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Inherited liver disease

Akiko Ohashi, Yusuke Saeki, Tomonori Harada, Masako Naito, Tomihisa Takahashi, Shin Aizawa, Hiroyuki Hasegawa
Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS) and aromatic amino acid hydroxylases. BH4 and 7,8-dihydrobiopterin (BH2) are metabolically interchangeable at the expense of NADPH. Exogenously administered BH4 can be metabolized by the body, similar to vitamins. At present, synthetic BH4 is used as an orphan drug for patients with inherited diseases requiring BH4 supplementation. BH4 supplementation has also drawn attention as a means of treating certain cardiovascular symptoms, however, its application in human patients remains limited...
2016: PloS One
M Holmström, A Nangarhari, J Öhman, A-S Duberg, A Majeed, S Aleman
INTRODUCTION: Hepatitis C virus (HCV) infection is common in patients with inherited bleeding disorders treated with clotting factor concentrates prior to the introduction of viral inactivation of these products. The long-term consequences of hepatitis C infection in Swedish patients are not fully understood. AIM: To examine the impact of HCV infection on liver-related morbidity and mortality in Swedish patients with inherited bleeding disorders. METHODS: We retrospectively collected data on 183 patients with inherited bleeding disorders infected with HCV who attended the Coagulation Unit at Karolinska University Hospital, Sweden...
October 5, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Ivo Barić, Christian Staufner, Persephone Augoustides-Savvopoulou, Yin-Hsiu Chien, Dries Dobbelaere, Sarah C Grünert, Thomas Opladen, Danijela Petković Ramadža, Bojana Rakić, Anna Wedell, Henk J Blom
Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up...
September 26, 2016: Journal of Inherited Metabolic Disease
Urszula Szlendak, Ksenia Bykowska, Agnieszka Lipniacka
Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system...
March 2016: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Ryan W Himes, Sarah E Barlow, Kevin Bove, Norma M Quintanilla, Rachel Sheridan, Rohit Kohli
Lysosomal acid lipase deficiency (LAL-D) is a classic lysosomal storage disorder characterized by accumulation of cholesteryl ester and triglyceride. Although it is associated with progressive liver injury, fibrosis, and end-stage liver disease in children and adolescents, LAL-D frequently presents with nonspecific signs that overlap substantially with other, more common, chronic conditions like nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, and certain inherited dyslipidemias. We present 2 children with NAFLD who achieved clinically significant weight reduction through healthy eating and exercise, but who failed to have the anticipated improvements in aminotransferases and γ-glutamyl transferase...
September 13, 2016: Pediatrics
Izabella Agostinho Pena, Lygia Azevedo Marques, Ângelo B A Laranjeira, José A Yunes, Marcos N Eberlin, Alex MacKenzie, Paulo Arruda
Lysine is catabolized in mammals through the saccharopine and pipecolate pathways - the former is mainly hepatic and renal, and the latter is believed to play a role in the cerebral lysine oxidation. Both pathways lead to the formation of aminoadipic semialdehyde (AASA) that is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). Mutations in the ALDH7A1 gene result in the accumulation of AASA and its cyclic form, piperideine-6-carboxylate (P6C), which causes pyridoxine-dependent epilepsy (PDE). P6C reacts with pyridoxal 5'-phosphate (PLP) causing its inactivation...
September 8, 2016: Biochimica et Biophysica Acta
R El-Khairi, L Vallier
Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) result in a multi-system disorder. HNF1B was initially discovered as a monogenic diabetes gene; however, renal cysts are the most frequently detected feature. Other clinical features include pancreatic hypoplasia and exocrine insufficiency, genital tract malformations, abnormal liver function, cholestasis and early-onset gout. Heterozygous mutations and complete gene deletions in HNF1B each account for approximately 50% of all cases of HNF1B-associated disease and may show autosomal dominant inheritance or arise spontaneously...
September 2016: Diabetes, Obesity & Metabolism
C Guth, U Beuers, K Beckh
Intermittent cholestatic liver disease may indicate an inherited deficiency of bile salt transport proteins. Episodes of cholestasis may start during pregnancy or during use of oral contraceptives or other medication. We describe the case of a 22-year-old mother with increasing jaundice and severe pruritus two weeks after starting hormonal contraception. A few months before she was suffering from intrahepatic cholestasis of pregnancy (ICP). Liver biopsy showed bland cholestasis with canalicular bile plugs...
September 2016: Zeitschrift Für Gastroenterologie
J Stollenwerk, M Schepke, E Biecker
BACKGROUND: Altered liver function tests are a common finding in clinical practice. Our retrospective study aimed to identify the diagnoses in a non-selected cohort of patients with altered liver tests and to investigate whether alpha-1 antitrypsin genotyping should be part of the diagnostic workup. PATIENTS AND METHODS: 501 patients who were admitted to our outpatient clinic for further evaluation of altered liver function tests were included in the study. The patients underwent a standardized diagnostic program with history taking, physical examination, laboratory tests and ultrasonography...
