Skip to main content Accessibility help
Hostname: page-component-768dbb666b-v9bzm Total loading time: 5.545 Render date: 2023-02-04T13:54:53.798Z Has data issue: true Feature Flags: { "useRatesEcommerce": false } hasContentIssue true

Section IV - Metabolic Liver Disease

Published online by Cambridge University Press:  19 January 2021

Frederick J. Suchy
University of Colorado, Children’s Hospital Colorado, Aurora
Ronald J. Sokol
University of Colorado, Children’s Hospital Colorado, Aurora
William F. Balistreri
Cincinnati Children’s Hospital Medical Center, Cincinnati
Jorge A. Bezerra
Cincinnati Children’s Hospital Medical Center, Cincinnati
Cara L. Mack
University of Colorado, Children’s Hospital Colorado, Aurora
Benjamin L. Shneider
Texas Children’s Hospital, Houston
Get access
Publisher: Cambridge University Press
Print publication year: 2021

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)



Eminoglu, TF, et al. Very long-chain acyl CoA dehydrogenase deficiency which was accepted as infanticide. Forensic Sci Int 2011;210(1–3):e13.CrossRefGoogle ScholarPubMed
Saudubray, JM,(2016). Clinical approach to inborn errors of metabolism in pediatrics. In Saudubray, JM, Walter, JH (Eds.), Inborn Metabolic Diseases: Diagnosis and Treatment (pp. 369). New York: Springer Berlin Heidelberg.CrossRefGoogle Scholar
Blau, N, Duran, M, Gibson, KM. (2008). Laboratory Guide to the Methods in Biochemical Genetics (pp. xxvi, 860). Berlin: Springer.CrossRefGoogle Scholar
Crushell, E, et al. Negative screening tests in classical galactosaemia caused by S135L homozygosity. J Inherit Metab Dis 2009;32(3):412–15.CrossRefGoogle ScholarPubMed
Vilarinho, S, Mistry, PK. Exome sequencing in clinical hepatology. Hepatology 2019;70(6):2185–92.CrossRefGoogle ScholarPubMed
Hegarty, R, et al. Inherited metabolic disorders presenting as acute liver failure in newborns and young children: King’s College Hospital experience. Eur J Pediatr 2015;174(10):1387–92.CrossRefGoogle Scholar
Li, H, et al. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab 2018;123(4):428–32.CrossRefGoogle ScholarPubMed
Chinsky, JM, et al. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med 2017;19(12). Doi: 10.1038/gim.2017.101CrossRefGoogle Scholar
Heissat, S, et al. Neonatal hemochromatosis: diagnostic work-up based on a series of 56 cases of fetal death and neonatal liver failure. J Pediatr 2015;166(1):6673.CrossRefGoogle ScholarPubMed
Salen, G, Steiner, RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis 2017;40(6):771–81.CrossRefGoogle Scholar
Bull, LN, Thompson, RJ. Progressive familial intrahepatic cholestasis. Clin Liver Dis 2018;22(4):657–69.CrossRefGoogle ScholarPubMed
Gheldof, A, et al. Clinical implementation of gene panel testing for lysosomal storage diseases. Mol Genet Genomic Med 2019;7(2):e00527.CrossRefGoogle ScholarPubMed
Walter, J, Laforêt, L.P. (2016). The glycogen storage diseases and related disorders. In Saudubray, BM, Walter, J (Eds.), Inborn Metabolic Diseases: Diagnosis and Treatment (pp. 121–37). New York: Springer Berlin Heidelberg.Google Scholar
Frazier, DM, et al. The tandem mass spectrometry newborn screening experience in North Carolina: 1997–2005. J Inherit Metab Dis 2006;29(1):7685.CrossRefGoogle ScholarPubMed
Matern, D. (2008). Acylcarnitines, including in vitro loading tests. In Blau, N (Ed.), Laboratory Guide to the Methods in Biochemical Genetics (pp. 171206). Berlin: Springer-Verlag.CrossRefGoogle Scholar
Rinaldo, P. (2008). Organic acids. In Blau, DM, Gibson, KM (Eds.), Laboratory Guide to the Methods in Biochemical Genetics pp. (137–70). Berlin: Springer-Verlag.Google Scholar
Vassault, A. (2008). Lactate, pyruvate, acetoacetate and 3-hydroxybutyrate. In Blau, DM, Gibson, KM (Eds.), Laboratory Guide to the Methods in Biochemical Genetics (pp. 3551). Berlin: Springer-Verlag.CrossRefGoogle Scholar
Coude, FX, et al. Secondary citrullinemia with hyperammonemia in four neonatal cases of pyruvate carboxylase deficiency. Pediatrics 1981;68(6):914.Google ScholarPubMed
Munnich, A, et al. Congenital lactic acidosis, alpha-ketoglutaric aciduria and variant form of maple syrup urine disease due to a single enzyme defect: dihydrolipoyl dehydrogenase deficiency. Acta Paediatr Scand 1982;71(1):167–71.CrossRefGoogle ScholarPubMed
Bonnefont, JP, et al. Alpha-ketoglutarate dehydrogenase deficiency presenting as congenital lactic acidosis. J Pediatr 1992;121(2):255–8.CrossRefGoogle ScholarPubMed
da Fonseca-Wollheim, F. Deamidation of glutamine by increased plasma gamma-glutamyltransferase is a source of rapid ammonia formation in blood and plasma specimens. Clin Chem 1990;36(8 Pt 1):1479–82.CrossRefGoogle ScholarPubMed
Tein, I. Neonatal metabolic myopathies. Semin Perinatol 1999;23(2):125–51.CrossRefGoogle ScholarPubMed
Chalmers, RA. Organic acids in urine of patients with congenital lactic acidoses: an aid to differential diagnosis. J Inherit Metab Dis 1984;7(Suppl 1):7989.CrossRefGoogle ScholarPubMed
Cowan, TM, et al. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med 2010;12(7):464–70.CrossRefGoogle Scholar
Bourgeron, T, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11(2):144–9.CrossRefGoogle ScholarPubMed
Bennett, MJ, et al. Secondary inhibition of multiple NAD-requiring dehydrogenases in respiratory chain complex I deficiency: possible metabolic markers for the primary defect. J Inherit Metab Dis 1993;16(3):560–2.CrossRefGoogle ScholarPubMed
Kerner, J, Hoppel, C. Fatty acid import into mitochondria. Biochim Biophys Acta 2000;1486(1):117.CrossRefGoogle ScholarPubMed
Rinaldo, P, et al. Sudden neonatal death in carnitine transporter deficiency. J Pediatr 1997;131(2):304–5.CrossRefGoogle ScholarPubMed
Raymond, K, et al. Medium-chain acyl-CoA dehydrogenase deficiency: sudden and unexpected death of a 45 year old woman. Genet Med 1999;1(6):293–4.CrossRefGoogle ScholarPubMed
Patel, JS, Leonard, JV. Ketonuria and medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 1995;18(1):98–9.CrossRefGoogle ScholarPubMed
Rinaldo, P, et al. Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr 1998;10(6):615–21.CrossRefGoogle ScholarPubMed
Burrage, LC, et al. Elevations of C14:1 and C14:2 plasma acylcarnitines in fasted children: a diagnostic dilemma. J Pediatr 2016;169:208–13 e2.CrossRefGoogle ScholarPubMed
Costa, CC, et al. Dynamic changes of plasma acylcarnitine levels induced by fasting and sunflower oil challenge test in children. Pediatr Res 1999;46(4):440–4.CrossRefGoogle ScholarPubMed
Drousiotou, A, et al. Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches. Clin Genet 2011;79(4):385–90.CrossRefGoogle ScholarPubMed
Stanley, CA, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991;30(5):709–16.CrossRefGoogle ScholarPubMed
Minkler, PE, et al. Quantification of carnitine and acylcarnitines in biological matrices by HPLC electrospray ionization-mass spectrometry. Clin Chem 2008;54(9):1451–62.CrossRefGoogle ScholarPubMed
Boles, RG, et al. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr 1998;132(6):924–33.CrossRefGoogle ScholarPubMed
Dietzen, DJ, et al. National academy of clinical biochemistry laboratory medicine practice guidelines: follow-up testing for metabolic disease identified by expanded newborn screening using tandem mass spectrometry; executive summary. Clin Chem 2009;55(9):1615–26.CrossRefGoogle ScholarPubMed
Ohura, T, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis 2007;30(2):139–44.CrossRefGoogle Scholar
Saheki, T, Song, YZ. (1993). Citrin deficiency. In Adam, MP et al. (Eds.), GeneReviews((R)). Seattle, WA.Google Scholar
Matthews, DE, et al. Alloisoleucine formation in maple syrup urine disease: isotopic evidence for the mechanism. Pediatr Res 1980;14(7):854–7.Google ScholarPubMed
Oglesbee, D, et al. Second-tier test for quantification of alloisoleucine and branched-chain amino acids in dried blood spots to improve newborn screening for maple syrup urine disease (MSUD). Clin Chem 2008;54(3):542–9.CrossRefGoogle Scholar
Van Hove, JLK, et al. (1993). Nonketotic hyperglycinemia. In Adam, MP et al. (Eds.), GeneReviews. Seattle, WA.Google ScholarPubMed
Watson, MS, Lloyd-Puryear, MA, Rinaldo, P, Howell, RR. Newborn screening: toward a uniform screening panel and system. Genet Med 2006;8(Suppl 1):1S252S.CrossRefGoogle Scholar
Turgeon, C, et al. Combined newborn screening for succinylacetone, amino acids, and acylcarnitines in dried blood spots. Clin Chem 2008;54(4):657–64.CrossRefGoogle ScholarPubMed
Tortorelli, S, et al. Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry. J Pediatr 2010;157(2):271–5.CrossRefGoogle ScholarPubMed
Turgeon, CT, et al. Determination of total homocysteine, methylmalonic acid, and 2-methylcitric acid in dried blood spots by tandem mass spectrometry. Clin Chem 2010;56(11):1686–95.CrossRefGoogle ScholarPubMed
McHugh, D, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med 2011;13(3):230–54.CrossRefGoogle ScholarPubMed
Marquardt, G, et al. Enhanced interpretation of newborn screening results without analyte cutoff values. Genet Med 2012;14(7):648–55.CrossRefGoogle ScholarPubMed
Calonge, N, et al. Committee report: method for evaluating conditions nominated for population-based screening of newborns and children. Genet Med 2010;12(3):153–9.CrossRefGoogle ScholarPubMed


