{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:17:19Z","timestamp":1793146639055,"version":"4.5.0"},"reference-count":53,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>At least 16 genetically determined conditions qualify as red blood cell enzymopathies. They range in frequency from ultrarare to rare, with the exception of glucose-6-phosphate dehydrogenase deficiency, which is very common. Nearly all these enzymopathies manifest as chronic hemolytic anemias, with an onset often in the neonatal period. The diagnosis can be quite easy, such as when a child presents with dark urine after eating fava beans, or it can be quite difficult, such as when an adult presents with mild anemia and gallstones. In general, 4 steps are recommended: (1) recognizing chronic hemolytic anemia; (2) excluding acquired causes; (3) excluding hemoglobinopathies and membranopathies; (4) pinpointing which red blood cell enzyme is deficient. Step 4 requires 1 or many enzyme assays; alternatively, DNA testing against an appropriate gene panel can combine steps 3 and 4. Most patients with a red blood cell enzymopathy can be managed by good supportive care, including blood transfusion, iron chelation when necessary, and splenectomy in selected cases; however, some patients have serious extraerythrocytic manifestations that are difficult to manage. In the absence of these, red blood cell enzymopathies are in principle amenable to hematopoietic stem cell transplantation and gene therapy\/gene editing.<\/jats:p>","DOI":"10.1182\/hematology.2021000266","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T12:12:42Z","timestamp":1639138362000},"page":"341-352","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":18,"title":["Diagnosis and clinical management of enzymopathies"],"prefix":"10.1182","volume":"2021","author":[{"given":"Lucio","family":"Luzzatto","sequence":"first","affiliation":[{"name":"Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; and University of Florence, Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"2021121012071601900_hem2021000266C1","first-page":"708","article-title":"Hemolytic anemias","volume-title":"Harrison's Principles of Internal Medicine","author":"Luzzatto","year":"2018"},{"issue":"3","key":"2021121012071601900_hem2021000266C2","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.pcl.2018.02.005","article-title":"Red blood cell enzyme disorders","volume":"65","author":"Grace","year":"2018","journal-title":"Pediatr Clin North Am"},{"key":"2021121012071601900_hem2021000266C3","volume-title":"Biochemistry","author":"Berg","year":"2002","edition":"5th"},{"issue":"5","key":"2021121012071601900_hem2021000266C4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1600-0609.1994.tb00094.x","article-title":"Glucose phosphate isomerase (GPI) \u201cMorcone\u201d: a new variant from Italy","volume":"52","author":"Alfinito","year":"1994","journal-title":"Eur J Haematol"},{"issue":"6","key":"2021121012071601900_hem2021000266C5","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1182\/blood.V88.6.2306.bloodjournal8862306","article-title":"Study of the molecular defects in glucose phosphate isomerase-deficient patients affected by chronic hemolytic anemia","volume":"88","author":"Baronciani","year":"1996","journal-title":"Blood"},{"issue":"6","key":"2021121012071601900_hem2021000266C6","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1182\/blood.V88.6.2321.bloodjournal8862321","article-title":"Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia","volume":"88","author":"Kanno","year":"1996","journal-title":"Blood"},{"issue":"6","key":"2021121012071601900_hem2021000266C7","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1172\/JCI111164","article-title":"Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency","volume":"72","author":"Vora","year":"1983","journal-title":"J Clin Invest"},{"issue":"4","key":"2021121012071601900_hem2021000266C8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.blre.2007.01.001","article-title":"Pyruvate kinase deficiency: the genotype-phenotype association","volume":"21","author":"Zanella","year":"2007","journal-title":"Blood Rev"},{"key":"2021121012071601900_hem2021000266C9","first-page":"1","article-title":"Part 1\u2014The congenital anaemias","volume-title":"The Haemolytic Anaemias","author":"Dacie","year":"1960"},{"issue":"2","key":"2021121012071601900_hem2021000266C10","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/bjh.14221","article-title":"A novel 33-gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias","volume":"175","author":"Roy","year":"2016","journal-title":"Br J