097/MOG.0000000000000624DOI Listing
May 2020

Severe Abdominal Manifestations in Juvenile Dermatomyositis.

J Pediatr Gastroenterol Nutr 2020 02;70(2):247-251

Laboratoire d'Immunogénétique des maladies auto-immunes de l'enfant, Institut Imagine, INSERM U 1163.

Juvenile dermatomyositis (JDM) is a rare and heterogeneous pediatric-onset idiopathic inflammatory myopathy. Gastrointestinal (GI) involvement occurs in 22% to 37% of JDM patients but has only been described in case reports. In this retrospective, single-center, observational study, we aimed to assess the causes and management of severe GI manifestations in JDM patients. We studied a cohort of 9 patients among 110 JDM patients followed during the study period (8.3%). The GI complications were related to JDM in most cases (17/19), with digestive tract involvement (n = 10), acute pancreatitis (n = 4), and hepatitis (n = 3). Three patients died from refractory JDM 2.9 years (2-3.6) after the JDM diagnosis. We highlight the need to consider pancreatitis as a main diagnostic factor in JDM patients with severe GI manifestations and the requirement of early aggressive treatment for these patients.
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http://dx.doi.org/10.1097/MPG.0000000000002575DOI Listing
February 2020

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

Am J Med Genet A 2020 01 25;182(1):29-37. Epub 2019 Oct 25.

AP-HP, Service de Génétique Clinique, Necker-Enfants malades University Hospital, Paris, France.

Rationale: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS.

Methods: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES).

Results: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT.

Conclusion: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.
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http://dx.doi.org/10.1002/ajmg.a.61364DOI Listing
January 2020

Optimization of the transition process of youth with liver disease in adulthood: A position paper from FILFOIE, the French network for paediatric and adult rare liver diseases.

Clin Res Hepatol Gastroenterol 2020 04 26;44(2):135-141. Epub 2019 Sep 26.

Filière de santé maladies rares du foie de l'adulte et de l'enfant (Filfoie), France; Unité d'hépatologie pédiatrique, centre de référence de l'atrésie des voies biliaire et des cholestases génétiques, université Paris René-Descartes, hôpital Necker, AP-HP, 75014 Paris, France.

Transition describes a progressive and highly coordinated process encompassing the transfer of a young patient from paediatric care to the adult-care system. Transfer of medical care for an adolescent to adult services is a complex and challenging task requiring close collaboration of both the paediatric and adult-care providers. It must take into account the medical, psychosocial and educational needs of the young adult. The Transition Working Group of the French Network for Rare Liver Diseases (FILFOIE) proposes recommendations and tools designed to optimise the transition process of adolescents and young adults with chronic liver disease from child-based to adult-based healthcare services, focusing on three key time points: preparation before the transfer, the transfer process to the adult service, and finally reception and follow-up within the adult-care service.
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http://dx.doi.org/10.1016/j.clinre.2019.07.018DOI Listing
April 2020

Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders.

Liver Int 2020 01 13;40(1):163-174. Epub 2019 Oct 13.

INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France.

Background And Aims: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.

Methods: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing.

Results: Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population.

Conclusions: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
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http://dx.doi.org/10.1111/liv.14260DOI Listing
January 2020

Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: The French experience.

J Inherit Metab Dis 2020 03 11;43(2):234-243. Epub 2020 Feb 11.

Reference Center of Pediatric Nephrology, Hôpital Universitaire Necker-Enfants Malades, APHP, Filière ORKID, ERKnet, University Paris Descartes, Paris, France.

Organ transplantation is discussed in methylmalonic aciduria (MMA) for renal failure, and poor quality of life and neurological outcome. We retrospectively evaluated 23 French MMA patients after kidney (KT), liver-kidney (LKT), and liver transplantation (LT). Two patients died, one after LKT, one of hepatoblastoma after KT. One graft was lost early after KT. Of 18 evaluable patients, 12 previously on dialysis, 8 underwent KT (mean 12.5 years), 8 LKT (mean 7 years), and 2 LT (7 and 2.5 years). At a median follow-up of 7.3 (KT), 2.3 (LKT), and 1.0 years (LT), no metabolic decompensation occurred except in 1 KT. Plasma and urine MMA levels dramatically decreased, more after LKT. Protein intake was increased more significantly after LKT than KT. Enteral nutrition was stopped in 7/8 LKT, 1/8 KT. Early complications were frequent after LKT. Neurological disorders occurred in four LKT, reversible in one. Five years after KT, four patients had renal failure. The metabolic outcomes were much better after LKT than KT. LKT in MMA is difficult but improves the quality of life. KT will be rarely indicated. We need more long-term data to indicate early LT, in the hope to delay renal failure and prevent neurodevelopmental complications.
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http://dx.doi.org/10.1002/jimd.12174DOI Listing
March 2020