Sveger, T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–21.CrossRefGoogle ScholarPubMed
Silverman, EK, Sandhaus, RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009;360: 2749–57.CrossRefGoogle ScholarPubMed
Perlmutter, DH. (2011). Alpha-1-antitrypsin deficiency. In Schiff, ER SM, Maddrey, WC (Eds.), Schiff’s Diseases of the Liver, 11th edn., (pp. 835–67). Oxford: Wiley-Blackwell.Google Scholar
Crystal, RG. Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy. J Clin Invest 1990;85:1343–52.Google ScholarPubMed
Carlson, JA, Rogers, BB, Sifers, RN, Finegold, MJ, Clift, SM, DeMayo, FJ, Bullock, DW, et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 1989;83:1183–90.CrossRefGoogle ScholarPubMed
Dycaico, MJ, Grant, SG, Felts, K, Nichols, WS, Geller, SA, Hager, JH, Pollard, AJ, et al. Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model. Science 1988;242:1409–12.CrossRefGoogle ScholarPubMed
Hidvegi, T, Ewing, M, Hale, P, Dippold, C, Beckett, C, Kemp, C, Maurice, N, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010;329:229–32.CrossRefGoogle Scholar
Marcus, NY, Brunt, EM, Blomenkamp, K, Ali, F, Rudnick, DA, Ahmad, M, Teckman, JH. Characteristics of hepatocellular carcinoma in a murine model of alpha-1-antitrypsin deficiency. Hepatol Res 2010;40:641–53.CrossRefGoogle Scholar
Janus, ED, Phillips, NT, Carrell, RW. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet 1985;1:152–4.Google ScholarPubMed
Silverman, EK, Province, MA, Rao, DC, Pierce, JA, Campbell, EJ. A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes. Am Rev Respir Dis 1990;142:1015–21.Google ScholarPubMed
Crystal, RG. Augmentation treatment for alpha1 antitrypsin deficiency. Lancet 2015;386:318–20.CrossRefGoogle ScholarPubMed
McElvaney, NG, Burdon, J, Holmes, M, Glanville, A, Wark, PA, Thompson, PJ, Hernandez, P, et al. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med 2017;5:5160.CrossRefGoogle Scholar
Wang, Y, Perlmutter, DH. Targeting intracellular degradation pathways for treatment of liver disease caused by alpha1-antitrypsin deficiency. Pediatr Res 2014;75:133–9.CrossRefGoogle ScholarPubMed
Teckman, JH, Qu, D, Perlmutter, DH. Molecular pathogenesis of liver disease in alpha1-antitrypsin deficiency.Hepatology 1996;24:1504–16.Google ScholarPubMed
Eriksson, S, Carlson, J, Velez, R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 1986;314:736–9.CrossRefGoogle ScholarPubMed
Zhou, H, Fischer, HP. Liver carcinoma in PiZ alpha-1-antitrypsin deficiency. Am J Surg Pathol 1998;22:742–8.CrossRefGoogle ScholarPubMed
Mostafavi, B, Diaz, S, Tanash, HA, Piitulainen, E. Liver function in alpha-1-antitrypsin deficient individuals at 37 to 40 years of age. Medicine 2017;96:e6180.CrossRefGoogle ScholarPubMed
Sveger, T. The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand 1988;77:847–51.CrossRefGoogle ScholarPubMed
Chu, AS, Chopra, KB, Perlmutter, DH. Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency more common in children or adults? Liver Transpl 2016;22:886–94.CrossRefGoogle ScholarPubMed
Volpert, D, Molleston, JP, Perlmutter, DH. Alpha1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastroenterol Nutr 2000;31:258–63.CrossRefGoogle ScholarPubMed
Schaefer, B, Mandorfer, M, Viveiros, A, Finkenstedt, A, Ferenci, P, Schneeberger, S, Tilg, H, et al. Heterozygosity for the alpha-1-antitrypsin Z allele in cirrhosis is associated with more advanced disease. Liver Transpl 2018;24:744–51.CrossRefGoogle Scholar
Piitulainen, E, Carlson, J, Ohlsson, K, Alpha, Sveger T. 1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest 2005;128:2076–81.CrossRefGoogle ScholarPubMed
Teckman, JH, Perlmutter, DH. Retention of mutant alpha(1)-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am J Physiol Gastrointest Liver Physiol 2000;279:G961–74.CrossRefGoogle Scholar
von Schonfeld, J, Breuer, N, Zotz, R, Liedmann, H, Wencker, M, Beste, M, Konietzko, N, et al. Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ). Digestion 1996;57:165–9.Google Scholar
Tomashefski, JF Jr., Crystal, RG, Wiedemann, HP, Mascha, E, Stoller, JK. Alpha 1-Antitrypsin Deficiency Registry Study Group. The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the National Registry for Individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol 2004;35:1452–61.CrossRefGoogle Scholar
Corley, M, Solem, A, Phillips, G, Lackey, L, Ziehr, B, Vincent, HA, Mustoe, AM, et al. An RNA structure-mediated, posttranscriptional model of human alpha-1-antitrypsin expression. Proc Natl Acad Sci U S A 2017;114:E10244E10253.CrossRefGoogle ScholarPubMed
Owen, MC, Brennan, SO, Lewis, JH, Carrell, RW. Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder. N Engl J Med 1983;309:694–8.CrossRefGoogle Scholar
Mast, AE, Enghild, JJ, Nagase, H, Suzuki, K, Pizzo, SV, Salvesen, G. Kinetics and physiologic relevance of the inactivation of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and antithrombin III by matrix metalloproteinases-1 (tissue collagenase), -2 (72-kDa gelatinase/type IV collagenase), and -3 (stromelysin). J Biol Chem 1991;266:15810–16.CrossRefGoogle Scholar
Janoff, A. Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis. Am Rev Respir Dis 1985;132:417–33.Google ScholarPubMed
Ni, K, Serban, KA, Batra, C, Petrache, I. Alpha-1 antitrypsin investigations using animal models of emphysema. Ann Am Thorac Soc 2016;13(Suppl4):S311–16.CrossRefGoogle ScholarPubMed
Borel, F, Sun, H, Zieger, M, Cox, A, Cardozo, B, Li, W, Oliveira, G, et al. Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A 2018;115:2788–93.CrossRefGoogle ScholarPubMed
Munch, J, Standker, L, Adermann, K, Schulz, A, Schindler, M, Chinnadurai, R, Pohlmann, S, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 2007;129:263–75.CrossRefGoogle ScholarPubMed
Forssmann, WG, The, YH, Stoll, M, Adermann, K, Albrecht, U, Tillmann, HC, Barlos, K, et al. Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci Transl Med 2010;2:63.CrossRefGoogle ScholarPubMed
Janciauskiene, SM, Bals, R, Koczulla, R, Vogelmeier, C, Kohnlein, T, Welte, T. The discovery of alpha1-antitrypsin and its role in health and disease. Respir Med 2011;105:1129–39.CrossRefGoogle ScholarPubMed
Perlmutter, DH, Cole, FS, Kilbridge, P, Rossing, TH, Colten, HR. Expression of the alpha 1-proteinase inhibitor gene in human monocytes and macrophages. Proc Natl Acad Sci U S A 1985;82:795–9.CrossRefGoogle ScholarPubMed
Koopman, P, Povey, S, Lovell-Badge, RH. Widespread expression of human alpha 1-antitrypsin in transgenic mice revealed by in situ hybridization. Genes Dev 1989;3:1625.CrossRefGoogle ScholarPubMed
Carlson, JA, Rogers, BB, Sifers, RN, Hawkins, HK, Finegold, MJ, Woo, SL. Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. J Clin Invest 1988;82:2636.CrossRefGoogle ScholarPubMed
Sidhar, SK, Lomas, DA, Carrell, RW, Foreman, RC. Mutations which impede loop/sheet polymerization enhance the secretion of human alpha 1-antitrypsin deficiency variants. J Biol Chem 1995;270:8393–6.CrossRefGoogle ScholarPubMed
Carrell, RW, Lomas, DA. Conformational disease. Lancet 1997;350:134–8.CrossRefGoogle ScholarPubMed
Lomas, DA, Evans, DL, Finch, JT, Carrell, RW. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992;357:605–7.CrossRefGoogle Scholar
Lomas, DA, Elliott, PR, Sidhar, SK, Foreman, RC, Finch, JT, Cox, DW, Whisstock, JC, et al. alpha 1-Antitrypsin Mmalton (Phe52-deleted) forms loop-sheet polymers in vivo. Evidence for the C sheet mechanism of polymerization. J Biol Chem 1995;270:16864–70.Google ScholarPubMed
Lomas, DA, Finch, JT, Seyama, K, Nukiwa, T, Carrell, RW. Alpha 1-antitrypsin Siiyama (Ser53–>Phe). Further evidence for intracellular loop-sheet polymerization. J Biol Chem 1993;268:15333–5.Google Scholar
Curiel, DT, Holmes, MD, Okayama, H, Brantly, ML, Vogelmeier, C, Travis, WD, Stier, LE, et al. Molecular basis of the liver and lung disease associated with the alpha 1-antitrypsin deficiency allele Mmalton. J Biol Chem 1989;264:13938–45.CrossRefGoogle ScholarPubMed
Mahadeva, R, Chang, WS, Dafforn, TR, Oakley, DJ, Foreman, RC, Calvin, J, Wight, DG, et al. Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. J Clin Invest 1999;103:9991006.CrossRefGoogle Scholar
Dafforn, TR, Mahadeva, R, Elliott, PR, Sivasothy, P, Lomas, DA. A kinetic mechanism for the polymerization of alpha1-antitrypsin. J Biol Chem 1999;274:9548–55.CrossRefGoogle ScholarPubMed
Yamasaki, M, Li, W, Johnson, DJ, Huntington, JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 2008;455:1255–8.CrossRefGoogle ScholarPubMed
Whisstock, JC, Silverman, GA, Bird, PI, Bottomley, SP, Kaiserman, D, Luke, CJ, Pak, SC, et al. Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions. J Biol Chem 2010;285:24307–12.Google ScholarPubMed
Yamasaki, M, Sendall, TJ, Pearce, MC, Whisstock, JC, Huntington, JA. Molecular basis of alpha1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer. EMBO Rep 2011;12:1011–17.CrossRefGoogle ScholarPubMed
Huang, X, Zheng, Y, Zhang, F, Wei, Z, Wang, Y, Carrell, RW, Read, RJ, et al. Molecular mechanism of Z alpha1-antitrypsin deficiency. J Biol Chem 2016;291:15674–86.CrossRefGoogle ScholarPubMed
Lin, L, Schmidt, B, Teckman, J, Perlmutter, DH. A naturally occurring nonpolymerogenic mutant of alpha 1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum. J Biol Chem 2001;276:33893–8.CrossRefGoogle ScholarPubMed
Schmidt, BZ, Perlmutter, DH. Grp78, Grp94, and Grp170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol 2005;289:G444–55.CrossRefGoogle ScholarPubMed
Kuznetsov, G, Nigam, SK. Folding of secretory and membrane proteins. N Engl J Med 1998;339:1688–95.CrossRefGoogle ScholarPubMed
Davis, RL, Shrimpton, AE, Holohan, PD, Bradshaw, C, Feiglin, D, Collins, GH, Sonderegger, P, et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature 1999;401:376–9.CrossRefGoogle ScholarPubMed
Perlmutter DH. Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med 2011;62:333–45.Google Scholar
Wu, Y, Whitman, I, Molmenti, E, Moore, K, Hippenmeyer, P, Perlmutter, DH. A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc Natl Acad Sci U S A 1994;91:9014–18.CrossRefGoogle ScholarPubMed
Kamimoto, T, Shoji, S, Hidvegi, T, Mizushima, N, Umebayashi, K, Perlmutter, DH, Yoshimori, T. Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 2006;281:4467–76.CrossRefGoogle Scholar
Kruse, KB, Brodsky, JL, McCracken, AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell 2006;17:203–12.CrossRefGoogle Scholar
Kruse, KB, Dear, A, Kaltenbrun, ER, Crum, BE, George, PM, Brennan, SO, McCracken, AA. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 2006;168:1299–308.CrossRefGoogle ScholarPubMed
Cabral, CM, Choudhury, P, Liu, Y, Sifers, RN. Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 2000;275:25015–22.CrossRefGoogle ScholarPubMed
Gelling, CL, Dawes, IW, Perlmutter, DH, Fisher, EA, Brodsky, JL. The endosomal protein-sorting receptor sortilin has a role in trafficking alpha-1 antitrypsin. Genetics 2012;192:889903.CrossRefGoogle Scholar
Long, OS, Benson, JA, Kwak, JH, Luke, CJ, Gosai, SJ, O’Reilly, LP, Wang, Y, et al. A C. elegans model of human alpha1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum Mol Genet 2014;23:5109–22.CrossRefGoogle Scholar
Mizushima, N, Yamamoto, A, Matsui, M, Yoshimori, T, Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101–11.CrossRefGoogle ScholarPubMed
Hidvegi, T, Mirnics, K, Hale, P, Ewing, M, Beckett, C, Perlmutter, DH. Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant alpha1-antitrypsin Z in the classical form of alpha1-antitrypsin deficiency. J Biol Chem 2007;282:27769–80.CrossRefGoogle Scholar
Hidvegi, T, Schmidt, BZ, Hale, P, Perlmutter, DH. Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem 2005;280:39002–15.CrossRefGoogle Scholar
Mukherjee, A, Hidvegi, T, Araya, P, Ewing, M, Stolz, DB, Perlmutter, DH. NFkappaB mitigates the pathological effects of misfolded alpha1-antitrypsin by activating autophagy and an integrated program of proteostasis mechanisms. Cell Death Differ 2019;26(3):455–69.CrossRefGoogle Scholar
Liao, Y, Shikapwashya, ON, Shteyer, E, Dieckgraefe, BK, Hruz, PW, Rudnick, DA. Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice. J Biol Chem 2004;279:43107–16.CrossRefGoogle ScholarPubMed
Teckman, JH, An, JK, Blomenkamp, K, Schmidt, B, Perlmutter, D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol 2004;286:G851–62.CrossRefGoogle ScholarPubMed
Hidvegi, T, Stolz, DB, Alcorn, JF, Yousem, SA, Wang, J, Leme, AS, Houghton, AM, et al. Enhancing autophagy with drugs or lung-directed gene therapy reverses the pathological effects of respiratory epithelial cell proteinopathy. J Biol Chem 2015;290:29742–57.CrossRefGoogle ScholarPubMed
Pastore, N, Attanasio, S, Granese, B, Castello, R, Teckman, J, Wilson, AA, Ballabio, A, et al. Activation of the c-Jun N-terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1-antitrypsin. Hepatology 2017;65:1865–74.CrossRefGoogle ScholarPubMed
Pan, S, Huang, L, McPherson, J, Muzny, D, Rouhani, F, Brantly, M, Gibbs, R, et al. Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology 2009;50:275–81.CrossRefGoogle ScholarPubMed
Pan, S, Wang, S, Utama, B, Huang, L, Blok, N, Estes, MK, Moremen, KW, et al. Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell 2011;22:2810–22.CrossRefGoogle ScholarPubMed
Iannotti, MJ, Figard, L, Sokac, AM, Sifers, RN. A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control. J Biol Chem 2014;289:11844–58.CrossRefGoogle Scholar
Chappell, S, Guetta-Baranes, T, Hadzic, N, Stockley, R, Kalsheker, N. Polymorphism in the endoplasmic reticulum mannosidase I (MAN1B1) gene is not associated with liver disease in individuals homozygous for the Z variant of the alpha1-antitrypsin protease inhibitor (PiZZ individuals). Hepatology 2009;50:1315, author reply 1315–16.CrossRefGoogle Scholar
Joly, P, Lachaux, A, Ruiz, M, Restier, L, Belmalih, A, Chapuis-Cellier, C, Francina, A, et al. SERPINA1 and MAN1B1 polymorphisms are not linked to severe liver disease in a French cohort of alpha-1 antitrypsin deficiency children. Liver Int 2017;37:1608–11.CrossRefGoogle ScholarPubMed
Chappell, S, Hadzic, N, Stockley, R, Guetta-Baranes, T, Morgan, K, Kalsheker, N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology 2008;47:127–32.Google ScholarPubMed
Hubner, RH, Leopold, PL, Kiuru, M, De, BP, Krause, A, Crystal, RG. Dysfunctional glycogen storage in a mouse model of alpha1-antitrypsin deficiency. Am J Respir Cell Mol Biol 2009;40:239–47.CrossRefGoogle Scholar
Piccolo, P, Annunziata, P, Soria, LR, Attanasio, S, Barbato, A, Castello, R, Carissimo, A, et al. Down-regulation of hepatocyte nuclear factor-4alpha and defective zonation in livers expressing mutant Z alpha1-antitrypsin. Hepatology 2017;66:124–35.CrossRefGoogle ScholarPubMed
Teckman, J, Perlmutter, DH. Conceptual advances in the pathogenesis and treatment of childhood metabolic liver disease.Gastroenterology 1995;108:1263–79.CrossRefGoogle ScholarPubMed
Tafaleng, EN, Chakraborty, S, Han, B, Hale, P, Wu, W, Soto-Gutierrez, A, Feghali-Bostwick, CA, et al. Induced pluripotent stem cells model personalized variations in liver disease resulting from alpha1-antitrypsin deficiency. Hepatology 2015;62:147–57.Google ScholarPubMed
Lindblad, D, Blomenkamp, K, Teckman, J. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 2007;46:1228–35.CrossRefGoogle Scholar
Dooley, S, Hamzavi, J, Ciuclan, L, Godoy, P, Ilkavets, I, Ehnert, S, Ueberham, E, et al. Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. Gastroenterology 2008;135:642–59.CrossRefGoogle ScholarPubMed
Bridges, JP, Wert, SE, Nogee, LM, Weaver, TE. Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J Biol Chem 2003;278:52739–46.CrossRefGoogle ScholarPubMed
Young, LR, Gulleman, PM, Bridges, JP, Weaver, TE, Deutsch, GH, Blackwell, TS, McCormack, FX. The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome. Am J Respir Crit Care Med 2012;186:1014–24.CrossRefGoogle ScholarPubMed
Bhuiyan, MS, Pattison, JS, Osinska, H, James, J, Gulick, J, McLendon, PM, Hill, JA, et al. Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 2013;123:5284–97.CrossRefGoogle ScholarPubMed
Doppler, K, Mittelbronn, M, Lindner, A, Bornemann, A. Basement membrane remodelling and segmental fibrosis in sporadic inclusion body myositis. Neuromuscul Disord 2009;19:406–11.CrossRefGoogle ScholarPubMed
Nogalska, A, D’Agostino, C, Terracciano, C, Engel, WK, Askanas, V. Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers. Am J Pathol 2010;177:1377–87.CrossRefGoogle ScholarPubMed
Rudnick, DA, Liao, Y, An, JK, Muglia, LJ, Perlmutter, DH, Teckman, JH. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology 2004;39:1048–55.CrossRefGoogle Scholar
Rudnick, DA, Perlmutter, DH. Alpha-1-antitrypsin deficiency: a new paradigm for hepatocellular carcinoma in genetic liver disease. Hepatology 2005;42:514–21.CrossRefGoogle ScholarPubMed
Ding, J, Yannam, GR, Roy-Chowdhury, N, Hidvegi, T, Basma, H, Rennard, SI, Wong, RJ, et al. Spontaneous hepatic repopulation in transgenic mice expressing mutant human alpha1-antitrypsin by wild-type donor hepatocytes. J Clin Invest 2011;121:1930–4.CrossRefGoogle ScholarPubMed
Kemmer, N, Kaiser, T, Zacharias, V, Neff, GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant Proc 2008;40:1492–4.CrossRefGoogle ScholarPubMed
Tannuri, AC, Gibelli, NE, Ricardi, LR, Santos, MM, Maksoud-Filho, JG, Pinho-Apezzato, ML, Silva, MM, et al. Living related donor liver transplantation in children. Transplant Proc 2011;43:161–4.CrossRefGoogle ScholarPubMed
Sarkar, S, Perlstein, EO, Imarisio, S, Pineau, S, Cordenier, A, Maglathlin, RL, Webster, JA, et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 2007;3:331–8.CrossRefGoogle ScholarPubMed
Li, C, Xiao, P, Gray, SJ, Weinberg, MS, Samulski, RJ. Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins. Proc Natl Acad Sci U S A 2011;108:14258–63.CrossRefGoogle Scholar
Mueller, C, Tang, Q, Gruntman, A, Blomenkamp, K, Teckman, J, Song, L, Zamore, PD, et al. Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol Ther 2012;20:590600.CrossRefGoogle ScholarPubMed
Guo, S, Booten, SL, Aghajan, M, Hung, G, Zhao, C, Blomenkamp, K, Gattis, D, et al. Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice. J Clin Invest 2014;124:251–61.CrossRefGoogle ScholarPubMed
Pastore, N, Blomenkamp, K, Annunziata, F, Piccolo, P, Mithbaokar, P, Maria Sepe, R, Vetrini, F, et al. Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol Med 2013;5:397412.CrossRefGoogle ScholarPubMed
Shen, S, Sanchez, ME, Blomenkamp, K, Corcoran, EM, Marco, E, Yudkoff, CJ, Jiang, H, et al. Amelioration of alpha-1 antitrypsin deficiency diseases with genome editing in transgenic mice. Hum Gene Ther 2018;29(8):861–73.CrossRefGoogle ScholarPubMed
Song, CQ, Wang, D, Jiang, T, O’Connor, K, Tang, Q, Cai, L, Li, X, et al. In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency. Hum Gene Ther 2018;29(8):853–60.CrossRefGoogle Scholar
Mallya, M, Phillips, RL, Saldanha, SA, Gooptu, B, Brown, SC, Termine, DJ, Shirvani, AM, et al. Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates. J Med Chem 2007;50:5357–63.CrossRefGoogle Scholar
Alam, S, Wang, J, Janciauskiene, S, Mahadeva, R. Preventing and reversing the cellular consequences of Z alpha-1 antitrypsin accumulation by targeting s4A. J Hepatol 2012;57:116–24.CrossRefGoogle Scholar
Burrows, JA, Willis, LK, Perlmutter, DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci U S A 2000;97:1796–801.CrossRefGoogle Scholar
Teckman, JH. Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study. J Pediatr Gastroenterol Nutr 2004;39:34–7.CrossRefGoogle ScholarPubMed
Bouchecareilh, M, Hutt, DM, Szajner, P, Flotte, TR, Balch, WE. Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of alpha1-antitrypsin deficiency. J Biol Chem 2012;287:38265–78.CrossRefGoogle ScholarPubMed
Fox, IJ, Chowdhury, JR, Kaufman, SS, Goertzen, TC, Chowdhury, NR, Warkentin, PI, Dorko, K, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 1998;338:1422–6.CrossRefGoogle ScholarPubMed
Yusa, K, Rashid, ST, Strick-Marchand, H, Varela, I, Liu, PQ, Paschon, DE, Miranda, E, et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011;478:391–4.CrossRefGoogle ScholarPubMed