Haematol"},{"issue":"5","key":"2021121012071601900_hem2021000266C11","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/ajh.25058","article-title":"Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias","volume":"93","author":"Russo","year":"2018","journal-title":"Am J Hematol"},{"issue":"11","key":"2021121012071601900_hem2021000266C12","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1182\/blood.2019000945","article-title":"Management of pyruvate kinase deficiency in children and adults","volume":"136","author":"Grace","year":"2020","journal-title":"Blood"},{"issue":"2","key":"2021121012071601900_hem2021000266C13","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.3324\/haematol.2018.196295","article-title":"Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study","volume":"104","author":"van Beers","year":"2019","journal-title":"Haematologica"},{"issue":"4","key":"2021121012071601900_hem2021000266C14","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1111\/bjh.12779","article-title":"Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios","volume":"165","author":"Mojzikova","year":"2014","journal-title":"Br J Haematol"},{"issue":"10","key":"2021121012071601900_hem2021000266C15","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1056\/NEJMoa1902678","article-title":"Safety and efficacy of mitapivat in pyruvate kinase deficiency","volume":"381","author":"Grace","year":"2019","journal-title":"N Engl J Med"},{"issue":"11","key":"2021121012071601900_hem2021000266C16","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1182\/blood.2019000944","article-title":"Glucose-6-phosphate dehydrogenase deficiency","volume":"136","author":"Luzzatto","year":"2020","journal-title":"Blood"},{"issue":"1","key":"2021121012071601900_hem2021000266C17","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1038\/jp.2008.216","article-title":"The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective","volume":"29","author":"Kaplan","year":"2009","journal-title":"J Perinatol"},{"key":"2021121012071601900_hem2021000266C18","first-page":"609","article-title":"Glucose-6-phosphate dehydrogenase deficiency","volume-title":"Nathan and Oski's Hematology and Oncology of Infancy and Childhood","author":"Luzzatto","year":"2015"},{"issue":"1","key":"2021121012071601900_hem2021000266C19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1056\/NEJMra1708111","article-title":"Favism and glucose-6-phosphate dehydrogenase deficiency","volume":"378","author":"Luzzatto","year":"2018","journal-title":"N Engl J Med"},{"issue":"1","key":"2021121012071601900_hem2021000266C20","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1542\/peds.2011-1580","article-title":"Lethal effect of a single dose of rasburicase in a preterm newborn infant","volume":"131","author":"Zaramella","year":"2013","journal-title":"Pediatrics"},{"issue":"7172","key":"2021121012071601900_hem2021000266C21","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0140-6736(61)91476-3","article-title":"Glucose-6-phosphate dehydrogenase deficiency. A new aetiological factor of severe neonatal jaundice","volume":"1","author":"Doxiadis","year":"1961","journal-title":"Lancet"},{"issue":"7304","key":"2021121012071601900_hem2021000266C22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0140-6736(63)93059-9","article-title":"Glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice in Nigeria: their relation to the use of prophylactic vitamin K","volume":"2","author":"Capps","year":"1963","journal-title":"Lancet"},{"issue":"6","key":"2021121012071601900_hem2021000266C23","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/j.1651-2227.1976.tb18006.x","article-title":"Erythrocyte glucose 6-phosphate dehydrogenase deficiency (G6PD type A\u2212) and neonatal jaundice","volume":"65","author":"Bienzle","year":"1976","journal-title":"Acta Paediatr Scand"},{"issue":"5","key":"2021121012071601900_hem2021000266C24","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1053\/j.semperi.2004.09.001","article-title":"Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus","volume":"28","author":"Kaplan","year":"2004","journal-title":"Semin Perinatol"},{"issue":"5","key":"2021121012071601900_hem2021000266C25","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1203\/01.PDR.0000141846.37253.AF","article-title":"Risk factors for severe hyperbilirubinemia in neonates","volume":"56","author":"Huang","year":"2004","journal-title":"Pediatr Res"},{"key":"2021121012071601900_hem2021000266C26","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.bcmd.2016.07.001","article-title":"Favism, the commonest form of severe hemolytic anemia in Palestinian children, varies in severity with three different