Management of Biliary Atresia in France 1986 to 2015: Long-term Results.

J Pediatr Gastroenterol Nutr 2019 10;69(4):416-424

Observatoire Français de l'Atrésie des Voies Biliaires et Centre de Référence Atrésie des Voies Biliaires-Cholestases Génétiques, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris.

Objectives: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available.

Methods: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed.

Results: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin ≤20 μmol/L) was documented in 516 patients (39%). Age at KOp (median 59 days, range 6-199) was stable over time. Survival with native liver after KOp was 41%, 35%, 26%, and 22% at 5, 10, 20, and 30 years, stable in the 4 cohorts. 25-year survival with native liver was 38%, 27%, 22%, and 19% in patients operated in the first, second, third month of life or later, respectively (P = 0.0001). Center caseloads had a significant impact on results in the 1986 to 1996 cohort only. 16%, 7%, 7%, and 8% of patients died without LT in the 4 cohorts (P = 0.0001). A total of 753 patients (55%) underwent LT. Patient survival after LT was 79% at 28 years. Five-year patient survival after LT was 76%, 91%, 88%, and 92% in cohorts 1 to 4, respectively (P < 0.0001). Actual BA patient survival (from diagnosis) was 81%. Five-year BA patient survival was 72%, 88%, 87%, and 87% in cohorts 1986 to 1996, 1997 to 2002, 2003 to 2009, and 2010 to 2015, respectively (P < 0.0001).

Conclusions: In France, 87% of patients with BA survive nowadays and 22% reach the age of 30 years without transplantation. Improvement of BA prognosis is mainly due to reduced mortality before LT and better outcomes after LT.
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http://dx.doi.org/10.1097/MPG.0000000000002446DOI Listing
October 2019

Seroprevalence of Hepatitis E virus infection in children after liver transplantation: A single-center experience in France.

Clin Res Hepatol Gastroenterol 2020 04 29;44(2):174-180. Epub 2019 Jun 29.

Unit of Pediatric Hepatology, Reference Center for Rare Pediatric Liver Diseases, Necker-Enfants-Malades University Hospital, AP-HP, 149, Sèvres Street, 75015 Paris, France; University of Paris-Descartes, Sorbonne Paris-Cité, 75006 Paris, France.

Introduction: Hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide, usually asymptomatic in children. However, a growing number of publications over the last decade have documented cases of chronic hepatitis related to HEV-genotype 3 infection, and progressing to cirrhosis in immuno-compromised patients, particularly in adult kidney transplant recipients. The aim of our study was to evaluate the prevalence and severity of HEV infection among pediatric liver transplant (PLT) recipients managed in our center.

Material And Methods: Between November 1 2014 and January 1 2016, PLT recipients (less than 18 years-old) were screened for HEV infection [determined by HEV serology, HEV- immunoglobulin M (IgM) and immunoglobulin G (IgG), and HEV-ribonucleic acid (RNA) by reverse transcriptase polymerase chain reaction] at their annual follow-up visit.

Results: Eighty children were tested for HEV infection a mean of 5.4±5.3 years after liver transplantation (LT). The main indication for LT was biliary atresia (n=47, 59%). The prevalence of HEV-IgG was 8% (n=6; age range 1.3 to 14.2 years-old at the time of HEV testing). Prevalence increased to 30% when considering only the 20 children with a past history of an unexplained episode of elevated transaminases since LT. None had HEV IgM, serum HEV-RNA, or increased transaminases at the time of HEV testing. Among the six IgG seropositive children, two had received intravenous immunoglobulins prior to screening and four children had a negative control (seroreversion) 3 to 42 months after the first testing.