Kosorok, MR, Wei, WH, Farrell, PM. The incidence of cystic fibrosis. Stat Med 1996;15:449–62.3.0.CO;2-X>CrossRefGoogle ScholarPubMed
Dodge, JA, Morison, S, Lewis, PA, et al. Incidence, population, and survival of cystic fibrosis in the UK, 1968–95. UK Cystic Fibrosis Survey Management Committee. Arch Dis Child 1997;77:493–6.Google Scholar
Anderson, D. Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study. Am J Dis Child 1938;56(2):344–99.Google Scholar
Quinton, PM. Chloride impermeability in cystic fibrosis. Nature 1983;301 (5899):421–2.CrossRefGoogle ScholarPubMed
Riordan, JR, Rommens, JM, Kerem, B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245 (4922):1066–73.CrossRefGoogle ScholarPubMed
Schwiebert, EM, Benos, DJ, Egan, ME, Stutts, MJ, Guggino, WB. CFTR is a conductance regulator as well as a chloride channel. Physiol Rev 1999;79(1 Suppl):S145S166.CrossRefGoogle ScholarPubMed
Gabriel, SE, Clarke, LL, Boucher, RC, Stutts, MJ. CFT R and outward rectifying chloride channels are distinct proteins with a regulatory relationship. Nature 1993;363(6426):263–8.CrossRefGoogle Scholar
Dutta, AK, Khimji, AK, Kresge, C, et al. Identification and functional characterization of TMEM16A, a Ca2+-activated Cl channel activated by extracellular nucleotides in biliary epithelium. J Biol Chem 2011;286: 766–76.CrossRefGoogle ScholarPubMed
Li, Q, Kresge, C, Bugde, A, Lamphere, M, Park, JY, Feranchak, AP. Regulation of mechanosensitive biliary epithelial transport by the epithelial Na(+) channel. Hepatology 2016;63(2):538–49. doi:10.1002/hep.28301CrossRefGoogle ScholarPubMed
Braunstein, GM, Roman, RM, Clancy, JP, et al. Cystic fibrosis transmembrane conductance regulator facilitates ATP release by stimulating a separate ATP release channel for autocrine control of cell volume regulation. J Biol Chem 2001;276:6621–30.CrossRefGoogle ScholarPubMed
Fouassier, L, Duan, CY, Feranchak, AP, et al. Ezrin-radixin-moesin-binding phosphoprotein 50 is expressed at the apical membrane of rat liver epithelia. Hepatology 2001;33:166–76.CrossRefGoogle ScholarPubMed
Cohn, JA, Strong, TV, Picciotto, MR, et al. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 1993;105:1857–64.CrossRefGoogle ScholarPubMed
Fitz, JG, Basavappa, S, McGill, J, Melhus, O, Cohn, JA. Regulation of membrane chloride currents in rat bile duct epithelial cells. J Clin Invest 1993;91:319–28.CrossRefGoogle ScholarPubMed
Fitz, JG. (1996). Cellular mechanisms of bile secretion. In Zakim, D, Boyer, TD (Eds.), Hepatology, 3rd edn (pp. 362–76). Philadelphia, PA: Saunders.Google Scholar
Dutta, AK, Khimji, AK, Sathe, M, et al. Identification and functional characterization of the intermediate-conductance Ca(2+)-activated K(+) channel (IK-1) in biliary epithelium. Am J Physiol Gastrointest Liver Physiol 2009;297:G1009G1018.CrossRefGoogle Scholar
Feranchak, AP, Sokol, RJ. Cholangiocyte biology and cystic fibrosis liver disease. Sem Liv Disease 2001;21:471–88.Google ScholarPubMed
Clarke, LL, Grubb, BR, Yankaskas, JR, et al. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr(–/–) mice. Proc Natl Acad Sci USA 1994;91:479–83.CrossRefGoogle ScholarPubMed
Dutta, AK, Khimji, AK, Kresge, C, Bugde, A, Dougherty, M, Esser, V, Ueno, Y, Glaser, SS, Alpini, G, Rockey, DC, Feranchak, AP. Identification and functional characterization of TMEM16A, a Ca2+-activated Cl channel activated by extracellular nucleotides, in biliary epithelium. J Biol Chem. 2011 Jan 7;286(1):766–76. doi: 10.1074/jbc.M110.164970. Epub 2010 Nov 1. Scholar
Feranchak, AP, Fitz, JG. Adenosine triphosphate release and purinergic regulation of cholangiocyte transport. Semin Liver Dis 2002;22:251–62.CrossRefGoogle ScholarPubMed
Dutta, AK, Woo, K, Doctor, RB, Fitz, JG, Feranchak, AP. Extracellular nucleotides stimulate Cl currents in biliary epithelia through receptor-mediated IP3 and Ca2+ release. Am J Physiol Gastrointest Liver Physiol 2008;295:G1004G1015.CrossRefGoogle ScholarPubMed
Woo, K, Dutta, AK, Patel, V, Kresge, C, Feranchak, AP. Fluid flow induces mechanosensitive ATP release, calcium signalling and Cl transport in biliary epithelial cells through a PKCzeta-dependent pathway. J Physiol 2008;586(Pt 11):2779–98.CrossRefGoogle ScholarPubMed
Fiorotto, R, Scirpo, R, Trauner, M, et al. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4–NF-κB: mediated inflammatory response in mice. Gastroenterology 2011;141(4):1498–508.e5. doi:10.1053/j.gastro.2011.06.052CrossRefGoogle ScholarPubMed
Fiorotto, R, Villani, A, Kourtidis, A, et al. The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology 2016;64(6):2118–34. doi:10.1002/hep.28817CrossRefGoogle ScholarPubMed
Gabriel, SE, Brigman, KN, Koller, BH, Boucher, RC, Stutts, MJ. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 1994;266(5182):107–9.CrossRefGoogle ScholarPubMed
Quinton, PM. Role of epithelial HCO3 transport in mucin secretion: lessons from cystic fibrosis. Am J Physiol Cell Physiol 2010;299:C1222C1233.CrossRefGoogle ScholarPubMed
Debray, D, El Mourabit, H, Merabtene, F, et al. Diet-induced dysbiosis and genetic background synergize with cystic fibrosis transmembrane conductance regulator deficiency to promote cholangiopathy in mice. Hepatol Commun 2018;2(12):1533–49. doi:10.1002/hep4.1266CrossRefGoogle ScholarPubMed
Scanlan, PD, Buckling, A, Kong, W, Wild, Y, Lynch, S V, Harrison, F. Gut dysbiosis in cystic fibrosis. J Cyst Fibros 2012;11(5):454–5. doi:10.1016/j.jcf.2012.03.007CrossRefGoogle ScholarPubMed
Parisi, GF, Papale, M, Rotolo, N, et al. Severe disease in cystic fibrosis and fecal calprotectin levels. Immunobiology 2017;222(3):582–6. doi:10.1016/j.imbio.2016.11.005CrossRefGoogle ScholarPubMed
Blanco, PG, Zaman, MM, Junaidi, O, et al. Induction of colitis in cftr −/− mice results in bile duct injury. Am J Physiol Liver Physiol. 2004;287(2):G491G496. doi:10.1152/ajpgi.00452.2003Google ScholarPubMed
Flass, T, Tong, S, Frank, DN, et al. Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis. PLoS One. 2015;10(2):e0116967. doi:10.1371/journal.pone.0116967CrossRefGoogle Scholar
Smith, JL, Lewindon, PJ, Hoskins, AC, et al. Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic fibrosis. Hepatology 2004;39:1673–82.CrossRefGoogle ScholarPubMed
Brazova, J, Sediva, A, Pospisilova, D, et al. Differential cytokine profile in children with cystic fibrosis. Clin Immunol. 2005;115(2):210–15. doi:10.1016/j.clim.2005.01.013CrossRefGoogle ScholarPubMed
Jacquot, J, Tabary, O, Le Rouzic, P, Clement, A. Airway epithelial cell inflammatory signalling in cystic fibrosis. Int J Biochem Cell Biol. 2008;40(9):1703–15. doi:10.1016/j.biocel.2008.02.002CrossRefGoogle ScholarPubMed
Paats, MS, Bergen, IM, Bakker, M, et al. Cytokines in nasal lavages and plasma and their correlation with clinical parameters in cystic fibrosis. J Cyst Fibros. 2013;12(6):623–9. doi:10.1016/j.jcf.2013.05.002CrossRefGoogle ScholarPubMed
McGill, JM, Yen, MS, Cummings, OW, et al. Interleukin-5 inhibition of biliary cell chloride currents and bile flow. Am J Physiol Gastrointest Liver Physiol 2001;280(4):G738–45. doi:10.1152/ajpgi.2001.280.4.G738CrossRefGoogle ScholarPubMed
Spirlì, C, Fabris, L, Duner, E, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 2003;124(3):737–53. doi:10.1053/gast.2003.50100CrossRefGoogle ScholarPubMed
Spirlì, C, Nathanson, MH, Fiorotto, R, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology 2001;121(1):156–69. doi:10.1053/gast.2001.25516CrossRefGoogle ScholarPubMed
Sun, H, Harris, WT, Kortyka, S, et al. Tgf-beta downregulation of distinct chloride channels in cystic fibrosis-affected epithelia. PLoS One. 2014;9(9):e106842. doi:10.1371/journal.pone.0106842CrossRefGoogle ScholarPubMed
Lewindon, PJ, Pereira, TN, Hoskins, AC, et al. The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Am J Pathol 2002;160:1705–15.CrossRefGoogle Scholar
Fiorotto, R, Amenduni, M, Mariotti, V, et al. Animal models for cystic fibrosis liver disease. Biochim Biophys Acta – Mol Basis Dis 2019;1865(5):965–9. doi:10.1016/j.bbadis.2018.07.026CrossRefGoogle ScholarPubMed
Bartlett, JR, Friedman, KJ, Ling, SC, et al. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009;302:1076–83.CrossRefGoogle ScholarPubMed
Duthie, A, Doherty, DG, Donaldson, PT, et al. The major histocompatibility complex influences the development of chronic liver disease in male children and young adults with cystic fibrosis. J Hepatol 1995;23:532–7.CrossRefGoogle Scholar
Cystic Fibrosis Foundation (CFF). 2017 Patient Registry: Annual Data Report. Cyst Fibros Found Patient Regist. 2017:92.Google Scholar
Vawter, GF, Shwachman, H. Cystic fibrosis in adults: an autopsy study. Pathol Annu 1979;14:357–82.Google Scholar
Debray, D, Kelly, D, Houwen, R, Strandvik, B, Colombo, C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros 2011;10:S29S36.CrossRefGoogle ScholarPubMed
Boëlle, P, Debray, D, Guillot, L, et al. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients. Hepatology 2019;69(4):1648–56. doi: Scholar
Koh, C, Sakiani, S, Surana, P, et al. Adult-onset cystic fibrosis liver disease: diagnosis and characterization of an underappreciated entity. Hepatology 2017;66(2):591601. doi: ScholarPubMed
Colombo, C, Apostolo, MG, Ferrari, M, et al. Analysis of risk factors for the development of liver disease associated with cystic fibrosis. J Pediatr 1994;124:393–9.CrossRefGoogle ScholarPubMed
Sokol, RJ, Durie, PR. Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr 1999;28(Suppl1):S1S13.Google ScholarPubMed
Flass, T, Narkewicz, MR. Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros. 2013;12(2):116–24. doi: ScholarPubMed
Sokol, RJ, Carroll, NM, Narkewicz, MR, et al. Liver blood tests during the first decade of life in children with cystic fibrosis identified by newborn screening. Pediatr Pulm 1994;10:275.Google Scholar
Woodruff, SA, Sontag, MK, Accurso, FJ, Sokol, RJ, Narkewicz, MR. Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen. J Cyst Fibros 2017;16(1):139–45. doi: ScholarPubMed
Loverdos, I, Gonska, T, Ling, SC. Platelet count enables early diagnosis of cystic fibrosis liver disease (Conference Workshop WS17.3). J Cyst Fibros. 2016;15:S28.CrossRefGoogle Scholar
Patriquin, H, Lenaerts, C, Smith, L, et al. Liver disease in children with cystic fibrosis: US-biochemical comparison in 195 patients. Radiology 1999;211: 229–32.CrossRefGoogle ScholarPubMed
Lenaerts, C, Lapierre, C, Patriquin, H, et al. Surveillance for cystic fibrosis- associated hepatobiliary disease: early ultrasound changes and predisposing factors. J Pediatr 2003;143:343–50.CrossRefGoogle ScholarPubMed
Narkewicz, MR. Cystic fibrosis liver disease: what is it and what happens as a result. Pediatr Pulmonol 2018;53(Supplement2):81–2. doi: Scholar
Ling, SC, Ye, W, Leung, DH, et al. Liver ultrasound patterns in children with cystic fibrosis correlate with non-invasive tests of liver disease. J Pediatr Gastroenterol Nutr 2019;69:351. doi:10.1097/mpg.0000000000002413CrossRefGoogle Scholar
Ling, SC. The use of serum biomarkers and imaging in the diagnosis and prediction of outcomes in CF liver disease. Pediatr Pulmonol 2018;53(Supplement2):8586. doi: Scholar
Sathe, MN, Freeman, AJ. Gastrointestinal, pancreatic, and hepatobiliary manifestations of cystic fibrosis. Pediatr Clin North Am 2016;63(4):679–98. doi: ScholarPubMed
Aqul, A, Jonas, MM, Harney, S, et al. Correlation of transient elastography with severity of cystic fibrosis-related liver disease. J Pediatr Gastroenterol Nutr 2017;64(4):505–11. doi: ScholarPubMed
Gominon, A-L, Frison, E, Hiriart, J-B, et al. Assessment of liver disease progression in cystic fibrosis using transient elastography. J Pediatr Gastroenterol Nutr 2018;66(3):455–60. doi: ScholarPubMed
Lewindon, PJ, Puertolas-Lopez, MV. , Ramm, LE, et al. Accuracy of transient elastography data combined with APRI in detection and staging of liver disease in pediatric patients with cystic fibrosis. Clin Gastroenterol Hepatol 2019. doi:10.1016/j.cgh.2019.03.015CrossRefGoogle Scholar
Leung, DH, Khan, M, Minard, CG, et al. Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease. Hepatology 2015;62(5):1576–83. doi: ScholarPubMed
Ling, SC, Ye, W, Leung, DH, et al. Baseline liver echotexture in children with cystic fibrosis predicts changes over time in non-invasive biomarkers of fibrosis and portal hypertension. J Pediatr Gastroenterol Nutr 2017;65(Supplement 1):77A-78A. doi: Scholar
Cook, NL, Pereira, TN, Lewindon, PJ, Shepherd, RW, Ramm, GA. Circulating microRNAs as noninvasive diagnostic biomarkers of liver disease in children with cystic fibrosis. J Pediatr Gastroenterol Nutr 2015;60(2):247–54. doi:10.1097/MPG.0000000000000600CrossRefGoogle ScholarPubMed
Heuman, DM. Hepatoprotective properties of ursodeoxycholic acid. Gastroenterology 1993;104:1865–70.CrossRefGoogle ScholarPubMed
Shimokura, GH, McGill, JM, Schlenker, T, Fitz, JG. Ursodeoxycholate increases cytosolic calcium concentration and activates Cl currents in a biliary cell line. Gastroenterology 1995;109:965–72.CrossRefGoogle Scholar
Colombo, C, Crosignani, A, Assaisso, M, et al. Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study. Hepatology 1992;16:924–30.CrossRefGoogle ScholarPubMed
Lindblad, A, Glaumann, H, Strandvik, B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology 1998;27:166–74.CrossRefGoogle ScholarPubMed
Nousia-Arvanitakis, S, Fotoulaki, M, Economou, H, Xefteri, M, Galli-Tsinopoulou, A. Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease. J Clin Gastroenterol 2001;32:324–8.CrossRefGoogle ScholarPubMed
Lindor, KD, Kowdley, KV, Luketic, VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50:808–14.CrossRefGoogle ScholarPubMed
Gong, Y, Huang, ZB, Christensen, E, Gluud, C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2008;8:CD000551.Google Scholar
Ooi, CY, Nightingale, S, Durie, PR, Freedman, SD. Ursodeoxycholic acid in cystic fibrosis-associated liver disease. J Cyst Fibros 2012;11:72–3.CrossRefGoogle ScholarPubMed
Cheng, K, Ashby, D, Smyth, RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev 2017;9:CD000222. doi: ScholarPubMed
Ye, W, Narkewicz, MR, Leung, DH, et al. Variceal hemorrhage and adverse liver outcomes in patients with cystic fibrosis cirrhosis. J Pediatr Gastroenterol Nutr 2018;66(1):122–7. doi: ScholarPubMed
Lemoine, C, Lokar, J, McColley, SA, Alonso, EM, Superina, R. Cystic fibrosis and portal hypertension: Distal splenorenal shunt can prevent the need for future liver transplant. J Pediatr Surg 2019. doi: Scholar
Molleston, J. Medical and surgical management of complication of portal hypertension in CF. Pediatr Pulmonol 2018;53:S84–5.Google Scholar
Gridelli, B. Liver: benefit of liver transplantation in patients with cystic fibrosis. Nat Rev Gastroenterol Hepatol 2011;8:187–8.CrossRefGoogle ScholarPubMed
Yang, Y, Raper, SE, Cohn, JA, Engelhardt, JF, Wilson, JM. An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer. Proc Natl Acad Sci USA 1993;90:4601–5.CrossRefGoogle ScholarPubMed
Becq, F, Mall, MA, Sheppard, DN, Conese, M, Zegarra-Moran, O. Pharmacological therapy for cystic fibrosis: from bench to bedside.J Cyst Fibros 2011;10(Suppl2):S129S145.CrossRefGoogle ScholarPubMed
Hayes, D, Warren, PS, McCoy, KS, Sheikh, SI. Improvement of hepatic steatosis in cystic fibrosis with ivacaftor therapy. J Pediatr Gastroenterol Nutr 2015;60(5):578–9. doi:10.1097/MPG.0000000000000765CrossRefGoogle ScholarPubMed
Chaudary, N. Triplet CFTR modulators: future prospects for treatment of cystic fibrosis. Ther Clin Risk Manag 2018;14:2375–83. doi:10.2147/TCRM.S147164CrossRefGoogle ScholarPubMed
Bodewes, FAJA, van der Wulp, MYM, Beharry, S, et al. Altered intestinal bile salt biotransformation in a cystic fibrosis (Cftr−/−) mouse model with hepato-biliary pathology. J Cyst Fibros 2015;14(4):440–6. doi:10.1016/j.jcf.2014.12.010CrossRefGoogle Scholar
Van de Peppel, IP, Bodewes, FAJA, Verkade, HJ, Jonker, JW. Bile acid homeostasis in gastrointestinal and metabolic complications of cystic fibrosis. J Cyst Fibros. 2019;18(3):313–20. doi:10.1016/j.jcf.2018.08.009CrossRefGoogle ScholarPubMed
Wiest, R, Albillos, A, Trauner, M, Bajaj, JS, Jalan, R. Targeting the gut-liver axis in liver disease. J Hepatol 2017;67(5):1084–103. doi:10.1016/j.jhep.2017.05.007CrossRefGoogle ScholarPubMed


