Publications by authors named "Peter Witters"

51 Publications

Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.

Orphanet J Rare Dis 2021 Feb 25;16(1):102. Epub 2021 Feb 25.

Department of Clinical Genomics, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.
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http://dx.doi.org/10.1186/s13023-021-01751-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908710PMC
February 2021

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype.

Eur Respir J 2020 Nov 12. Epub 2020 Nov 12.

Department of Development and Regeneration, CF Centre, Woman and Child, KU Leuven, Leuven, Belgium.

Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in CF disease progression is poorly described.We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-(172)) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validated , in CFTR knock-out mice and in CF patient-derived ECs.Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR knock-out mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by using CFTR modulators VX770-VX809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.
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http://dx.doi.org/10.1183/13993003.00261-2020DOI Listing
November 2020

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

Liver Int 2020 11;40(11):2602-2611

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background & Aims: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters.

Methods: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted.

Results: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa.

Conclusions: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.
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http://dx.doi.org/10.1111/liv.14658DOI Listing
November 2020

Fulminant Wilson Disease in Children: Recovery After Plasma Exchange Without Transplantation.

J Pediatr Gastroenterol Nutr 2020 12;71(6):720-725

Department of Pediatrics.

Objectives: Since 2005, a New Wilson Index (NWI) ≥11 is used as a predictor of death without transplantation in fulminant Wilson disease (WD). Plasma exchange is advocated as a new treatment modality.

Methods: We present a patient with fulminant WD treated with plasma exchange. All published cases applying plasma exchange for fulminant WD were reviewed systematically.

Results: A 14-year-old girl presented with hemolysis and fulminant liver failure. She had no encephalopathy; NWI was 14. As a bridge to transplantation plasma exchange was started immediately. Complete remission was achieved with plasma exchange and later chelation therapy with D-penicillamine. She is now at 3-year transplant-free survival. Literature review identified 37 patients presenting with fulminant WD and NWI ≥11 who were treated with plasma exchange. Seventeen of these patients (ie, 46%) recovered without transplantation.

Conclusions: Multiple case reports and case series demonstrate transplant free survival after plasma exchange and subsequent chelation therapy, despite a NWI ≥11. Plasma exchange affects the clinical course and is a therapeutic option in children and young adults presenting with fulminant WD.
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http://dx.doi.org/10.1097/MPG.0000000000002894DOI Listing
December 2020

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management.

J Inherit Metab Dis 2021 Jan 15;44(1):148-163. Epub 2020 Sep 15.

Department of Clinical Genomics and Laboratory of Medical Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.
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http://dx.doi.org/10.1002/jimd.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855268PMC
January 2021

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

Two cases of non-alcoholic fatty liver disease caused by biallelic ABHD5 mutations.

J Hepatol 2020 05 24;72(5):1030-1032. Epub 2020 Feb 24.

Metabolic Center, University Hospitals Leuven, 49 Herestraat, Leuven 3000, Belgium.

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http://dx.doi.org/10.1016/j.jhep.2019.12.013DOI Listing
May 2020

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG.

Genet Med 2020 Jun 27;22(6):1102-1107. Epub 2020 Feb 27.

Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium.

Purpose: We studied galactose supplementation in SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG), caused by monoallelic pathogenic variants in SLC35A2 (Xp11.23), encoding the endoplasmic reticulum (ER) and Golgi UDP-galactose transporter. Patients present with epileptic encephalopathy, developmental disability, growth deficiency, and dysmorphism.

Methods: Ten patients with SLC35A2-CDG were supplemented with oral D-galactose for 18 weeks in escalating doses up to 1.5 g/kg/day. Outcome was assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS, ten patients) and by glycomics (eight patients).