Conclusion: The prevalence of HEV infection in our cohort is low and similar to other pediatric reports. We saw no cases of chronic hepatitis or fibrosis attributable to HEV. The lower immunosuppressive regimen used in PLT children compared to other solid organ transplant recipients may account for this good outcome.
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http://dx.doi.org/10.1016/j.clinre.2019.06.002DOI Listing
April 2020

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα.

Nat Commun 2019 04 5;10(1):1566. Epub 2019 Apr 5.

Institut Necker-Enfants Malades (INEM), 75014, Paris, France.

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.
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http://dx.doi.org/10.1038/s41467-019-09598-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451001PMC
April 2019

Genetics in biliary atresia.

Curr Opin Gastroenterol 2019 03;35(2):73-81

INSERM U1151/CNRS UMR 8253, Institut Necker-Enfants Malades (INEM), Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Purpose Of Review: Biliary atresia is a poorly understood deadly disease. Genetic predisposition factors are suspected albeit not firmly established. This review summarizes recent evidence of genetic alterations in biliary atresia.

Recent Findings: Whole-genome association studies in biliary atresia patients identified four distinct predisposition loci with four different genes potentially involved in the disease occurrence. Variations in these genes were searched for, but none were found in patients with biliary atresia suggesting complex mechanisms.

Summary: Despite decades since its description and decades of intensive researches, cause of biliary atresia disease remains enigmatic. The inheritance of biliary atresia is not Mendelian. Genetic predisposition factor is one of the explored fields to explain biliary atresia pathogenicity. Biliary atresia has been associated with several inborn syndromes, chromosome anomalies, and gene polymorphisms in specific populations. Four predisposition loci encompassing genes relevant to the disease have been identified, but no pathogenic variations were found in biliary atresia patients. Few reported cases of isolated biliary atresia manifestation in the context of known genetic diseases suggest coincidental findings. Alternatives to classic genetic alterations are proposed to explain genetic predisposition in biliary atresia including noncoding and epigenetic factors. Biliary atresia is most likely related to complex traits making its genetic exploration challenging.
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http://dx.doi.org/10.1097/MOG.0000000000000509DOI Listing
March 2019

CCDC115-CDG: A new rare and misleading inherited cause of liver disease.

Mol Genet Metab 2018 07 9;124(3):228-235. Epub 2018 May 9.

AP-HP, Bichat University Hospital, Biochemistry, Paris, France; INSERM UMR-1193 "Mécanismes cellulaires et moléculaires de l'adaptation au stress et cancérogenèse", Université Paris-Sud, Châtenay-Malabry, France. Electronic address:

Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed.
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http://dx.doi.org/10.1016/j.ymgme.2018.05.002DOI Listing
July 2018

Type I interferon-mediated autoinflammation due to DNase II deficiency.

Nat Commun 2017 12 19;8(1):2176. Epub 2017 Dec 19.

Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.
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http://dx.doi.org/10.1038/s41467-017-01932-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736616PMC
December 2017

Preoperative risk factors for intra-operative bleeding in pediatric liver transplantation.

Pediatr Transplant 2016 Dec 29;20(8):1065-1071. Epub 2016 Sep 29.

Pediatric surgery unit, Hôpital Necker enfants malades, Paris, France.

This study analyzes the preoperative risk factors for intra-operative bleeding in our recent series of pediatric LTs. Between November 2009 and November 2014, 84 consecutive isolated pediatric LTs were performed in 81 children. Potential preoperative predictive factors for bleeding, amount of intra-operative transfusions, postoperative course, and outcome were recorded. Cutoff point for intra-operative HBL was defined as intra-operative RBC transfusions ≥1 TBV. Twenty-six patients (31%) had intra-operative HBL. One-year patient survival after LT was 66.7% (CI 95%=[50.2-88.5]) in HBL patients and 83.8% (CI 95%=[74.6-94.1]) in the others (P=.054). Among 13 potential preoperative risk factors, three of them were identified as independent predictors of high intra-operative bleeding: abdominal surgical procedure(s) prior to LT, factor V level ≤30% before transplantation, and ex situ parenchymal transsection of the liver graft. Based on these findings, we propose a simple score to predict the individual hemorrhagic risk related to each patient and graft association. This score may help to better anticipate intra-operative bleeding and improve patient's management.
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http://dx.doi.org/10.1111/petr.12794DOI Listing
December 2016

DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.