Mason, HH, Turner, ME. Chronic galactosemia. Am J Dis Child 1935;50:359.CrossRefGoogle Scholar
Wada, Y, Kikuchi, A, Arai-Ichinoi, N, Sakamoto, O, Takezawa, Y, Iwasawa, S, Niihori, T Nyuzuki, H. U. A.: biallelic GALM pathogenic variants cause a novel type of galactosemia. Genet Med 2019;6:1286–94.Google Scholar
Donnell, GN, Bergren, WR, Cleland, RS. Galactosemia. Pediatr Clin North Am 1960;7:315–32.CrossRefGoogle ScholarPubMed
Gitzelmann, R. Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res 1967;1:1423.CrossRefGoogle Scholar
Gitzelmann, R, Steinmann, B, Mitchell, B, et al. Uridine diphosphate galactose-4- epimerase deficiency. IV. Report of eight cases in three families. Helv Paediatr Acta 1977;31:441–52.Google ScholarPubMed
Holton, JB, Gillett, MG, MacFaul, R, et al. Galactosemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency.Arch Dis Child 1981;56: 885–7.CrossRefGoogle ScholarPubMed
Holton, JB. Galactosaemia: pathogenesis and treatment. J Inherit Metab Dis 1996;19:37.CrossRefGoogle ScholarPubMed
Hopfer, U. (1987). Membrane transport mechanisms for hexoses and amino acids in the small intestine. In Johnson, LR, Christensen, J, Jackson, MJ (Eds.) Physiology of the Gastrointestinal Tract, 2nd edn. (pp. 1499–526). New York: Raven Press.Google Scholar
Timson, DJ. Type IV galactosemia. Genet Med 2019;21(6):1283–5.CrossRefGoogle ScholarPubMed
Shin-Buehring, YS, Beier, T, Tan, A, et al. Galactokinase and galactose-1-phosphate uridyltransferase (transferase) and galactokinase in human fetal organs. Pediatr Res 1977;11:1012.CrossRefGoogle ScholarPubMed
Coelho, AI, Rubio-Gozalbo, ME, Vicente, JB, Rivera, I. Sweet and sour: an update on classic galactosemia. J Inherit Metab Dis 2017;40(3):325–42.CrossRefGoogle ScholarPubMed
Segal, S, Blair, A. Some observations on the metabolism of d-galactose in normal man. J Clin Invest 1961;40:2016–25.CrossRefGoogle Scholar
Tygstrup, N. Determination of the hepatic elimination capacity (LM) of galactose by single injection. ScandJ Clin Lab Invest 1966;92(Suppl. 18):118–25.Google Scholar
Lemaire, HG, Muller-Hill, B. Nucleotide sequences of the gal E gene and the gal T gene of E. coli. Nucleic Acids Res 1986;14:7705–11.CrossRefGoogle Scholar
Flach, JE, Reichardt, TKV, Elsas, LJ. Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase. Mol Biol Med 1990;7:365–9.Google ScholarPubMed
Field, TL, Reznikoff, WS, Frey, PA. Galactose-1-phosphate uridylyltransferase: identification of histidine-164 and histidine-166 as critical residues by site-directed mutagenesis. Biochemistry 1989;28:2094–9.CrossRefGoogle ScholarPubMed
Reichardt, JKV, Woo, SLC. Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridyl transferase. Proc Natl Acad Sci USA 1991;88:2633–7.CrossRefGoogle Scholar
Calderon, FR, Pharsalker, AR, Crockett, DK, et al. Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene. Hum Mutat 2007;28:939–43.CrossRefGoogle ScholarPubMed
Tyfield, L, Reichardt, J, Fridovich-Keil, J, et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 1999;13:417–30.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
Reichardt, JK, Levy, HL, Woo, SL. Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure–function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry 1992;31:5430–3.CrossRefGoogle ScholarPubMed
Berry, GT. (1993). Classic galactosemia and clinical variant galactosemia. In Adam, MP, Ardinger, HH, Pagon, RA, Wallace, SE, Bean, LJ, Stephens, K, Amemiya, A. GeneReviews®. Seattle: University of Washington.Google Scholar
Wang, BB, Xu, YK, Ng, WG, et al. Molecular and biochemical basis of galactosemia. Mol Genet Metab 1998;63:263–9.CrossRefGoogle ScholarPubMed
Welling, L, Bernstein, LE, Berry, GT, Burlina, AB, Eyskens, F, Gautschi, M, Grünewald, S, Gubbels, CS. International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis 2017;40(2):171–6.CrossRefGoogle Scholar
Levy, HL, Sepe, SJ, Shih, VE, et al. Sepsis due to Escherichia coli in neonates with galactosemia. N Engl J Med 1977;297:823–5.CrossRefGoogle ScholarPubMed
Litchfield, WJ, Wells, WW. Effects of galactose on free radical reactions of polymorphonuclear leukocytes. Arch Biochem Biophys 1978;188:2630.CrossRefGoogle ScholarPubMed
Segal, S, Blair, A, Roth, H. The metabolism of galactose by patients with congenital galactosemia. Am J Med 1965;38:6270.CrossRefGoogle Scholar
Segal, S. (1989). Disorders of galactose metabolism. In Stanbury, JB, Wyngaarden, JB, Frederickson, DS (Eds.) The Metabolic Basis of Inherited Disease, 6th edn. (pp. 453–80). New York: McGraw- Hill.Google Scholar
Belman, AL, Moshe, SL, Zimmerman, RD. Computered tomographic demonstration of cerebral edema in a child with galactosemia. Pediatrics 1986;78:606–9.Google Scholar
Sidbury, JB Jr. (1960). The role of galactose-1-phosphate in the pathogenesis of galactosemia. In Gardner, LE (Ed.), Molecular Genetics and Human Disease (p. 61). Springfield, IL: Charles C Thomas.Google Scholar
Tada, K. Glycogenesis and glycolysis in the liver from congenital galactosemia. Tohoku J Exp Med 1964;82:168–71.CrossRefGoogle ScholarPubMed
Keppler, D, Decker, K. Studies on the mechanisms of galactosamine hepatitis: accumulation of galactosamine-1-phosphate and its inhibition of UDP-glucose pyrophosphorylase. EurJ Biochem 1969;10:219–25.CrossRefGoogle Scholar
Quan-Ma, R, Wells, W. The distribution of galactitol in tissues of rats fed galactose. Biochem Biophys Res Commun 1965;20:486–90.CrossRefGoogle ScholarPubMed
Schwarz, V. The value of galactose phosphate determinations in the treatment of galactosemia. Arch Dis Child 1960;35:428–32.CrossRefGoogle Scholar
Thier, S, Fox, M, Rosenberg, L, et al. Hexose inhibition of amino acid uptake in the rat kidney cortex slice. Biochim Biophys Acta 1964;93:106–15.Google ScholarPubMed
Saunders, S, Isselbacher, KJ. Inhibition of intestinal amino acid transport by hexoses. Biochim Biophys Acta 1965;102:397409.CrossRefGoogle ScholarPubMed
van Heyningen, R. Formation of polyols by the lens of the rat with “sugar” cataract. Nature 1959;184:194–5.CrossRefGoogle Scholar
Kinoshita, JH, Dvornik, D, Krami, M, et al. The effect of aldose reductase inhibitor on the galactose-exposed rabbit lens. Biochim Biophys Acta 1968;158:472–5.Google ScholarPubMed
Dische, Z, Zelmenis, G, Youlous, J. Studies on protein and protein synthesis during the development of galactose cataract. Am J Ophthalmol 1957;44:332–40.CrossRefGoogle Scholar
Kinoshita, JH, Merola, LO, Tung, B. Changes in cation permeability in the galactose-exposed rabbit lens. Exp Eye Res 1968;7:8090.CrossRefGoogle ScholarPubMed
Granett, SE, Kozak, LP, McIntyre, JP, et al. Studies on cerebral energy metabolism during the course of galactose neurotoxicity in chicks.J Neurochem 1972;19:1659–70.CrossRefGoogle ScholarPubMed
Malone, JI, Wells, HJ, Segal, S. Galactose toxicity in the chick: hyperosmolality. Science 1971;174:952–4.CrossRefGoogle ScholarPubMed
Knull, HR, Wells, WW. Recovery from galactose-induced neurotoxicity in the chick by the administration of glucose. J Neurochem 1973;20:415–22.CrossRefGoogle ScholarPubMed
Woolley, DW, Gommi, BW. Serotonin receptors, IV: specific deficiency of receptors in galactose poisoning and its possible relationship to the idiocy of galactosemia. Proc Natl Acad Sci USA 1964;52:1419.CrossRefGoogle ScholarPubMed
Sanders, RD, Spencer, JB, Epstein, MP, et al. Biomarkers of ovarian function in girls and women with classic galactosemia. Fertil Steril 2009;92:344–51.CrossRefGoogle ScholarPubMed
Roe, TF, Hallat, JG, Donnell, GN, et al. Childbearing by a galactosemic woman. J Pediatr 1971;78:1026–30.CrossRefGoogle ScholarPubMed
Robbins, SL, Cotran, RS. (1979). Diseases of infancy and childhood. In Robbins, SL, Cotran, RS (Eds.), Pathologic Basis of Disease, 2nd edn. (p. 582). Philadelphia, PA: Saunders.Google Scholar
Smetana, HF, Olen, E. Hereditary galactose disease. Am J Clin Pathol 1962;38:325.CrossRefGoogle ScholarPubMed
Xu, YK, Kaufman, FR, Donnell, GN, et al. Radiochemical assay of minute quantities of galactose-1-phosphate uridyl transferase activity in erythrocytes and leukocytes of galactosemia patients. Clin Chim Acta 1995;235:125–36.CrossRefGoogle ScholarPubMed
Kliegman, RM, Sparks, JW. Perinatal galactose metabolism. J Pediatr 1985;107:831–41.CrossRefGoogle ScholarPubMed
Mellman, WJ, Tedesco, TA, Feige, P. Estimation of the gene frequency of the Duarte variant of galactose-1-phosphate uridyl transferase. Ann Hum Genet 1968;32:1.CrossRefGoogle Scholar
Brandt, NJ. Frequency of heterozygotes for hereditary galactosemia in a normal population. Acta Genet 1967;17:289.Google Scholar
Scriver, CR. Population screening: report of a workshop. Prog Clin Biol Res 1985;163B:89152.Google ScholarPubMed
Pasquali, M, Yu, C, Coffee, B. Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine 2018;1:311.CrossRefGoogle Scholar
Kleijer, WJ, Janse, HC, van Diggelen, OP, et al. First-trimester diagnosis of galactosaemia. Lancet 1986;i:748.CrossRefGoogle Scholar
Koch, R, Donnell, GN, Fishler, K, et al. Galactosemia. In Kelley, VC (ed.) Practice of Pediatrics. Hagerstown, MD: Harper & Row, 1979, p. 14.Google Scholar
Rubio-Gozalbo, ME, Haskovic, M, Bosch, AM, Burnyte, B, Coelho, AI, Cassiman, D, Couce, ML, Dawson, C. The natural history of classic galactosemia: lessons from the GalNet registry. Orphanet J Rare Dis 2019;1:86.CrossRefGoogle Scholar
Manis, FR, Cohn, LB, McBride-Chang, C, et al. A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine. J Inherit Metab Dis 1997;20:549555.CrossRefGoogle ScholarPubMed
Berry, GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr 1995;154(Suppl. 2):S53S64.CrossRefGoogle ScholarPubMed
Boxer, MB, Shen, M, Tanega, C, et al. Toward improved therapy for classic galactosemia. Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information, 2010 (updated March 3, 2011).Google Scholar
Renner, C, Razeghi, S, Uberall, MA, et al. Hormone replacement therapy in galactosaemic twins with ovarian failure and severe osteoporosis. J Inherit Metab Dis 1999;22:194–5.CrossRefGoogle ScholarPubMed
Hennermann, JB, Schadewaldt, P, Vetter, B, et al. Features and outcome of galactokinase deficiency in children diagnosed by newborn screening. J Inherit Metab Dis 2011;34:399407.CrossRefGoogle ScholarPubMed
Sangiuolo, F, Magnani, M, Stambolian, D, et al. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat 2004;23:396.CrossRefGoogle ScholarPubMed