variants of G6PD deficiency within the same community","volume":"60","author":"Reading","year":"2016","journal-title":"Blood Cells Mol Dis"},{"issue":"5","key":"2021121012071601900_hem2021000266C27","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1172\/JCI133530","article-title":"Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusion","volume":"130","author":"Francis","year":"2020","journal-title":"J Clin Invest"},{"issue":"8","key":"2021121012071601900_hem2021000266C28","doi-asserted-by":"crossref","first-page":"3560","DOI":"10.1182\/blood-2006-08-042531","article-title":"Molecular basis of glutathione reductase deficiency in human blood cells","volume":"109","author":"Kamerbeek","year":"2007","journal-title":"Blood"},{"issue":"3","key":"2021121012071601900_hem2021000266C29","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1365-2141.2008.07017.x","article-title":"Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency","volume":"141","author":"Percy","year":"2008","journal-title":"Br J Haematol"},{"issue":"6","key":"2021121012071601900_hem2021000266C30","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1248\/bpb.19.796","article-title":"Molecular cloning and expression of human liver biliverdin-IX beta reductase","volume":"19","author":"Komuro","year":"1996","journal-title":"Biol Pharm Bull"},{"issue":"8","key":"2021121012071601900_hem2021000266C31","doi-asserted-by":"crossref","first-page":"e484","DOI":"10.1097\/MPH.0000000000001482","article-title":"A new homozygous mutation (c.393-394del TA\/c.393-394del TA) in the NT5C3 gene associated with pyrimidine-5\u2032-nucleotidase deficiency: a case report","volume":"41","author":"K\u00f6ker","year":"2019","journal-title":"J Pediatr Hematol Oncol"},{"issue":"2","key":"2021121012071601900_hem2021000266C32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-2141.2006.05992.x","article-title":"Hereditary pyrimidine 5\u2032-nucleotidase deficiency: from genetics to clinical manifestations","volume":"133","author":"Zanella","year":"2006","journal-title":"Br J Haematol"},{"issue":"4","key":"2021121012071601900_hem2021000266C33","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/ajim.4700050409","article-title":"Basophilic stippling of red blood cells: a nonspecific finding of multiple etiology","volume":"5","author":"Cheson","year":"1984","journal-title":"Am J Ind Med"},{"key":"2021121012071601900_hem2021000266C34","doi-asserted-by":"crossref","first-page":"923","DOI":"10.3389\/fphys.2019.00923","article-title":"The effects of different signaling pathways in adenylyl cyclase stimulation on red blood cells deformability","volume":"10","author":"Semenov","year":"2019","journal-title":"Front Physiol"},{"issue":"6","key":"2021121012071601900_hem2021000266C35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1136\/jclinpath-2019-205718","article-title":"Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A&gt;G and c.413G&gt;A)","volume":"72","author":"Dongerdiye","year":"2019","journal-title":"J Clin Pathol"},{"issue":"13","key":"2021121012071601900_hem2021000266C36","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1182\/blood-2005-04-1622","article-title":"The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis","volume":"106","author":"van Wijk","year":"2005","journal-title":"Blood"},{"issue":"11","key":"2021121012071601900_hem2021000266C37","doi-asserted-by":"crossref","first-page":"e1004711","DOI":"10.1371\/journal.pgen.1004711","article-title":"A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia","volume":"10","author":"Mamoune","year":"2014","journal-title":"PLoS Genet"},{"key":"2021121012071601900_hem2021000266C38","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41531-017-0014-4","article-title":"Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?","volume":"3","author":"Sakaue","year":"2017","journal-title":"NPJ Parkinsons Dis"},{"key":"2021121012071601900_hem2021000266C39","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.freeradbiomed.2013.11.022","article-title":"Inborn defects in the antioxidant systems of human red blood cells","volume":"67","author":"van Zwieten","year":"2014","journal-title":"Free Radic Biol Med"},{"issue":"1","key":"2021121012071601900_hem2021000266C40","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1097\/MPH.0000000000000811","article-title":"A rare cause of neonatal hemolytic anemia: glutathione synthetase deficiency","volume":"40","author":"Soylu Ustkoyuncu","year":"2018","journal-title":"J Pediatr Hematol Oncol"},{"issue":"11","key":"2021121012071601900_hem2021000266C41","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.3324\/haematol.11238","article-title":"Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin","volume":"92","author":"Ma\u00f1\u00fa