Results: SLC35A2-CDG patients demonstrated improvements in overall Nijmegen Pediatric CDG Rating Scale (NPCRS) score (P = 0.008), the current clinical assessment (P = 0.007), and the system specific involvement (P = 0.042) domains. Improvements were primarily in growth and development with five patients resuming developmental progress, which included postural control, response to stimuli, and chewing and swallowing amelioration. Additionally, there were improvements in gastrointestinal symptoms and epilepsy. One patient in our study did not show any clinical improvement. Galactose supplementation improved patients' glycosylation with decreased ratios of incompletely formed to fully formed glycans (M-gal/disialo, P = 0.012 and monosialo/disialo, P = 0.017) and increased levels of a fully galactosylated N-glycan (P = 0.05).

Conclusions: Oral D-galactose supplementation results in clinical and biochemical improvement in SLC35A2-CDG. Galactose supplementation may partially overcome the Golgi UDP-galactose deficiency and improves galactosylation. Oral galactose is well tolerated and shows promise as dietary therapy.
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http://dx.doi.org/10.1038/s41436-020-0767-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275909PMC
June 2020

Novel Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis.

Mol Ther Methods Clin Dev 2020 Jun 13;17:337-348. Epub 2020 Jan 13.

Department of Pediatrics, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.
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http://dx.doi.org/10.1016/j.omtm.2019.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013133PMC
June 2020

Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients.

JIMD Rep 2020 Jan 25;51(1):76-81. Epub 2019 Nov 25.

Department of Clinical Genomics Mayo Clinic Rochester Rochester Minnesota.

Background: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation (CDG). Hypoglycemia has been reported in various CDG including PMM2-CDG. The frequency and etiology of hypoglycemia in PMM2-CDG are not well studied.

Methods: We conducted a systematic review of the literature on genetically and/or biochemically confirmed PMM2-CDG patients who developed hypoglycemia. Prospective follow-up information on the patients who received diazoxide therapy was collected and evaluated.

Results: A total of 165 peer-reviewed articles reporting on 933 PMM2-CDG patients were assessed. Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients). Among these 10 patients, seven were successfully treated with diazoxide. However, most patients remained on therapy longer than a year to stay free of hypoglycemia.

Conclusion: Hypoglycemia is a rarely reported finding in patients with PMM2-CDG. Diazoxide-responsive hyperinsulinism was found to have a good prognosis on medication in our PMM2-CDG patients with hypoglycemia. No genotype-phenotype correlation was observed with respect to hyperinsulinism. A prospective study should be undertaken to explore the hypothesis that hypoglycemia is underdiagnosed in PMM2-CDG and to evaluate whether hyperinsulinism is always associated with hypoglycemia.
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http://dx.doi.org/10.1002/jmd2.12085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012739PMC
January 2020

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

Genet Med 2020 05 6;22(5):908-916. Epub 2020 Jan 6.

Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.

Purpose: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking.

Methods: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients.

Results: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%).

Conclusion: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.
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http://dx.doi.org/10.1038/s41436-019-0739-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200590PMC
May 2020

Oxygraphy Versus Enzymology for the Biochemical Diagnosis of Primary Mitochondrial Disease.

Metabolites 2019 Oct 10;9(10). Epub 2019 Oct 10.

Clinical Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium.

Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of the mitochondrial oxidative phosphorylation (OXPHOS) complexes remains the gold standard, oxygraphy could offer several advantages. To this end, we compared the diagnostic performance of both techniques in a cohort of 34 genetically defined PMD patient fibroblast cell lines. We observed that oxygraphy slightly outperformed enzymology for sensitivity (79 ± 17% versus 68 ± 15%, mean and 95% CI), and had a better discriminatory power, identifying 58 ± 17% versus 35 ± 17% as "very likely" for oxygraphy and enzymology, respectively. The techniques did, however, offer synergistic diagnostic prediction, as the sensitivity rose to 88 ± 11% when considered together. Similarly, the techniques offered varying defect specific information, such as the ability of enzymology to identify isolated OXPHOS deficiencies, while oxygraphy pinpointed PDHC mutations and captured POLG mutations that were otherwise missed by enzymology. In summary, oxygraphy provides useful information for the diagnosis of PMD, and should be considered in conjunction with enzymology for the diagnosis of PMD.
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http://dx.doi.org/10.3390/metabo9100220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835216PMC
October 2019

Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update.