Sachs, B, Sternfeld, L, Kraus, G. Essential fructosuria: its pathophysiology. Am J Dis Child 1974;63:252.CrossRefGoogle Scholar
Steinmann, B, Gitzelmann, R, Van den Berghe, G. Disorders of fructose metabolism. In Scriver, C, Beaudet, A, Sly, W, et al. (eds.) The Metabolic and Molecular Bases of Inherited Disease, vol 1, 8th edn. New York: McGraw-Hill, 2000, pp. 14891520.Google Scholar
Chalmers, RA, Pratt, RTC. Idiosyncrasy to fructose. Lancet 1956;ii:340.Google Scholar
Froesch, ER, Prader, A, Labhart, A, et al. Hereditary fructose intolerance, a congenital metabolic disorder unknown until now.Schweiz Med Wochenschr 1957;87:1168–71.Google ScholarPubMed
Baker, L, Winegrad, AI. Fasting hypoglycemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet 1970;ii:1316.CrossRefGoogle Scholar
Thorens, B. Glucose transporters in the regulation of intestinal, renal, and liver glucose fluxes. Am J Physiol 1996;270:G541–53.Google ScholarPubMed
Rottmann, WH, Tolan, DR, Penhoet, EE. Complete amino acid sequence for human aldolase B derived from cDNA and genomic clones. Proc Natl Acad Sci USA 1984;81:2738–42.CrossRefGoogle ScholarPubMed
Lench, NJ, Telford, EA, Andersen, SE, et al. An EST and STS-based YAC contig map of human chromosome 9q22.3. Genomics 1996;38:199205.CrossRefGoogle ScholarPubMed
Chambers, RA, Pratt, RTC. Idiosyncrasy to fructose. Lancet 1956;ii:340.CrossRefGoogle Scholar
Froesch, VER, Prader, A, Labhart, A, et al. Die hereditare Fructoseintoleranz, eine bisher nicht bekannte kongenitale Stoffwechselstorung. Schweiz Med Wochenschr 1957;87:1168–71.Google Scholar
Hers, HG, Joassin, G. Anomaly of hepatic aldolase in intolerance to fructose.] Enzymol Biol Clin 1961;1:414.CrossRefGoogle Scholar
Penhoet, EE, Kochman, M, Rutter, WJ. Isolation of fructose diphosphate aldolases A, B and C. Biochemistry 1969;8:4391–5.CrossRefGoogle Scholar
Henry, I, Gallano, P, Besmond, C, et al. The structural gene for aldolase B (ALDB) maps to 9q13-32. Ann Hum Genet 1985;49:173–80.CrossRefGoogle Scholar
Tolan, DR, Penhoet, EE. Characterization of the human aldolase B gene. Mol Biol Med 1986;3:245–64.Google ScholarPubMed
Cross, NC, Tolan, DR, Cox, TM. Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell 1988;53:881–5.CrossRefGoogle ScholarPubMed
Cross, NC, de Franchis, R, Sebastio, G, et al. Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 1990;335:306–9.CrossRefGoogle ScholarPubMed
Sebastio, G, de Franchis, R, Strisciuglio, P, et al. Aldolase B mutations in Italian families affected by hereditary fructose intolerance. J Med Genet 1991;28:241–3.CrossRefGoogle ScholarPubMed
Tolan, DR, Brooks, CC. Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans. Biochem Med Metab Biol 1992;48:1925.CrossRefGoogle ScholarPubMed
Rellos, P, Sygusch, J, Cox, TM. Expression, purification, and characterization of natural mutants of human aldolase B. Role of quaternary structure in catalysis. J Biol Chem 2000;275:1145–51.Google ScholarPubMed
Coffee, EM, Tolan, DR. Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J Inherit Metab Dis 2010;33:715–25.CrossRefGoogle ScholarPubMed
Cornblath, M, Rosenthal, IM, Reisner, SH, et al. Hereditary fructose intolerance. N Engl J Med 1963;269:1271–8.CrossRefGoogle ScholarPubMed
Li, H, Byers, HM, Diaz-Kuan, A, Vos, MB, Hall, PL, Tortorelli, S, Singh, R, Wallenstein, MB. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab 2018;123(4):428–32.CrossRefGoogle ScholarPubMed
Odievre, M, Gentil, C, Gautier, M, et al. Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients. Am J Dis Child 1978;132: 605–8.CrossRefGoogle ScholarPubMed
Schulte, MJ, Widukind, L. Fatal sorbitol infusion in a patient with fructose-sorbitol intolerance. Lancet 1977;2:188.CrossRefGoogle Scholar
Morris, RC, Jun, Ueki I, et al. Absence of renal fructose-1-phosphate aldolase activity in hereditary fructose intolerance. Nature 1967;214:920–1.CrossRefGoogle ScholarPubMed
Froesch, ER, Prader, A, Wolf, HP, et al. Hereditary fructose intolerance. Helv Paediatr Acta 1959;14:99112.Google ScholarPubMed
Froesch, ER. (1978). Essential fructosuria, hereditary fructose intolerance, and fructose-1,6-diphosphatase deficiency. In Stanbury, JB, Wyngaarden, JB, Fredrickson, DS (Eds.) The Metabolic Basis of Inherited Disease, 4th edn., p. 131. New York: McGraw-Hill.Google Scholar
van Den Berg, G, Hue, L, Hers, HG. Effect of administration of fructose on glycolytic action of glucagon. An investigation of the pathogeny of hereditary fructose intolerance. Biochem J 1973;134:637.Google Scholar
Raivio, KO, Kekomaki, MP, Maenpaa, PH. Depletion of liver adenine nucleotides induced by D-fructose. Dose-dependence and specificity of the fructose effect. Biochem Pharmacol 1969;18:2615–24.CrossRefGoogle ScholarPubMed
Levin, B, Oberholzer, VG, Snodgrass, GJ, et al. Fructosaemia. An inborn error of fructose metabolism. Arch Dis Child 1963;38:220–30.CrossRefGoogle ScholarPubMed
Schwartz, R, Gamsu, H, Mulligan, PB, et al. Transient intolerance to exogenous fructose in the newborn. J Clin Invest 1964;43:333–40.CrossRefGoogle ScholarPubMed
Perheentupa, J, Pitkanen, E, Nikkila, EA, et al. Hereditary fructose intolerance. A clinical study of four cases. Ann Paediatr Fenn 1962;8:221–35.Google ScholarPubMed
Nikkila, EA, Perheentupa, J. Non- esterified fatty acids and fatty liver in hereditary fructose intolerance. Lancet 1962;ii:1280.CrossRefGoogle Scholar
Morris, RC Jr. An experimental renal acidification defect in patients with hereditary fructose intolerance. II. Its distinction from classic renal tubular acidosis; its resemblance to the renal acidification defect associated with the Fanconi syndrome of children with cystinosis. J Clin Invest 1968;47:1648–63.Google ScholarPubMed
Melancon, SB, Khachadurian, AK, Nadler, HL, et al. Metabolic and biochemical studies in fructose 1,6-diphosphatase deficiency. J Pediatr 1973;82:650–7.CrossRefGoogle ScholarPubMed
Kikawa, Y, Shin, YS, Inuzuka, M, et al. Diagnosis of fructose-1,6-bisphosphatase deficiency using cultured lymphocyte fraction: a secure and noninvasive alternative to liver biopsy. J Inherit Metab Dis 2002;25:41–6.CrossRefGoogle ScholarPubMed
Elpeg, ON. The molecular background of glycogen metabolism disorders. J Pediatr Endocrinol Metab 1999;12:263379.Google Scholar
Hers, HG. The control of glycogen metabolism in the liver. Ann Rev Biochem 1976;45:167–89.CrossRefGoogle ScholarPubMed
von Gierke, E. Glykogenspeicherkrankheit der Leber und Nieren [Hepato-nephromegalia glykogenica]. Beitr Pathol Anat 1929;82:497513.Google Scholar
Cori, GT, Cori, CF. Glucose-6- phosphatase of the liver in glycogen storage disease. J Biol Chem 1952;199:661–7.CrossRefGoogle ScholarPubMed
Cori, GT. Glycogen structure and enzyme deficiencies in glycogen storage disease. Harvey Lect 1953;48:145–71.Google Scholar
Chen, SY, Pan, CJ, Nandigama, K, et al. The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic. FASEB 2008;22:2206–13.CrossRefGoogle ScholarPubMed
Shelly, LL, Lei, KJ, Pan, CJ, et al. Isolation of the gene for murine glucose-6- phosphatase, the enzyme deficient in glycogen storage disease type 1A. J Biol Chem 1993;268:21482–5.CrossRefGoogle ScholarPubMed
Lei, KJ, Pan, CJ, Shelly, LL, et al. Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. J Clin Invest 1994;93:1994–9.CrossRefGoogle ScholarPubMed
Chou, JY and Masfield, B. Mutations in the glucose-6-phosphate (G6PC) gene that cause type 1a glycogen storage disease. Hum Mutat 2008;29:921–30.CrossRefGoogle Scholar
Kishnani, PS, Austin, SL, Abdenur, JE, Arn, P, Bali, DS, Boney, A, Chung, WK, Dagli, AI. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 2014;16(11):e1.CrossRefGoogle ScholarPubMed
Stroppiano, M, Regis, S, DiRocco, M, et al. Mutations in the glucose-6-phosphatase gene of 53 Italian patients with glycogen storage disease type Ia. J Inherit Metab Dis 1999;22:43–9.CrossRefGoogle ScholarPubMed
Melis, D, Pivonello, R, Parenti, G, et al. The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1: evidence of different growth patterns and insulin-like growth factor levels in patients with glycogen storage disease type 1a and 1b. J Pediatr 2010;156;663–70.CrossRefGoogle ScholarPubMed
Hers, H, Van Hoof, F, de Barsy, T. (1989). Glycogen storage disease. In Stanbury, JB, Wyngaarden, JB, Frederickson, DS (Eds.), The Metabolic Basis of Inherited Disease, 6th edn., pp. 425–52. New York: McGraw- Hill.Google Scholar
Rake, JP, Visser, G, Labrune, P, Leonard, JV, Ullrich, K, Smit, G, Peter, A. European study on glycogen storage disease type I (ESGSD I): guidelines for management of glycogen storage disease type I. Eur J Pediatr 2002;161(Suppl. 1):112–19.CrossRefGoogle Scholar
Ghishan, FK, Greene, HL. (1990). Inborn errors of metabolism that cause permanent injury to the liver. In Zakim, D, Boyer, T (Eds.), Hepatology: A Textbook of Liver Disease, vol. 49, 2nd edn., pp. 1300–48. Philadelphia, PA: Saunders.Google Scholar
Fernandes, J, Berger, R, Smit, GPA. Lactate as a cerebral metabolic fuel for glucose-6-phosphatase deficient children. Pediatr Res 1984;18:335–9.CrossRefGoogle ScholarPubMed
Coire, CI, Qizilbash, AH, Castelli, MF. Hepatic adenomata in type Ia glycogen storage disease. Arch Pathol Lab Med 1987;111:166–9.Google ScholarPubMed
Slonim, AE, Lacy, WW, Terry, A, et al. Nocturnal intragastric therapy in type I glycogen storage disease: effect on hormonal and amino acid metabolism. Metabolism 1979;28:707–15.CrossRefGoogle ScholarPubMed
Sadeghi-Nejad, A, Presente, E, Binkiewicz, A, et al. Studies in type I glycogenesis of the liver. The genesis and disposition of lactate. J Pediatr 1974;85:4954.CrossRefGoogle Scholar
Jakovcic, S, Khachadurian, AK, Hsia, DY. The hyperlipidemia in glycogen storage disease. J Lab Clin Med 1966;68:769–79.Google ScholarPubMed
Forget, PP, Fernandes, J, Begemann, PH. Triglyceride clearing in glycogen storage disease. Pediatr Res 1974;8:114–19.CrossRefGoogle ScholarPubMed
Fine, RN, Strauss, J, Donnell, GN. Hyperuricemia in glycogen-storage disease type 1. Am J Dis Child 1966;112:572–6.Google ScholarPubMed
Jakovcic, S, Sorensen, LB. Studies of uric acid metabolism in glycogen storage disease associated with gouty arthritis. Arthritis Rheum 1967;10:129–34.CrossRefGoogle ScholarPubMed