Hum Mutat 2016 10 24;37(10):1025-9. Epub 2016 Aug 24.

Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.

Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.
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http://dx.doi.org/10.1002/humu.23031DOI Listing
October 2016

Biliary atresia: Clinical advances and perspectives.

Clin Res Hepatol Gastroenterol 2016 Jun 5;40(3):281-287. Epub 2016 Jan 5.

Pediatric Hepatology Unit, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; UMR1163, Imagine Institute, hôpital Necker-Enfants-Malades, Paris, France. Electronic address:

Biliary atresia (BA) is a rare and severe inflammatory and obliterative cholangiopathy that affects both extra- and intrahepatic bile ducts. BA symptoms occur shortly after birth with jaundice, pale stools and dark urines. The prognosis of BA has dramatically changed in the last decades: before the Kasai operation most BA patients died, while nowadays with the sequential treatment with Kasai operation±liver transplantation BA patient survival is close to 90%. Early diagnosis is very important since the chances of success of the Kasai procedure decrease with time. The causes of BA remain actually unknown but several mechanisms including genetic and immune dysregulation may probably lead to the obliterative cholangiopathy. Current research focuses on the identification of blood or liver factors linked to the pathogenesis of BA that could become therapeutic targets and avoid the need for liver transplantation. No similar disease leading to total obstruction of the biliary tree exists in older children or adults. But understanding the physiopathology of BA may highlight the mechanisms of other destructive cholangiopathies, such as sclerosing cholangitis.
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http://dx.doi.org/10.1016/j.clinre.2015.11.010DOI Listing
June 2016

Influence of donor-recipient CYP3A4/5 genotypes, age and fluconazole on tacrolimus pharmacokinetics in pediatric liver transplantation: a population approach.

Pharmacogenomics 2014 Jun;15(9):1207-21

Laboratory of Analytical Biochemistry, Cliniques Universitaires Saint-Luc & Louvain Centre for Toxicology & Applied Pharmacology (LTAP), UCL, Avenue Mounier 53, Box B1-52-12, 1200, Brussels, Belgium.

Aim: To characterize the effect of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes as well as relevant patient characteristics on tacrolimus pharmacokinetics in pediatric liver transplantation.

Patients & Methods: Data from 114 pediatric liver transplant recipients were retrospectively collected during the first 3 months following transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling, including characterization of influential covariates.

Results: A two-compartment model with first order elimination best fitted the data. Estimates of apparent volume of the central compartment, intestinal clearance, hepatic clearance and intercompartmental clearance were 79 l, 0.01 l/h, 10.9 l/h and 105 l/h, respectively. Time post-transplantation, recipient age, donor CYP3A5 and CYP3A4 genotypes and fluconazole administration significantly influenced tacrolimus apparent clearance while bodyweight influenced volume of distribution.

Conclusion: The proposed model displayed acceptable fitting performances and enabled identification of statistically significant and clinically relevant covariates on tacrolimus pharmacokinetics in the early pediatric post liver transplantation period.
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http://dx.doi.org/10.2217/pgs.14.75DOI Listing
June 2014

MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease.

Hepatology 2014 Jul 27;60(1):301-10. Epub 2014 May 27.

Department of Pediatric Gastroenterology and Hepatology, Necker Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes-Sorbonne Cité, Paris, France; INSERM, UMR 781, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.

Unlabelled: Microvillous inclusion disease (MVID) is a congenital disorder of the enterocyte related to mutations in the MYO5B gene, leading to intractable diarrhea often necessitating intestinal transplantation (ITx). Among our cohort of 28 MVID patients, 8 developed a cholestatic liver disease akin to progressive familial intrahepatic cholestasis (PFIC). Our aim was to investigate the mechanisms by which MYO5B mutations affect hepatic biliary function and lead to cholestasis in MVID patients. Clinical and biological features and outcome were reviewed. Pretransplant liver biopsies were analyzed by immunostaining and electron microscopy. Cholestasis occurred before (n = 5) or after (n = 3) ITx and was characterized by intermittent jaundice, intractable pruritus, increased serum bile acid (BA) levels, and normal gamma-glutamyl transpeptidase activity. Liver histology showed canalicular cholestasis, mild-to-moderate fibrosis, and ultrastructural abnormalities of bile canaliculi. Portal fibrosis progressed in 5 patients. No mutation in ABCB11/BSEP or ATP8B1/FIC1 genes were identified. Immunohistochemical studies demonstrated abnormal cytoplasmic distribution of MYO5B, RAB11A, and BSEP in hepatocytes. Interruption of enterohepatic BA cycling after partial external biliary diversion or graft removal proved the most effective to ensure long-term remission.