Genet Med 2020 02 19;22(2):268-279. Epub 2019 Sep 19.

Department of Clinical Genomics, Laboratory of Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.

Congenital disorders of glycosylation (CDG) are a group of clinically and genetically heterogeneous metabolic disorders. Over 150 CDG types have been described. Most CDG types are ultrarare disorders. CDG types affecting N-glycosylation are the most common type of CDG with emerging therapeutic possibilities. This review is an update on the available therapies for disorders affecting the N-linked glycosylation pathway. In the first part of the review, we highlight the clinical presentation, general principles of management, and disease-specific therapies for N-linked glycosylation CDG types, organized by organ system. The second part of the review focuses on the therapeutic strategies currently available and under development. We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and pharmacological chaperones and outline the anticipated expansion of the therapeutic possibilities in CDG. We aim to provide a comprehensive update on the treatable aspects of CDG types involving N-linked glycosylation, with particular emphasis on disease-specific treatment options for the involved organ systems; call for natural history studies; and present current and future therapeutic strategies for CDG.
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http://dx.doi.org/10.1038/s41436-019-0647-2DOI Listing
February 2020

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Hepatology 2020 02 19;71(2):658-669. Epub 2019 Aug 19.

Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Universitat de Barcelona, Barcelona, Spain.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.
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http://dx.doi.org/10.1002/hep.30817DOI Listing
February 2020

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Am J Hum Genet 2019 05 11;104(5):835-846. Epub 2019 Apr 11.

Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. Electronic address:

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506806PMC
May 2019

International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up.

J Inherit Metab Dis 2019 01;42(1):5-28

Department of Clinical Genomics, Mayo Clinic, Rochester, New York.

Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.
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http://dx.doi.org/10.1002/jimd.12024DOI Listing
January 2019

Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates.

J Clin Densitom 2020 Jul - Sep;23(3):340-348. Epub 2018 Dec 21.

Center for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium; Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium. Electronic address:

Background: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium.

Methodology: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation.

Results: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations.

Conclusions: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.
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http://dx.doi.org/10.1016/j.jocd.2018.12.006DOI Listing
December 2018

Optimisation of children z-score calculation based on new statistical techniques.

PLoS One 2018 20;13(12):e0208362. Epub 2018 Dec 20.

Instituto de Investigación Sanitaria La Fe, Valencia, Spain.

Background: Expressing anthropometric parameters (height, weight, BMI) as z-score is a key principle in the clinical assessment of children and adolescents. The Centre for Disease Control and Prevention (CDC) growth charts and the CDC-LMS method for z-score calculation are widely used to assess growth and nutritional status, though they can be imprecise in some percentiles.

Objective: To improve the accuracy of z-score calculation by revising the statistical method using the original data used to develop current z-score calculators.

Design: A Gaussian Process Regressions (GPR) was designed and internally validated. Z-scores for weight-for-age (WFA), height-for-age (HFA) and BMI-for-age (BMIFA) were compared with WHO and CDC-LMS methods in 1) standard z-score cut-off points, 2) simulated population of 3000 children and 3) real observations 212 children aged 2 to 18 yo.

Results: GPR yielded more accurate calculation of z-scores for standard cut-off points (p<0.001) with respect to CDC-LMS and WHO approaches. WFA, HFA and BMIFA z-score calculations based on the 3 different methods using simulated and real patients, showed a large variation irrespective of gender and age. Z-scores around 0 +/- 1 showed larger variation than the values above and below +/- 2.

Conclusion: The revised z-score calculation method was more accurate than CDC-LMS and WHO methods for standard cut-off points. On simulated and real data, GPR based calculation provides more accurate z-score determinations, and thus, a better classification of patients below and above cut-off points. Statisticians and clinicians should consider the potential benefits of updating their calculation method for an accurate z-score determination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208362PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301782PMC
May 2019

Propeptide glycosylation and galectin-3 binding decrease proteolytic activation of human proMMP-9/progelatinase B.

FEBS J 2019 03 30;286(5):930-945. Epub 2018 Nov 30.

Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven, Belgium.

Matrix metalloproteinases (MMPs) are secreted as proenzymes, containing propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP-9 propeptide is unique in the MMP family because of its post-translational modification with an N-linked oligosaccharide. ProMMP-9 activation by MMP-3 occurs stepwise by cleavage of the propeptide in an aminoterminal (pro-AT) and carboxyterminal (pro-CT) peptide. We chemically synthesized aglycosyl pro-AT and pro-CT and purified recombinant glycosylated pro-AT . First, we report new cleavage sites in the MMP-9 propeptide by MMP-3 and neutrophil elastase. Additionally, we demonstrated with the use of western blot analysis a higher resistance of glycosylated versus aglycosyl pro-AT against proteolysis by MMP-3, MMP-9, meprin α, neutrophil elastase and by protease-rich synovial fluids from rheumatoid arthritis patients. Moreover, we investigated the effect of glycosylation on proteolytic activation of human proMMP-9 with the use of zymography and dye-quenched gelatin cleavage analysis. Compared to recombinant Sf-9 proMMP-9 glycoforms, larger oligosaccharides of human neutrophil proMMP-9 increased resistance against proteolytic activation. Additionally, proMMP-9 from Congenital Disorder of Glycosylation patients, compared to healthy controls, showed a higher activation rate by MMP-3. Finally, we demonstrated that glycan-galectin-3 interactions reduced proMMP-9 activation. In conclusion, modification of MMP-9 propeptide glycosylation is a fine-tuning mechanism and co-determines the specific activity of MMP-9 in physiology and pathology. ENZYMES: MMP-9 EC 3.4.24.35, MMP-3 EC 3.4.24.17, meprin α EC 3.4.24.18, neutrophil elastase EC 3.4.21.37, trypsin EC 3.4.21.4 and PNGase F EC 3.5.1.52.
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http://dx.doi.org/10.1111/febs.14698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379967PMC
March 2019

Long-term follow-up in PMM2-CDG: are we ready to start treatment trials?

Genet Med 2019 05 8;21(5):1181-1188. Epub 2018 Oct 8.

Pediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium.

Purpose: PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution.

Methods: We performed data analysis on PMM2-CDG patients' clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years.

Results: On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases.

Conclusion: PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.
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http://dx.doi.org/10.1038/s41436-018-0301-4DOI Listing
May 2019

Central nervous involvement is common in PGM1-CDG.

Mol Genet Metab 2018 11 21;125(3):200-204. Epub 2018 Aug 21.

Metabolic Center, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Center of Individualized Medicine, Department of Clinical Genomics, Mayo Clinic, Rochester, USA. Electronic address:

PGM1, the enzyme responsible for the reversible inter-conversion of glucose-1-P and glucose-6-P, is also involved in glycosylation, leading to a wide range of clinical manifestations, such as congenital malformations, hypoglycemia, hormonal dysregulation, myopathy, hepatopathy, and cardiomyopathy. So far, PGM1 deficiency has not been associated with central nervous system involvement or intellectual disability. Seizures and neurologic involvement in PGM1-CDG were thought to be a consequence of hypoglycemia. We reviewed all reported PGM1 deficient patients for the presence of the central nervous system involvement, their treatment and disease history. We detected 17 patients out of the 41 reported PGM1-CDG cases with significant neurologic involvement. Several of these patients had no severe hypoglycemic episodes, or were adequately treated for hypoglycemia with no recurrent episodes of low blood sugars, while one patient had no reported hypoglycemic episodes. We suggest that neurological symptoms are frequent in PGM1-CDG and could present even in the absence of hypoglycemia. The central nervous system should be assessed early on during the diagnostic process to optimize outcome in patients with PGM1-CDG.
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http://dx.doi.org/10.1016/j.ymgme.2018.08.008DOI Listing
November 2018

Gastrostomy Tube Insertion in Pediatric Patients With Autosomal Recessive Polycystic Kidney Disease (ARPKD): Current Practice.