Zhang, B, Zeng, X. Tophaceous gout in a female premenopausal patient with an unexpected diagnosis of glycogen storage disease type Ia: a case report and literature review. Clin Rheumatol 2016;35(11):2851–6.CrossRefGoogle Scholar
Corby, DG, Putnam, CW, Greene, HL. Impaired platelet function in glucose-6-phosphatase deficiency. J Pediatr 1974;85:71–6.CrossRefGoogle ScholarPubMed
Cooper, RA. Abnormalities of cell- membrane fluidity in the pathogenesis of disease. N Engl J Med 1977;297:371–7.Google ScholarPubMed
Roe, TF, Kogut, MD, Buckingham, BA, et al. Hepatic tumors in glycogen- storage disease type I. Pediatr Res 1979;13:931.Google Scholar
Bali, DS, Chen, YT, Austin, S, Goldstein, JL. Glycogen storage disease type I. In Adam, MP, Ardinger, HH, Pagon, RA, Wallace, SE, Bean, LJ, Stephens, K, Amemiya, A. GeneReviews®. Seattle, WA: University of Washington, 1993.Google Scholar
McAdams, AJ, Hug, G, Bove, KE. Glycogen storage disease, types I to X: criteria for morphologic diagnosis. Hum Pathol 1974;5:463–87.CrossRefGoogle ScholarPubMed
Greene, HL, Slonim, AE, Burr, IM, et al. Type I glycogen storage disease: five years of management with nocturnal intragastric feeding. J Pediatr 1980;96:590–5.CrossRefGoogle ScholarPubMed
Senior, B, Loridan, L. Studies of liver glycogenoses, with particular reference to the metabolism of intravenously administered glycerol. N Engl J Med 1968;279:958–65.CrossRefGoogle Scholar
Arion, WJ, Wallin, BK, Lange, AJ, et al. On the involvement of a glucose6-phosphate transport system in the function of microsomal glucose6-phosphatase. Mol Cell Biochem 1975;6:7583.CrossRefGoogle Scholar
Skaug, WA, Warford, LL, Figueroa, JM, et al. Glycogenesis type IB: possible membrane transport defect. South Med J 1981;74:761–4.CrossRefGoogle Scholar
Zakim, D, Edmondson, DE. The role of the membrane in the regulation of activity of microsomal glucose-6- phosphatase. J Biol Chem 1982;257:1145–8.CrossRefGoogle ScholarPubMed
Hiraiwa, H, Pan, CJ, Lin, B, et al. Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b. J Biol Chem 1999;274:5532–6.CrossRefGoogle ScholarPubMed
Annabi, B, Hiraiwa, H, Mansfield, BC, et al. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am J Hum Genet 1998;62:400–5.CrossRefGoogle ScholarPubMed
Chen, LY, Pan, CJ, Shieh, JJ, et al. Structure–function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib. Hum Mol Genet 2002;11:3199–207.CrossRefGoogle ScholarPubMed
Visser, G, Rake, JP, Labrune, P, Leonard, JV, Moses, S, Ullrich, K, Wendel, U, Smit, G, Peter, A. Consensus guidelines for management of glycogen storage disease type 1b – European Study on Glycogen Storage Disease Type 1. Eur J Pediatr 2002;161(Suppl. 1):120–3.Google Scholar
Forbes, GB. Glycogen storage disease: report of a case with abnormal glycogen structure in liver and skeletal muscle. J Pediatr 1953;42:645–53.CrossRefGoogle ScholarPubMed
Illingworth, B, Cori, GT. Structure of glycogens and amylopectins: III. Normal and abnormal human glycogen. J Biol Chem 1952;199:653–60.CrossRefGoogle ScholarPubMed
Chen, Y-T, He, J-K, Ding, J-H, et al. Glycogen debranching enzyme: purification, antibody characterization, and immunoblot analyses of type III glycogen storage disease. Am J Hum Genet 1987;41:1002–15.Google ScholarPubMed
van Hoof, F, Hers, HG. The subgroups of type III glycogenosis. Eur J Biochem 1967;2:265–70.Google Scholar
Ding, J-H, de Barsy, T, Brown, BI, et al. Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III. J Pediatr 1990;116:95100.CrossRefGoogle ScholarPubMed
Bao, Y, Dawson, TL Jr, Chen, YT. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5´ flanking region. Genomics 1996;38:155–65.CrossRefGoogle ScholarPubMed
Yang-Feng, TL, Zheng, K, Yu, J, et al. Assignment of the human glycogen debrancher gene to chromosome 1p21. Genomics 1992;13:931–4.CrossRefGoogle ScholarPubMed
Yang, BZ, Ding, JH, Enghild, JJ, et al. Molecular cloning and nucleotide sequence of cDNA encoding human muscle glycogen debranching enzyme. J Biol Chem 1992;267:9294–9.CrossRefGoogle ScholarPubMed
Bao, Y, Yang, BZ, Dawson, TL Jr., et al. Isolation and nucleotide sequence of human liver glycogen debranching enzyme mRNA: identification of multiple tissue-specific isoforms. Gene 1997;197:389–98.CrossRefGoogle ScholarPubMed
Okubo, M, Kanda, F, Horinishi, A, et al. Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448 R) of the glycogen debranching enzyme gene found in a homozygous patient. Hum Mutat 1999;14:542–3.3.0.CO;2-0>CrossRefGoogle Scholar
Shen, J, Bao, Y, Liu, HM, et al. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J Clin Invest 1996;98:352–7.CrossRefGoogle Scholar
Shen, JJ, Chen, YT. Molecular characterization of glycogen storage disease type III. Curr Mol Med 2002;2:167–75.CrossRefGoogle ScholarPubMed
van Creveld, S, Huijing, F. Glycogen storage disease: biochemical and clinical data in sixteen cases. Am J Med 1965;38:554–61.CrossRefGoogle ScholarPubMed
Ugawa, Y, Inoue, K, Takemura, T, et al. Accumulation of glycogen in peripheral nerve axons in adult-onset type III glycogenosis. Ann Neurol 1986;19:294–7.CrossRefGoogle ScholarPubMed
Alagille, D, Odievre, M. (1979). Inborn errors of metabolism. In Alagille, D, Odievre, M (Eds.), Liver and Biliary Tract Disease in Children, pp. 196242. New York: Wiley.Google Scholar
Hug, G, Krill, CE Jr, Perrin, EV, et al. Cori’s disease (amylo-1,6-glucosidase deficiency): report of a case in a Negro child. N Engl J Med 1963;268:113–20.CrossRefGoogle Scholar
Slonim, AE, Terry, AB, Moran, R, et al. Differing food consumption for nocturnal intragastric therapy in types I and III glycogen storage disease. Pediatr Res 1978;12:512894.CrossRefGoogle Scholar
Borowitz, SM, Greene, HL. Cornstarch therapy in a patient with type III glycogen storage disease. J Pediatr Gastroenterol Nutr 1987;6:631–4.Google Scholar
Valayannopoulos, V, Bajolle, F, Arnoux, JB, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III with DL-3- hydroxybutyrate, ketogenic and high protein diet. Pediatr Res 2011;70:638–41.CrossRefGoogle Scholar
Mayorandan, S, Meyer, U, Hartmann, H, Anibh, M. Glycogen storage disease type III: modified Atkins diet improves myopathy. Orphanet J Rare Dis 2014;9:196.CrossRefGoogle ScholarPubMed
Anderson, DH. (1952). Studies on glycogen disease with report of a case in which the glycogen was abnormal. In Ajjar, VA (Ed.), Carbohydrate Metabolism, p. 28. Baltimore, MD: Johns Hopkins University Press.Google Scholar
Illingworth, B, Cori, GT. Structure of glycogens and amylopectins. III. Normal and abnormal human glycogen. J Biol Chem 1952;199:653–60.CrossRefGoogle ScholarPubMed
Brown, BI, Brown, DH. Lack of an alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase in a case of type IV glycogenosis. Proc Natl Acad Sci USA 1966;56:725–9.CrossRefGoogle Scholar
Andersen, DH. Familial cirrhosis of the liver with storage of abnormal glycogen. Lab Invest 1956;5:1120.Google ScholarPubMed
Thon, VJ, Khalil, M, Cannon, JF. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast. J Biol Chem 1993;268:7509–13.CrossRefGoogle ScholarPubMed
Bao, Y, Kishnani, P, Wu, J-Y, et al. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest 1996;97:941–8.CrossRefGoogle ScholarPubMed
Li, SC, Hwu, WL, Lin, JL, et al. Association of the congenital neuromuscular form of glycogen storage disease type IV with a large deletion and recurrent frameshift mutation. J Child Neurol 2012;27:204–8.CrossRefGoogle ScholarPubMed
Shen, J, Liu, HM, McConkie-Rosell, A, et al. Prenatal diagnosis of glycogen storage disease type IV using PCR-based DNA mutation analysis. Prenat Diagn 1999;9:837–9.Google Scholar
Magoulas, PL, El-Hattab, AW. Glycogen storage disease type IV. In Adam, MP, Ardinger, HH, Pagon, RA, Wallace, SE, Bean, LJ, Stephens, K, Amemiya, A, GeneReviews®. Seattle, WA: University of Washington, 1993.Google Scholar
Schochet, SS, McCormick, WF, Zellweger, H. Type IV glycogenosis (amylopectinosis): light and electron microscopic observations. Arch Pathol 1970;90:354–63.Google ScholarPubMed
Ferguson, IT, Mahon, M, Cumming, WJK. An adult case of Andersen’s disease: type IV glycogenosis. J Neurol Sci 1983;60:337–51.CrossRefGoogle ScholarPubMed
Das, BB, et al. Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence. Pediatr Transplant 2005:9:261–5.CrossRefGoogle ScholarPubMed
Bruno, C, Servidei, S, Shanske, G, et al. Glycogen branching enzyme deficiency in adult polyglucosan body disease. Ann Neurol 1993;33:8893.CrossRefGoogle ScholarPubMed
Witters, P, Morava, E. (2016). Congenital Disorders of Glycosylation: Review. Chichester: John Wiley & Sons, Ltd. doi: 10.1002/9780470015902.a0026783Google Scholar
Marques-da-Silva, D, Dos Reis Ferreira, V, Monticelli, M, Janeiro, P, Videira, PA, Witters, P, Jaeken, J, Cassiman, D. Liver involvement in congenital disorders of glycosylation. A systematic review of the literature. J Inherit Metab Dis 2017;40(2):195207. doi: 10.1007/s10545-016-0012-4.CrossRefGoogle ScholarPubMed
Altassan, R, Péanne, R, Jaeken, J, Barone, R, Bidet, M, et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: diagnosis, treatment and follow-up. J Inherit Metab Dis 2019;42(1):528.CrossRefGoogle ScholarPubMed
Witters, P, Honzik, T, Bauchart, E, Altassan, R, Pascreau, T, Bruneel, A, Vuillaumier, S, Seta, N, Borgel, D, Matthijs, G, Jaeken, J, Meersseman, W, Cassiman, D, Pascale de, L, Morava, E. Long-term follow-up in PMM2-CDG: are we ready to start treatment trials? Genet Med 2019;21(5):1181–8. doi:10.1038/s41436-018-0301-4CrossRefGoogle ScholarPubMed
Verheijen, J, Tahata, S, Kozicz, T, Witters, P, Morava, E. Therapeutic approaches in congenital disorders of glycosylation involving N-linked glycosylation: an update. Genet Med 2019. doi: 10.1038/s41436-019-0647-2CrossRefGoogle Scholar
Radenkovic, S, Bird, MJ, Emmerzaal, TL, Wong, SY, Felgueira, C, et al. The metabolic map into the pathomechanism and treatment of PGM1-CDG. Am J Hum Genet 2019;104(5):835–46. doi: 10.1016/j.ajhg.2019.03.003CrossRefGoogle ScholarPubMed
Tegtmeyer, LC, Rust, S, van Scherpenzeel, M, Ng, BG, Losfeld, ME, et al. T. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 2014;370(6):533–42.CrossRefGoogle Scholar
Baker, P, Ayres, L, Gaughan, S, Weisfeld-Adams, J. Hereditary fructose intolerance. In Adam, MP, Ardinger, HH, Pagon, RA, Wallace, SE, Bean, LJ, Stephens, K, Amemiya, A. GeneReviews®. Seattle, WA: University of Washington, 1993.Google Scholar