Conclusion: MVID patients are at risk of developing a PFIC-like liver disease that may hamper outcome after ITx. Our results suggest that cholestasis in MVID patients results from (1) impairment of the MYO5B/RAB11A apical recycling endosome pathway in hepatocytes, (2) altered targeting of BSEP to the canalicular membrane, and (3) increased ileal BA absorption. Because cholestasis worsens after ITx, indication of a combined liver ITx should be discussed in MVID patients with severe cholestasis. Future studies will need to address more specifically the effect of MYO5B dysfunction in BA homeostasis.
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http://dx.doi.org/10.1002/hep.26974DOI Listing
July 2014

A patient with Simpson-Golabi-Behmel syndrome, biliary cirrhosis and successful liver transplantation.

Am J Med Genet A 2014 Mar 19;164A(3):774-7. Epub 2013 Dec 19.

Medical Genetics Unit, Centre Hospitalier Universitaire d'Amiens, Amiens, France.

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) -OMIM 312870- is a rare X-linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre- and post-natal macrosomia, distinctive facial dysmorphism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patient's liver disease is also proposed.
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http://dx.doi.org/10.1002/ajmg.a.36335DOI Listing
March 2014

Genetic variations creating microRNA target sites in the FXN 3'-UTR affect frataxin expression in Friedreich ataxia.

PLoS One 2013 30;8(1):e54791. Epub 2013 Jan 30.

INSERM U781 Hôpital Necker-Enfants Malades, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.

Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by GAA repeat expansion within the first intron of the frataxin gene. It has been suggested that the repeat is responsible for the disease severity due to impaired transcription thereby reducing expression of the protein. However, genotype-phenotype correlation is imperfect, and the influence of other gene regions of the frataxin gene is unknown. We hypothesized that FRDA patients may harbor specific regulatory variants in the 3'-UTR. We sequenced the 3'-UTR region of the frataxin gene in a cohort of 57 FRDA individuals and 58 controls. Seven single nucleotide polymorphisms (SNPs) out of 19 were polymorphic in our case-control sample. These SNPs defined several haplotypes with one reaching 89% of homozygosity in patients versus 24% in controls. In another cohort of 47 FRDA Reunionese patients, 94% patients were found to be homozygous for this haplotype. We found that this FRDA 3'-UTR conferred a 1.2-fold decrease in the expression of a reporter gene versus the alternative haplotype configuration. We established that differential targeting by miRNA could account for this functional variability. We specifically demonstrated the involvement of miR-124 (i.e hsa-mir-124-3p) in the down-regulation of FRDA-3'-UTR. Our results suggest for the first time that post-transcriptional regulation of frataxin occurs through the 3'-UTR and involves miRNA targeting. We propose that the involvement of miRNAs in a FRDA-specific regulation of frataxin may provide a rationale to increase residual levels of frataxin through miRNA-inhibitory molecules.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559822PMC
August 2013

MicroRNAs in genetic disease: rethinking the dosage.

Curr Gene Ther 2012 Aug;12(4):292-300

Inserm U-Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.

To date, the general assumption was that most mutations interested protein-coding genes only. Thus, only few illustrations have mentioned here that mutations may occur in non-protein coding genes such as microRNAs (miRNAs). We thus report progress in delineating their contribution as phenotypic modulators, genetic switches and fine-tuners of gene expression. We reasoned that browsing their contribution to genetic disease may provide a framework for understanding the proper requirements to devise miRNA-based therapy strategies, in particular the relief of an appropriate dosage. Gain and loss of function of miRNA enforce the need to respectively antagonize or supply the miRNAs. We further categorized human disease according to the different ways in which the miRNA was altered arising either de novo, or inherited whether as a mendelian or as an epistatic trait, uncovering its role in epigenetics. We discuss how improving our knowledge on the contribution of miRNAs to genetic disease may be beneficial to devise appropriate gene therapy strategies.
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http://dx.doi.org/10.2174/156652312802083602DOI Listing
August 2012

Specificities of sclerosing cholangitis in childhood.