Front Pediatr 2018 4;6:164. Epub 2018 Jun 4.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal disorder of childhood. Early renal disease in ARPKD may require renal replacement therapy and is associated with failure to thrive resulting in a need for nasogastric tube feeding or gastrostomy. In ARPKD patients, the benefit of a gastrostomy in nutrition and growth needs to be weighed against the potential risk of complications of congenital hepatic fibrosis (CHF) and portal hypertension like variceal bleeding. CHF in ARPKD has thus been considered as a relative contraindication for gastrostomy insertion. Yet, data on gastrostomies in pediatric patients with ARPKD is lacking. We conducted a web-based survey study among pediatric nephrologists, pediatric hepatologists and pediatric gastroenterologists on their opinions on and experiences with gastrostomy insertion in ARPKD patients. 196 participants from 39 countries shared their opinion. 45% of participants support gastrostomy insertion in all ARPKD patients, but portal hypertension is considered to be a contraindication by a subgroup of participants. Patient-specific data was provided for 38 patients indicating complications of gastrostomy that were in principal comparable to non-ARPKD patients. Bleeding episodes were reported in 3/38 patients (7.9%). Two patients developed additional severe complications. Gastrostomy was retrospectively considered as the right decision for the patient in 35/38 (92.1%) of the cases. This report on the results of an online survey gives first insights into the clinical practice of gastrostomy insertion in ARPKD patients. For the majority of participating physicians benefits of gastrostomy insertion retrospectively outweigh complications and risks. More data will be required to lay the foundation for clinical recommendations.
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http://dx.doi.org/10.3389/fped.2018.00164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994991PMC
June 2018

Liver transplantation for very severe hepatopulmonary syndrome due to vitamin A-induced chronic liver disease in a patient with Shwachman-Diamond syndrome.

Orphanet J Rare Dis 2018 05 2;13(1):69. Epub 2018 May 2.

Laboratory of Inborn Errors of Immunity, Department of Microbiology and Immunology, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.

Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting.
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http://dx.doi.org/10.1186/s13023-018-0818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930429PMC
May 2018

Long-term outcome of transjugular intrahepatic portosystemic shunt for portal hypertension in autosomal recessive polycystic kidney disease.

Dig Liver Dis 2018 07 15;50(7):707-712. Epub 2018 Mar 15.

Department of Pediatric Hepatology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Background: Autosomal recessive polycystic kidney disease (ARPKD) with congenital hepatic fibrosis (CHF) causes portal hypertension and its complications. A transjugular intrahepatic portosystemic shunt (TIPSS) could serve as a symptomatic treatment for portal hypertension-related symptoms in these children.

Aims: To study the effect of TIPSS on portal hypertension, liver and kidney function and the long term complications.

Materials And Methods: We report on 5 children with CHF treated with a TIPSS to manage severe portal hypertension related symptoms.

Results: Mean follow-up time was 7 years and 2 months. At the end of follow-up there was a reduction of spleen size (p = 0.715) and hypersplenism with a rise in platelet count (p = 0.465). Esophageal varices and ascites disappeared in all patients. Liver and kidney function remained stable. In two patients endotipsitis was suspected and two patients developed an in-stent stenosis. There was no sign of encephalopathy in our patients.

Conclusion: TIPSS using ePTFE-covered stent is a feasible and effective alternative for surgical portosystemic shunting in children with CHF, also on the long term. It can postpone the need of a liver transplantation but close monitoring remains important for early diagnosis of endotipsitis or stent dysfunction related to stenosis.
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http://dx.doi.org/10.1016/j.dld.2018.03.009DOI Listing
July 2018

Revisiting mitochondrial diagnostic criteria in the new era of genomics.

Genet Med 2018 04 26;20(4):444-451. Epub 2017 Oct 26.

Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

PurposeDiagnosing primary mitochondrial diseases (MDs) is challenging in clinical practice. The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying MD and the need for a muscle biopsy. In this new genetic era with next-generation sequencing in routine practice, we aim to validate the diagnostic value of MDC.MethodsWe retrospectively studied MDC in a multicenter cohort of genetically confirmed primary MD patients.ResultsWe studied 136 patients (61 male, 91 nuclear DNA (nDNA) mutations). Forty-five patients (33%) had probable MD and 69 (51%) had definite MD according to the MDC. A muscle biopsy was performed in 63 patients (47%). Patients with nDNA mutations versus mitochondrial DNA mutations were younger (6.4 ± 9.7 versus 19.5 ± 17.3 y) and had higher MDC (7.07 ± 1.12/8 versus 5.69 ± 1.94/8). At a cutoff of 6.5/8, the sensitivity to diagnose patients with nDNA mutations is 72.5% with a positive predictive value of 69.5%. In the nDNA mutation group, whole-exome sequencing could diagnose patients with lower scores (MDC (6.84 ± 1.51/8) compared to Sanger sequencing MDC (7.44 ± 1.13/8, P = 0.025)). Moreover 7/8 patients diagnosed with possible MD by MDC were diagnosed by whole-exome sequencing.ConclusionMDC remain very useful in the clinical diagnosis of MD, in interpreting whole-exome results and deciding on the need for performing muscle biopsy.
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http://dx.doi.org/10.1038/gim.2017.125DOI Listing
April 2018

Renal involvement in PMM2-CDG, a mini-review.

Mol Genet Metab 2018 03 28;123(3):292-296. Epub 2017 Nov 28.

Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Tulane University Medical School, Department of Pediatrics, New Orleans, LA, USA. Electronic address:

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-linked glycosylation disorder. The majority of patients present with a multisystem phenotype, including central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction and abnormal coagulation. Renal abnormalities including congenital malformations and altered renal function are part of the multisystem manifestations of congenital disorders of glycosylation. We reviewed the literature on 933 patients with molecularly and/or enzymatically confirmed PMM2 deficiency to evaluate the incidence of renal involvement in PMM2-CDG. Renal abnormalities were reported in 56 patients. Congenital abnormalities were present in 41 out of these 55. Cystic kidney and mild proteinuria were the most common findings. One of the most severe renal manifestations, congenital nephrotic syndrome, was detected in 6 children. Renal manifestations were not associated with the presence of specific PMM2 alleles. This review summarizes the reported renal abnormalities in PMM2-CDG and draws attention to the pathophysiological impact of abnormal glycosylation on kidney structure and function.
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http://dx.doi.org/10.1016/j.ymgme.2017.11.012DOI Listing
March 2018

Expanding the phenotype of metabolic cutis laxa with an additional disorder of N-linked protein glycosylation.

Eur J Hum Genet 2018 05 30;26(5):618-621. Epub 2017 Nov 30.

Metabolic Center, Department of Pediatrics, University Hospitals Leuven, Herestraat 49, Leuven, B-3000, Belgium.

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http://dx.doi.org/10.1038/s41431-017-0044-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945621PMC
May 2018

Nutritional Therapies in Congenital Disorders of Glycosylation (CDG).

Nutrients 2017 Nov 7;9(11). Epub 2017 Nov 7.

Metabolic Center, University Hospitals Leuven, B-3000 Leuven, Belgium.

Congenital disorders of glycosylation (CDG) are a group of more than 130 inborn errors of metabolism affecting -linked, -linked protein and lipid-linked glycosylation. The phenotype in CDG patients includes frequent liver involvement, especially the disorders belonging to the -linked protein glycosylation group. There are only a few treatable CDG. Mannose-Phosphate Isomerase (MPI)-CDG was the first treatable CDG by high dose mannose supplements. Recently, with the successful use of d-galactose in Phosphoglucomutase 1 (PGM1)-CDG, other CDG types have been trialed on galactose and with an increasing number of potential nutritional therapies. Current mini review focuses on therapies in glycosylation disorders affecting liver function and dietary intervention in general in -linked glycosylation disorders. We also emphasize now the importance of early screening for CDG in patients with mild hepatopathy but also in cholestasis.
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http://dx.doi.org/10.3390/nu9111222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707694PMC
November 2017

Isolated sulfite oxidase deficiency.