Pereira","year":"2007","journal-title":"Haematologica"},{"issue":"10","key":"2021121012071601900_hem2021000266C42","doi-asserted-by":"crossref","first-page":"e400","DOI":"10.1016\/S2352-3026(15)00191-X","article-title":"G6PD deficiency: a polymorphism balanced by heterozygote advantage against malaria","volume":"2","author":"Luzzatto","year":"2015","journal-title":"Lancet Haematol"},{"issue":"1","key":"2021121012071601900_hem2021000266C43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.4269\/ajtmh.18-0612","article-title":"Evaluation of a novel quantitative test for glucose-6-phosphate dehydrogenase deficiency: bringing quantitative testing for glucose-6-phosphate dehydrogenase deficiency closer to the patient","volume":"100","author":"Pal","year":"2019","journal-title":"Am J Trop Med Hyg"},{"issue":"9","key":"2021121012071601900_hem2021000266C44","doi-asserted-by":"crossref","first-page":"905","DOI":"10.7205\/MILMED.171.9.905","article-title":"Prevalence of glucose-6-phosphate dehydrogenase deficiency in U.S. Army personnel","volume":"171","author":"Chinevere","year":"2006","journal-title":"Mil Med"},{"issue":"5158","key":"2021121012071601900_hem2021000266C45","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1038\/2191041a0","article-title":"Relationship between the genes for glucose-6-phosphate dehydrogenase and for haemoglobin in a Nigerian population","volume":"219","author":"Luzzatto","year":"1968","journal-title":"Nature"},{"issue":"2","key":"2021121012071601900_hem2021000266C46","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1182\/blood.V91.2.706","article-title":"Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency","volume":"91","author":"Cocco","year":"1998","journal-title":"Blood"},{"issue":"1","key":"2021121012071601900_hem2021000266C47","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12936-019-2652-y","article-title":"Molecular characterization and mapping of glucose-6-phosphate dehydrogenase (G6PD) mutations in the Greater Mekong Subregion","volume":"18","author":"Bancone","year":"2019","journal-title":"Malar J"},{"key":"2021121012071601900_hem2021000266C48","doi-asserted-by":"crossref","first-page":"609103","DOI":"10.3389\/fphys.2020.609103","article-title":"A proposed concept for defective mitophagy leading to late stage ineffective erythropoiesis in pyruvate kinase deficiency","volume":"11","author":"van Vuren","year":"2020","journal-title":"Front Physiol"},{"issue":"6856","key":"2021121012071601900_hem2021000266C49","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1136\/bmj.305.6856.760","article-title":"Pyruvate kinase deficiency. Association with G6PD deficiency","volume":"305","author":"Mahendra","year":"1992","journal-title":"BMJ"},{"issue":"20","key":"2021121012071601900_hem2021000266C50","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1182\/blood-2012-03-416032","article-title":"Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase-deficient children receiving dapsone","volume":"120","author":"Pamba","year":"2012","journal-title":"Blood"},{"issue":"3","key":"2021121012071601900_hem2021000266C51","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1046\/j.1365-2141.2003.03980.x","article-title":"Pyrimidine 5\u2032 nucleotidase deficiency","volume":"120","author":"Rees","year":"2003","journal-title":"Br J Haematol"},{"issue":"11","key":"2021121012071601900_hem2021000266C52","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1182\/blood-2016-11-753525","article-title":"AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency","volume":"130","author":"Kung","year":"2017","journal-title":"Blood"},{"issue":"2","key":"2021121012071601900_hem2021000266C53","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.hoc.2015.11.006","article-title":"Glucose-6-phosphate dehydrogenase deficiency","volume":"30","author":"Luzzatto","year":"2016","journal-title":"Hematol Oncol Clin North Am"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/341\/1851446\/341luzzatto.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/341\/1851446\/341luzzatto.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T22:51:37Z","timestamp":1699915897000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2021\/1\/341\/482939\/Diagnosis-and-clinical-management-of-enzymopathies"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12,10]]},"published-print":{"date-parts":[[2021,12,10]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2021000266","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,10]]},"published":{"date-parts":[[2021,12,10]]}}}