Clin Res Hepatol Gastroenterol 2012 Dec 23;36(6):530-5. Epub 2012 May 23.

Pôle médicochirurgical, Hépatologie Pédiatrique, Hôpital Universitaire Necker-Enfants-Malades, AP-HP, 149, rue de Sèvres, 75015 Paris, France.

Sclerosing cholangitis (SC) is a chronic cholestatic disease characterized by inflammation and obliterative fibrosis of the bile ducts, leading to biliary cirrhosis and ultimately to liver failure. Four main clinical forms can be distinguished in children: i) neonatal SC, most probably a genetic disease transmitted by autosomal recessive inheritance; ii) SC associated with strong features of autoimmunity (referred as autoimmune sclerosing cholangitis) with quite good response to immuno-suppression iii) primary SC of unknown etiology (i.e. without features of autoimmunity) and iv) SC secondary to various diseases, including Langerhans cell histiocytosis and immunodeficiencies. Ursodesoxycholic acid is considered the treatment of choice for all forms of SC but without proof of its effectiveness in preventing progression to secondary biliary cirrhosis. In patients with immunodeficiencies, early bone marrow transplantation is the only way to prevent secondary SC. Liver transplantation remains the only validated treatment in children with biliary cirrhosis. Recurrence of SC after liver transplantation has not been clearly demonstrated in children; however, recurrence of Langerhans cell histiocytosis with bile duct injury has been reported. For patients with severe immunodeficiency, a two-step liver then bone marrow transplantation protocol may be proposed.
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http://dx.doi.org/10.1016/j.clinre.2012.04.003DOI Listing
December 2012

Biliary atresia: does ethnicity matter?

J Hepatol 2012 Sep 14;57(3):700-1; author reply 702. Epub 2012 Apr 14.

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http://dx.doi.org/10.1016/j.jhep.2012.03.011DOI Listing
September 2012

Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy.

Proc Natl Acad Sci U S A 2012 Mar 12;109(13):4980-5. Epub 2012 Mar 12.

Département de Génétique and Groupe de Recherche Immunopathologies et Maladies Infectieuses, Université de La Réunion, Centre Hospitalier Régional de La Réunion, 97405 Saint-Denis, La Réunion, France.

The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.
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http://dx.doi.org/10.1073/pnas.1111596109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323976PMC
March 2012

[Cholelithiasis in infants, children and adolescents].

Presse Med 2012 May 21;41(5):466-73. Epub 2011 Nov 21.

AP-HP, CHU Necker-Enfants-Malades, pôle médicochirurgical, hépatologie pédiatrique, 75015 Paris, France.

The prevalence of cholelithiasis is estimated within 0.13% and 2% of children under 19 years of age. Pigment stones are the commonest type of gallstones in children, without recognizable predisposing factors in infants or secondary to a predisposing disease such as chronic hemolysis and ileal disease in children. In adolescents, idiopathic cholesterol gallstones accounts for the majority, such as in adults. Gallbladder stones are found in 80 to 90% of cases and common bile duct stones in 10 to 20% of cases. When common bile duct stones are found, a choledocal cyst with anomalous pancreatobiliary duct junction needs to be excluded. Magnetic resonance cholangiopancreatography should be performed in first line. Cholecystectomy is not indicated for silent gallstones, except in children with a predisposing disease such as chronic hemolysis. Treatment of common bile duct stones includes interventional radiologic, endoscopic or surgical procedures. Stone extraction may be performed at endoscopic retrograde cholangiopancreatography with or without sphincterotomy, combined with laparoscopic cholecystectomy. In children without a predisposing disease or no residual gallstones indicating a cholescystectomy, conservative management (percutaneous cholangiography with biliary drainage) may be proposed in specialised centers, especially for infants. A hepaticojejunostomy is indicated in cases of choledocal cyst with anomalous pancreatobiliary duct junctions.
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http://dx.doi.org/10.1016/j.lpm.2011.09.018DOI Listing
May 2012