ABSTRACT
PURPOSE: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. METHODS: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. CONCLUSION: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Subject(s)
Cerebellar Ataxia , Genomics , Cohort Studies , DNA Copy Number Variations/genetics , Humans , Peroxins , Receptors, Cytoplasmic and Nuclear , United States , Exome SequencingABSTRACT
ABSTRACT: Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat-soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat-loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low-fat diet with essential fatty acid supplementation, high doses of fat-soluble vitamins, and regular and life-long follow-up.The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat-soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders.
Subject(s)
Abetalipoproteinemia , Hypobetalipoproteinemias , Abetalipoproteinemia/diagnosis , Abetalipoproteinemia/genetics , Adult , Apolipoproteins B , Child , Humans , Hypobetalipoproteinemias/diagnosis , Hypobetalipoproteinemias/genetics , Lipids , Vitamin EABSTRACT
ABSTRACT: Intractable ascites is a rare condition in children mainly caused by cirrhosis or lymphatic disorders. Internal drainage may be considered as rescue therapy. In our department, 4 patients ages from 2âmonths to 15âyears old underwent a peritoneovenous shunt (PVS) placement between 2010 and 2020. The surgically inserted device was a pumping device that enabled to drain ascites from the peritoneum into the venous system via the internal jugular vein (Denver shunt, BD Company, NJ). Immediate efficient drainage was achieved in all cases and lasted up to 9âyears. Two major complications occurred: a postoperative fat embolism requiring urgent temporary ligation of the shunt and endocarditis shortly after inguinal hernia repair performed 16âmonths after placement of the shunt. Implementation of a PVS may be a useful procedure in patients with refractory ascites. Chylous ascites should be drained and washed totally before activating the device to avoid fat embolism. Antibiotic prophylaxis is required when abdominal surgery is planned while the device is in place.
Subject(s)
Chylous Ascites , Peritoneovenous Shunt , Ascites/etiology , Ascites/surgery , Child , Drainage , Humans , Liver CirrhosisABSTRACT
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.
Subject(s)
Amino Acid Metabolism, Inborn Errors/surgery , Kidney Transplantation , Liver Transplantation , Adolescent , Adult , Child , Child, Preschool , Female , France , Humans , Infant , Infant, Newborn , Male , Prognosis , Quality of Life , Retrospective Studies , Severity of Illness Index , Treatment OutcomeABSTRACT
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.
Subject(s)
Liver Failure/surgery , Liver Transplantation , Postoperative Hemorrhage/etiology , Adolescent , Area Under Curve , Blood Transfusion , Child , Child, Preschool , Erythrocytes/cytology , Female , Humans , Infant , Intraoperative Period , Living Donors , Male , Postoperative Hemorrhage/prevention & control , Postoperative Period , Reoperation , Retrospective Studies , Risk Factors , Tissue Donors , Treatment OutcomeSubject(s)
Genetic Predisposition to Disease , Hepatic Encephalopathy/genetics , Liver Failure/genetics , Liver Failure/pathology , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Biopsy, Needle , Cause of Death , Disease Progression , Female , Humans , Immunohistochemistry , Infant , Infant, Newborn , Life Expectancy , Liver Function Tests , Pedigree , Phenotype , Risk Assessment , Survival Rate , Twins, MonozygoticABSTRACT
Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive disorder of phenylalanine and tyrosine catabolism due to a deficiency of fumarylacetoacetate hydrolase. HT1 has a large clinical spectrum with acute forms presenting before six months of age, subacute forms with initial symptoms occurring between age 6 and 12 months, and chronic forms after 12 months of age. Without treatment, HT1 results in the accumulation of toxic metabolites leading to liver disease, proximal tubular dysfunction, and porphyria-like neurological crises. Since the early nineties, the outcome of HT1 has dramatically changed due to its treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone). In some countries, HT1 is included in the newborn screening program based on the analysis of succinylacetone concentration on dried blood spots. In the present study, we report clinical and laboratory parameters data on 33 HT1 patients focusing on clinical presentation and therapeutic management at the time of diagnosis. Eighteen patients were diagnosed with the acute form (median age at presentation 2.5 months), 6 with the subacute form (median age at presentation 10 months), and 5 with the chronic form of HT1 (median age at presentation 15 months). Four patients were diagnosed pre-symptomatically in the setting of a family history of HT1. Among the 29 symptomatic patients, hepatomegaly was found in 83% of patients and prolonged coagulation times due to hepatocellular insufficiency was observed in 93% of patients. HT1 diagnosis was confirmed by increased urine succinylacetone in all patients. All patients but 2 were treated with nitisinone immediately at diagnosis. During follow-up, 2 patients received liver transplant for high grade dysplasia or hepatocellular carcinoma, 10 patients exhibited some form of neurocognitive impairments. Our data confirm that HT1 is a severe treatable liver disease that should be detected at the earliest, ideally by newborn screening and appropriately treated.
ABSTRACT
AIMS: After liver transplantation (LT), synthesis of coagulation factors by the graft recovers faster for pro thrombotic than anti thrombotic factors, resulting in a potential pro thrombotic imbalance. We studied the thrombotic and hemorrhagic complications in our pediatric LT series, providing supplementation of fresh frozen plasma (FFP) and/or antithrombin (AT) in the prophylactic antithrombotic regimen. METHODS: This was a retrospective observational single center study. All isolated pediatric LTs performed between 1/11/2009 and 31/12/2019 (n = 181) were included. Postoperatively, in addition to low molecular weight heparin, 22 patients (12%) received FFP (10 ml/kg twice daily for 10 days), 27 patients (15%) were given FFP (reduced duration) and AT (50-100 IU/kg/day if AT activity remained <70%), and 132 (73%) received AT only. Complications, outcome, and coagulation profiles in postoperative days 0-10 were analyzed. RESULTS: In all three treatment groups, AT activity normalized by day 4 while prothrombin remained <70% of normal until day 9. Hepatic artery thrombosis (HAT), portal vein thrombosis (PVT), and hemorrhagic complications occurred in 2.8%, 3.3%, and 3.9% of LTs. One- and 5-year patient and graft survival were 88% (±2.4% Standard Error) and 84% (±2.5%), and 86% (±2.6%) and 84% (±2.7%), respectively, without difference between groups. HAT were associated with low AT on days 0 and 1, and PVT with low AT on day 0. CONCLUSIONS: Low antithrombin activity after LT was associated with postoperative thromboses. FFP and/or AT supplementation allowed early normalization of AT activity, while thrombotic or hemorrhagic complications were rare, suggesting efficient and safe management of post-LT coagulopathy.
Subject(s)
Liver Transplantation , Thrombosis , Venous Thrombosis , Anticoagulants , Antithrombin III , Antithrombins/therapeutic use , Child , Dietary Supplements , Fibrinolytic Agents/therapeutic use , Heparin, Low-Molecular-Weight , Humans , Liver Transplantation/adverse effects , Portal Vein , Prothrombin , Retrospective Studies , Risk Factors , Thrombosis/etiology , Thrombosis/prevention & control , Venous Thrombosis/etiologyABSTRACT
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 1st 2014 and January 1st 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.
Subject(s)
Hepatitis E/epidemiology , Liver Transplantation , Postoperative Complications/epidemiology , Postoperative Complications/virology , Adolescent , Child , Child, Preschool , Female , France/epidemiology , Hepatitis Antibodies/blood , Hepatitis E/blood , Hepatitis E virus/immunology , Humans , Infant , Male , Postoperative Complications/blood , Prevalence , Seroepidemiologic Studies , Severity of Illness IndexABSTRACT
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.