September 2016: Zeitschrift Für Gastroenterologie
Nesli Ece Sen, Jessica Drost, Suzana Gispert, Sylvia Torres-Odio, Ewa Damrath, Michael Klinkenberg, Hamid Hamzeiy, Gülden Akdal, Halil Güllüoğlu, A Nazlı Başak, Georg Auburger
Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for motor neuron disease (ALS and FTLD) and perhaps also for Levodopa-responsive Parkinson's disease (PD). In view of the established role of ATXN2 for RNA processing in periods of cell stress and the expression of ATXN2 in blood cells such as platelets, we investigated whether global deep RNA sequencing of whole blood from SCA2 patients identifies a molecular profile which might serve as diagnostic biomarker...
September 3, 2016: Neurobiology of Disease
Tingxia Lv, Xiaojin Li, Wei Zhang, Xinyan Zhao, Xiaojuan Ou, Jian Huang
Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype-phenotype correlations remain to be explored...
October 2016: European Journal of Medical Genetics
Robert A Sandhaus
Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy...
August 2016: Annals of the American Thoracic Society
R Okawa, O Iijima, M Kishino, H Okawa, S Toyosawa, H Sugano-Tajima, T Shimada, T Okada, K Ozono, T Ooshima, K Nakano
BACKGROUND AND OBJECTIVE: Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non-specific alkaline phosphatase (TNSALP) activity. The disease is caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL) encoding TNSALP. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia...
August 26, 2016: Journal of Periodontal Research
Honghao Wang, Nan Cheng, Jianjian Dong, Xun Wang, Yongsheng Han, Renmin Yang, Yongzhu Han
BACKGROUND: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism, resulting in pathological accumulation of Cu in many organs and tissues, predominantly in the liver and brain. Cu deposition may lead to neuroinflammation in the brain of WD patients. Pentraxin 3 (PTX3) may play an important role in innate immunity and in WD. We compared plasma PTX3 concentrations in WD patients and healthy controls, and to determine whether PTX3 concentration was associated with neurological disease severity...
November 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Mouna Gourine, Mohammed Arrar, Anwer Cherrak
Pachydermoperiostosis or primary hypertrophic osteoarthropathy is a rare disorder with autosomal inheritance. It is characterized by finger clubbing, periostosis and sometimes skin changes as pachydermia. It occurs more commnly in young and male subjects. An underlying disease as cardiac, pulmonary or liver diseases has to be excludesd in front of any hypertrophic osteoarthropathy. We report the case of a 24 year-old man presenting an incomplete form of PDP. The familial search revealed a similar case in the sibship...
February 2016: La Tunisie Médicale
Erik Stites, Alexander C Wiseman
Kidney transplantation has proven to be the gold standard therapy for severe chronic kidney disease (CKD) due to multiple etiologies in individuals deemed eligible from a surgical standpoint. While kidney transplantation is traditionally considered in conditions of native kidney disease such as diabetes and immunological or inherited causes of kidney disease, an increasing indication for kidney transplantation is kidney dysfunction in the setting of other severe organ dysfunction that requires transplant, such as severe liver or heart disease...
October 2016: Transplantation Reviews
Heike Wolf, Markus Damme, Stijn Stroobants, Rudi D'Hooge, Hans Christian Beck, Irm Hermans-Borgmeyer, Renate Lüllmann-Rauch, Thomas Dierks, Torben Lübke
Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine...
September 1, 2016: Disease Models & Mechanisms
Tassos Grammatikopoulos, Melissa Sambrotta, Sandra Strautnieks, Pierre Foskett, A S Knisely, Bart Wagner, Maesha Deheragoda, Chris Starling, Giorgina Mieli-Vergani, Joshua Smith, University Of Washington Center For Mendelian Genomics, Laura Bull, Richard J Thompson
BACKGROUND & AIMS: Neonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver-biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance. METHODS: From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families)...
July 25, 2016: Journal of Hepatology
Catherine M Greene, Stefan J Marciniak, Jeffrey Teckman, Ilaria Ferrarotti, Mark L Brantly, David A Lomas, James K Stoller, Noel G McElvaney
α1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded α1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of α1-antitrypsin and liver disease...
2016: Nature Reviews. Disease Primers
Valérie Decostre, Pascal Laforêt, Aleksandra Nadaj-Pakleza, Marie De Antonio, Sylvain Leveugle, Gwenn Ollivier, Aurélie Canal, Kahina Kachetel, François Petit, Bruno Eymard, Anthony Behin, Karim Wahbi, Philippe Labrune, Jean-Yves Hogrel
Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1...
September 2016: Neuromuscular Disorders: NMD
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