J Inherit Metab Dis 2018 01 4;41(1):101-108. Epub 2017 Oct 4.

Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.

Isolated sulfite oxidase deficiency (ISOD) is a life-threatening, autosomal recessive disease characterized by severe neurological impairment. As no long-term effective treatment is available, distinction from other treatable diseases, such as molybdenum cofactor deficiency (MoCD) type A, should be made. We reviewed 47 patients (45 previously reported in the literature). Cases were reviewed for consanguinity, sex, age at onset, death, clinical findings (including spasticity, seizures, psychomotor retardation, feeding difficulties, ectopia lentis, microcephaly), laboratory findings [urinary sulfite, S-sulfocysteine (in plasma and urine), plasma cystine, total homocysteine, uric acid, and oxypurines in urine] and radiological findings (including cerebral/cerebellar atrophy, cystic white matter changes, ventriculomegaly). We also aligned the published SUOX gene mutations to the reference sequence NM_000456.2. Onset occurred mostly during the first 72 h of life (57%) and within the first year of life in all but two patients (96%). All patients presented with neurological abnormalities, such as neonatal axial hypotonia and/or peripheral hypertonia (100%), (pharmacoresistant) seizures (84%), or developmental delay (97%). Feeding problems were also common. As found in our review, measurement of homocysteine in plasma, amino acids in plasma/urine, and sulfite in fresh urine supports the diagnosis of ISOD. Analysis of uric acid (plasma) and oxypurines (urine) is useful to rule out MoCD. In all patients in whom brain magnetic resonance imaging/computed tomography (MRI/CT) was performed, brain abnormalities were found. The purpose of this literature review is to provide a thorough overview of clinical, neuroimaging, biochemical, and genetic findings of patients with ISOD.
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http://dx.doi.org/10.1007/s10545-017-0089-4DOI Listing
January 2018

Cystic Fibrosis-related Liver Disease: Research Challenges and Future Perspectives.

J Pediatr Gastroenterol Nutr 2017 10;65(4):443-448

*Pediatric Hepatology Unit, APHP-Hôpital Necker and UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France †Digestive Health Institute, Children's Hospital Colorado and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine Aurora, CO ‡Pediatric Gastroenterology and Hepatology, Department Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, University of Groningen, Groningen, The Netherlands §CF Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy ||Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition, Institut Hospitalo-Universitaire & Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires, Service d'Hépatologie, Paris, France ¶Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam #Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands **The Liver Unit, Birmingham Children's Hospital, Birmingham, UK ††Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada ‡‡Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition, Institut Hospitalo-Universitaire & Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière §§Paris-Descartes, Sorbonne Paris-Cité University, INSERM U-1223 - Pasteur Institute, and Hepatology Unit, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France ||||Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria ¶¶Department of Paediatric Gastroenterology, Hepatology and Nutrition University Hospitals Leuven, Leuven, Belgium ##Department of Paediatric Kidney, Liver and Metabolic Diseases, Division of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany ***Pediatric Gastroenterology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Objectives: Hepatobiliary complications are a leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Knowledge of the underlying pathological aspects and optimal clinical management is, however, sorely lacking.

Methods: We provide a summary of the lectures given by international speakers at the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) monothematic conference on cystic fibrosis-related liver disease (CFLD) held in Paris in January 2016, to discuss the status of our current knowledge of liver disease in CF patients, to define the critical areas that need to be addressed, and to resolve actions to elucidate relevant mechanisms of disease to optimise future therapeutic options.

Conclusions: The need for a universal consensus on the definition of CFLD to clarify disease stage and to identify relevant biomarkers to assess disease severity was highlighted. A deeper understanding of the pathophysiology and prognostic factors for the long-term evolution of CFLD is fundamental to move forward and has a strong bearing on identifying potential treatments. Novel experimental models and new treatment options under investigation are discussed and offer hope for the near future of CFLD.
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http://dx.doi.org/10.1097/MPG.0000000000001676DOI Listing
October 2017