Czlonkowska, A, Litwin, T, Dusek, P, et al. Wilson disease. Nat Rev Disease Primers 2018;4:21.CrossRefGoogle ScholarPubMed
Gollan, JL. Studies on the nature of complexes formed by copper with human alimentary secretions and their influence on copper absorption in the rat. Clin Sci Mol Med 1975;49:237.Google ScholarPubMed
Klomp, LW, Liu, SJ, Yuan, DS, et al. Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem 1997;272:9221–6.CrossRefGoogle ScholarPubMed
Harrison, MD, Jones, CE, Dameron, CT. Copper chaperones: function, structure and copper-binding properties. J Biol Inorg Chem 1999;4:145–53.CrossRefGoogle ScholarPubMed
Portnoy, ME, Rosenzweig, AC, Roe, T, et al. Structure-function analyses of the ATX1 metallochaperone. J Biol Chem 1999;274:15041–5.CrossRefGoogle ScholarPubMed
Sternlieb, I, Morell, AG, Tucker, WD, et al. The incorporation of copper into ceruloplasmin in vivo: studies with copper 64 and copper 67. J Clin Invest 1961;40:1834.CrossRefGoogle Scholar
Miyajima, H. Aceruloplasminemia: an iron metabolic disorder. Neuropathology 2003;23:345–50.CrossRefGoogle Scholar
Frieden, E, Hsieh, HS. The biological role of ceruloplasmin and its oxidase activity. Adv Exp Med Biol 1976;74:505.CrossRefGoogle ScholarPubMed
Scheinberg, IH, Cook, CD, Murphy, JA. The concentration of copper and ceruloplasmin in maternal and infant plasma at delivery. J Clin Invest 1954;33:963.Google Scholar
Schilsky, ML, Sternlieb, I. Overcoming obstacles to the diagnosis of Wilson’s disease. Gastroenterology 1997;113:350–3.Google Scholar
Rosencrantz, R, Schilsky, M. Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Sem Liver Disease 2011;31:245–59.CrossRefGoogle ScholarPubMed
Frommer, DJ. Defective biliary excretion of copper in Wilson’s disease. Gut 1974;15:125.CrossRefGoogle ScholarPubMed
Mueller, T, Van de Sluis, B, Zhernakova, A, et al. The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis. J Hepatol 2003;38:164–8.Google Scholar
Tao, TY, Liu, F, Klomp, L, et al. The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 2003;278:41593–6.CrossRefGoogle ScholarPubMed
Stuehler, B, Reichert, J, Stemmel, W, Schaefer, M. .Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J Mol Med 2004;82:629–6.CrossRefGoogle ScholarPubMed
Evans, GW. Copper homeostasis in the mammalian system. Physiol Rev 1973;53:535.CrossRefGoogle ScholarPubMed
Reed, GB, Butt, EM, Landing, BH. Copper in childhood liver disease. A histologic, histochemical and chemical survey. Arch Pathol 1972;93:249.Google ScholarPubMed
Sokol, RJ, Twedt, D, McKim, JM Jr, et al. Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology 1994;107:1788–98.CrossRefGoogle ScholarPubMed
Valko, M, Morris, H, Cronin, MT. Metals, toxicity and oxidative stress. Curr Med Chem 2005;12(10):1161–208.CrossRefGoogle ScholarPubMed
Mufti, AR, Burstein, E, Csomos, RA, et al. XIAP is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Mol Cell 2006;21(6):775–85.CrossRefGoogle ScholarPubMed
Sokol, RJ. Abnormal hepatic mitochondrial respiration and cytochrome C oxidase activity in rats with copper overload. Gastroenterology 1993;105:178–87.CrossRefGoogle ScholarPubMed
Mansouri, A, Gaou, I, Fromenty, B, et al. Premature oxidative aging of hepatic mitochondrial DNA in Wilson’s disease. Gastroenterology 1997;113:599605.CrossRefGoogle ScholarPubMed
Wilson, AK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912;34:295.CrossRefGoogle Scholar
Bull, PC, Thomas, GR, Rommens, JM, et al. The Wilson’s disease gene is a putative copper transporting P-type ATPase similar to the Menkes’ gene. Nat Genet 1993;5:327–37.CrossRefGoogle Scholar
Wilson, DC, Phillips, MJ, Cox, DW, Roberts, EA. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr 2000;137:719–22.CrossRefGoogle ScholarPubMed
Walshe, JM. (1982). The liver in Wilson’s disease (hepatolenticular degeneration). In: Schiff, L, Schiff, ER, (Eds.), Diseases of the Liver (pp. 1037–50). Philadelphia: JB Lippincott.Google Scholar
Scheinberg, IH, Sternlieb, I, (Eds.). (1984). Wilson’s disease. Philadelphia: WB Saunders.Google Scholar
Schilsky, ML, Scheinberg, IH, Sternlieb, I. Prognosis of Wilsonian chronic active hepatitis. Gastroenterology 1991;100:762–7.CrossRefGoogle ScholarPubMed
Walshe, JM, Waldenstrom, E, Sams, V, Nordlinder, H, Westermark, K. Abdominal malignancies in patients with Wilson’s disease. QJM 2003;96:657–62.CrossRefGoogle ScholarPubMed
Factor, SM, Cho, S, Sternlieb, I, et al. The cardiomyopathy of Wilson’s disease. Myocardial alterations in nine cases. Virchows Arch [A] 1982;397:301–11.Google ScholarPubMed
Korman, JD, Volenberg, I, Balko, J, Webster, J, Schiodt, FV, Squires, RH Jr, Fontana, RJ, Lee, WM, Schilsky, ML. Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008;48:1168–74.CrossRefGoogle ScholarPubMed
Ferenci, P, Caca, K, Loudianos, G, Mieli-Vergani, G, Tanner, S, Sternlieb, I, Schilsky, M, Cox, D, Berr, F. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139–42.CrossRefGoogle ScholarPubMed
DaCosta, CM, Baldwin, D, Portmann, B, et al. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson’s disease. Hepatology 1992;15:609–15.Google Scholar
Steindl, P, Ferenci, P, Dienes, HP, et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997;113:212–18.CrossRefGoogle ScholarPubMed
Sternlieb, I. Mitochondrial and fatty changes in hepatocytes of patients with Wilson’s disease. Gastroenterology 1968;55:354.CrossRefGoogle ScholarPubMed
Williams, FJB, Walshe, JM. Wilson’s disease. An analysis of the cranial computerized tomographic appearances found in 60 patients and the changes in response to treatment with chelating agents. Brain 1981;104:735–52.Google ScholarPubMed
Linne, T, Agartz, I, Saaf, J, et al. Cerebral abnormalities in Wilson disease as evaluated by ultra-low-field magnetic resonance imaging and computerized image processing. Magn Reson Imaging 1990;8:819–24.CrossRefGoogle ScholarPubMed
Brewer, GJ, Askari, F, Lorincz, MT, Carlson, M, Schilsky, M, Kluin, KJ, Hedera, P, Moretti, P, Fink, JK, Tankanow, R, Dick, RB, Sitterly, J. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006;63(4):521–7.CrossRefGoogle Scholar
Walshe, JM. Penicillamine, a new oral therapy for Wilson’s disease. Am J Med 1956;21:487–95.CrossRefGoogle ScholarPubMed
Brewer, GJ, Terry, CA, Aisen, AM, Hill, GM. Worsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy. Arch Neurol 1987;44:490–3.CrossRefGoogle ScholarPubMed
Weiss, KH, Czlonkowska, A, Hedera, P, Ferenci, P. WTX1010 – an investigational drug for the treatment of Wilson Disease. Expert Opin Invest Drugs 2018;27:561–7.CrossRefGoogle ScholarPubMed
Socha, P, Janczyk, W, Dhawan, A, et al. Wilson’s Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;66(2):334–44.CrossRefGoogle ScholarPubMed
Santiago, R, Gottrand, F, Debray, D, Bridoux, L, Lachaux, A, Morali, A, Lapeyre, D, Lamireau, T. Zinc therapy for Wilson disease in children in French pediatric centers. J Pediatr Gastroenterol Nutr 2015;61(6):613–18.CrossRefGoogle ScholarPubMed
Weiss, KH, Gotthardt, DN, Klemm, D, Merle, U, Ferenci-Foerster, D, Schaefer, M, Ferenci, P, Stremmel, W. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology 2011;140(4):1189–98.CrossRefGoogle Scholar
Garoufalia, Z, Prodromidou, A, Machairas, N, Kostakis, ID, Stamopoulos, P, Zavras, N, Fouzas, sI, Sotiropoulos, GC. Liver transplantation for Wilson’s disease in non-adult patients: a systematic review. Transplant Proc 2019;51(2):443–5.CrossRefGoogle ScholarPubMed
Nazer, H, Ede, RJ, Mowat, AP, et al. Wilson’s disease: clinical presentation and use of prognostic index. Gut 1986;27:1377–81.CrossRefGoogle ScholarPubMed
Dhawan, A, Taylor, RM, Cheeseman, P, De Silva, P, et al. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transplantation 2005;11:441–8.CrossRefGoogle ScholarPubMed
Sternlieb, I. Wilson’s disease and pregnancy. Hepatology 2000;31:531–2.CrossRefGoogle Scholar
Tanner, MS. Role of copper in Indian childhood cirrhosis. Am J Clin Nutr 1998;67(suppl):1074–81.CrossRefGoogle ScholarPubMed
Müller, T, Feichtinger, H, Berger, H, et al. Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 1996;347:877–80.CrossRefGoogle Scholar
O’Neill, NC, Tanner, MS. Uptake of copper from brass vessels by bovine milk and its relevance to Indian childhood cirrhosis. J Pediatr Gastroenterol Nutr 1989;9:167–72.CrossRefGoogle ScholarPubMed
Nayak, NC, Chitale, AR. Indian Childhood cirrhosis (ICC) & ICC-like diseases: the changing scenario of facts versus notions. Indian J Med Res 2013;137:1029–42.Google ScholarPubMed
Bhave, SA, Pandit, AN, Pradhan, AM, et al. Liver disease in India. Arch Dis Child 1982;57:922.CrossRefGoogle ScholarPubMed
Tanner, MS, Bhave, SA, Pradham, AM, et al. Clinical trials of penicillamine in Indian childhood cirrhosis. Arch Dis Child 1987;62:1118–24.CrossRefGoogle ScholarPubMed
Horslen, SP, Tanner, MS, Lyon, TDB, et al. Copper associated childhood cirrhosis. Gut 1994;35:1497–500.CrossRefGoogle ScholarPubMed
Scheinberg, IH, Sternlieb, I. Is non-Indian childhood cirrhosis caused by excess dietary copper. Lancet 1994;344:1002–4.CrossRefGoogle ScholarPubMed
Saito, T. Presenting symptoms and natural history of Wilson’s disease. Eur J Pediatr 1987;146:261–5.CrossRefGoogle Scholar
Giagheddu, A, Demelisa, L, Puggioni, G, Nurchi, AM, Contu, L, Pirari, G, Deplano, A, Rachele, MG. Epidemiologic study of hepatolenticular degeneration (Wilson’s disease) in Sardinia (1902–1983). Acta Neurol Scand 1985;72:4355.CrossRefGoogle Scholar
Dobyns, WB, Goldstein, NP, Gordon, H. Clinical spectrum of Wilson’s disease (hepatolenticular degeneration). Mayo Clin Proc 1979;54:3542.Google Scholar
Stremmel, W, Meyerrose, KW, Niederau, C, et al. Wilson’s disease: clinical presentation, treatment and survival. Ann Intern Med 1991;115:720–6.CrossRefGoogle ScholarPubMed
Aksoy, M, Erdem, S. Wilson’s disease in Turkey, a review of 49 cases in 41 families. New Istanbul Contrib Clin Sci 1975;11:92–7.Google ScholarPubMed
Oder, W, Grimm, G, Kollegger, H, et al. Neurological and neuropsychiatric spectrum of Wilson’s disease: a prospective study of 45 cases. J Neurol 1991;238:281–7.Google ScholarPubMed
Park, RHR, McCabe, P, Fell, GS, et al. Wilson’s disease in Scotland. Gut 1991;32:1541–5.CrossRefGoogle ScholarPubMed
Martinelli, D, Dionisi-Vici, C. AP1S1 defect causing MEDNIK syndrome: a new adaptinopathy associated with defective copper metabolism. Ann N Y Acad Sci 2014;1314:5563.CrossRefGoogle ScholarPubMed
Martinelli, D, Travaglini, L, Drouin, CA, et al. MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain 2013;136(Pt 3):872–81.CrossRefGoogle ScholarPubMed
Ranucci, G, Iorio, R. (2019). Disorders that mimic Wilson disease. In: Kerkar, N, Roberts, EA (Eds.). Clinical and translational perspectives on Wilson disease (pp. 419–25). London: Academic Press, Elsevier.Google Scholar
Shneider, BL. ABCB4 disease presenting with cirrhosis and copper overload- potential confusion with Wilson disease. J Clin Exp Hepatol 2011;1:115227.CrossRefGoogle ScholarPubMed

Websites of Interest

GeneReviews – Wilson Disease: [last accessed June 21, 2020].

Wilson Disease Association: [last accessed June 21, 2020].

National Organization for Rare Disorders: [last accessed June 21, 2020].

Genetics and Rare Disease Information Center: [last accessed June 21, 2020].


Pietrangelo, A, Caleffi, A, Corradini, E. Non-HFE hepatic iron overload. Semin Liver Dis 2011;31:302–18.CrossRefGoogle ScholarPubMed
Bacon, BR, Adams, PC, Kowdley, DV, et al. Diagnosis and Management of Hemochromatosis: 2011 Practice Guideline by the AASLD. Hepatology 2011;54(1):328–43.CrossRefGoogle Scholar
Evstatiev, R, Gasche, C. Iron sensing and signalling. Gut 2012;61:933–52.CrossRefGoogle ScholarPubMed
Vaulont, S, Lou, DQ, Viatte, L, Kahn, A. Of mice and men: the iron age. J Clin Invest 2005;115:2079–82.CrossRefGoogle ScholarPubMed
De Domenico, I, Ward, DM, Kaplan, J. Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis 2011;31:272–9.CrossRefGoogle ScholarPubMed
Pietrangelo, A. Hepcidin in human iron disorders: therapeutic implications. J Hepatol 2011;54:173–81.CrossRefGoogle ScholarPubMed
Huang, FW, Pinkus, JL, Pinkus, GS, Fleming, MD, Andrews, NC. A mouse model of juvenile hemochromatosis. J Clin Invest 2005;115:2187–91.CrossRefGoogle ScholarPubMed
Feder, JN, Gnirke, A, Thomas, W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399408.CrossRefGoogle ScholarPubMed
Pietrangelo, A. Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology 2015;149:1240–51.CrossRefGoogle ScholarPubMed
Phatak, PD, Sham, RL, Raubertas, RF, et al. Prevalence of hereditary hemochromatosis in 16031 primary care patients. Ann Intern Med 1998;129:954–61.CrossRefGoogle ScholarPubMed
Olynyk, JK, Cullen, DJ, Aquilia, S, et al. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718–24.CrossRefGoogle ScholarPubMed
Edwards, CQ, Griffen, LM, Goldgar, D, et al. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988;318:1355–62.CrossRefGoogle ScholarPubMed
Ramrakhiani, S, Bacon, R. Hemochromatosis: advances in molecular genetics and clinical diagnosis. J Clin Gastroenterol 1998;