Comorbidities and complications in adults with pyruvate kinase deficiency.

OBJECTIVES: Pyruvate kinase (PK) deficiency is caused by PKLR gene mutations, leading to defective red blood cell glycolysis and hemolytic anemia. Rates of comorbidities and complications by transfusion history and relative to the general population remain poorly quantified. METHODS: Data for patients aged ≥ 18 years with two confirmed PKLR mutations were obtained from the PK deficiency Natural History Study (NCT02053480). Frequencies of select conditions were compared with an age- and sex-matched cohort from a general insured US population without PK deficiency. RESULTS: Compared with the matched population (n = 1220), patients with PK deficiency (n = 122) had significantly higher lifetime rates of osteoporosis, liver cirrhosis, and pulmonary hypertension; splenectomy and cholecystectomy rates were also significantly higher in the 8 years before the index date. Sixty-five (53.3%) patients with PK deficiency were classified as regularly transfused, 30 (24.6%) as occasionally transfused, and 27 (22.1%) as never transfused. Regularly transfused patients were significantly more likely than never transfused patients to have had splenectomy, cholecystectomy, and/or thrombosis. Liver iron overload was reported in 62% of patients and occurred regardless of transfusion cohort. CONCLUSIONS: Even never transfused patients with PK deficiency had higher rates of select comorbidities and complications than individuals without PK deficiency.

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.

Management of pyruvate kinase deficiency in children and adults.

Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.

Prevalence of pyruvate kinase deficiency: A systematic literature review.

OBJECTIVES: Pyruvate kinase deficiency (PK deficiency) is a rare disorder caused by compound heterozygosity or homozygosity for > 300 mutations in the PKLR gene. To understand PK deficiency prevalence, we conducted a systematic literature review. METHODS: We queried Embase and Medline for peer-reviewed references reporting PK deficiency prevalence/incidence, PKLR mutant allele frequency (MAF) among the general population, or crude results from which these metrics could be derived. RESULTS: Of 1390 references screened, 1296 were excluded after title/abstract review; 60 were excluded after full-text review. Four of the remaining 34 studies were considered high-quality for estimating PK deficiency prevalence. Two high-quality studies identified cases from source populations of known sizes, producing estimates of diagnosed PK deficiency prevalence of 3.2 and 8.5 per million. Another high-quality study derived an estimate of diagnosed PK deficiency prevalence of 6.5 per million by screening jaundiced newborns. The final high-quality study estimated total diagnosed and undiagnosed PK deficiency prevalence to be 51 per million through extrapolation from observed MAFs. CONCLUSIONS: We conclude that prevalence of clinically diagnosed PK deficiency is likely between 3.2 and 8.5 per million in Western populations, while the prevalence of diagnosed and undiagnosed PK deficiency could possibly be as high as 51 per million.

Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: Disease-specific assessments.

INTRODUCTION: Currently recommended patient-reported outcome (PRO) measures for patients with pyruvate kinase (PK) deficiency are non-disease-specific. The PK Deficiency Diary (PKDD) and PK Deficiency Impact Assessment (PKDIA) were developed to be more targeted measures for capturing the symptoms and impacts of interest to this patient population. METHODS: The instruments were developed based on concept elicitation interviews with 21 adults and modified based on 20 cognitive interviews. The domain structure and item concepts of the PKDD and PKDIA were compared with currently recommended measures, the EORTC QLQ-C30 and the SF-36v2®. RESULTS: The PKDD is a seven-item measure of the core signs and symptoms of PK deficiency. The PKDIA is a 14-item measure of the impacts of PK deficiency on patients' health-related quality of life (HRQoL). Minimal similarities were found between the new measures and the EORTC QLQ-C30 (eg, 43% of concepts were similar to the PKDD; 42% were similar to the PKDIA) and SF-36v2® (57% of concepts were similar to the PKDD; 17% were similar to the PKDIA). CONCLUSIONS: The PKDD and PKDIA fill a gap in the existing outcomes measurement strategy for PK deficiency. Future work includes psychometric evaluation of these newly developed measures.

The burden of disease in pyruvate kinase deficiency: Patients' perception of the impact on health-related quality of life.

OBJECTIVES: This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). METHODS: Interviews with 21 adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods. RESULTS: The most common signs and symptoms reported were yellow eyes (n = 19), tiredness (n = 18), yellow skin (n = 17), fatigue (n = 15), low energy (n = 13), and shortness of breath (n = 13). Furthermore, signs and symptoms of PK deficiency negatively impact the ability to perform physical activities, appearance, social activities, emotional states, activities of daily living, leisure activities, work and/or school, sleep, and cognitive states of those living with PK deficiency. A conceptual model is presented that further demonstrates the profound impact that signs and symptoms of PK deficiency have on dimensions of patients' HRQoL. CONCLUSIONS: This is the first study that provides patient perspective on the burden of living with PK deficiency and lays the foundation for future studies to examine the effect of pharmacologic interventions on overall HRQoL for patients living with PK deficiency.

Pyruvate kinase deficiency as a cause of extreme hyperbilirubinemia in neonates from a polygamist community.

Neonatal hemolytic jaundice is a risk factor for kernicterus. Pyruvate kinase (PK) deficiency is a rare cause of neonatal hemolytic jaundice, with a prevalence estimated at 1 case per 20,000 births in the United States, but with a higher prevalence among the Amish communities in Pennsylvania and Ohio. We discovered four neonates with PK deficiency born in a small community of polygamists. All four had early, severe, hemolytic jaundice. PK deficiency should be considered in neonates with early hemolytic, Coombs-negative, non-spherocytic jaundice, particularly in communities with considerable consanguinity. Such cases should be recognized early and managed aggressively to prevent kernicterus.

Molecular characterization of PK-LR gene in pyruvate kinase-deficient Italian patients.

We studied the PK-LR gene in 15 unrelated Italian patients with congenital hemolytic anemia associated with erythrocyte pyruvate kinase (PK) deficiency. Fourteen different mutations were detected among 26 mutated alleles identified: a five-nucleotide (nt) deletion (227 to 231), two splice-site (1269C and IVS3(-2)c), 10 missense (514C, 787T, 823A, 993A, 994A, 1168A, 1456T, 1529A, 1552A, and 1594T) and one nonsense mutation(s) (721T). Eight of these (deletion 227-231, 1269C, IVS3(-2)c, 514C, 787T, 823A, 1168A, and 1552A) were novel. Moreover, a new polymorphic site was detected in the 3' untranslated region of the mRNA (C/T, nucleotide 1738). The deletion 227-231 causes a stop codon after amino acid 77, probably resulting in an unstable gene product. Mutations 1269C and IVS3(-2)c lead to an alteration of the 5' and 3' splice-site consensus sequence, respectively; cDNA analysis failed to reveal any abnormal transcript, suggesting that these mutations generate an unstable mRNA that is rapidly degraded. Of the five new missense mutations, 823A (Gly275-Arg) and 1168A (Asp390-Asn) involve highly conserved amino acids, 514C (Glu172-Gln) and 1552A (Arg518-Ser), although found in less conserved regions, affect the balance of the electric charges of the protein. Mutation 787T (Gly263-Trp) is likely to determine strong modifications in the local structure of the molecule. The most frequent mutation in Italy appears to be 1456T (seven of 30 alleles), followed by 1529A (three of 30) and 994A (three of 30). A correlation was found between mutations, biochemical characteristics of the enzyme, and clinical course of the disease.

Evidence for founder effect of the Glu104Asp substitution and identification of new mutations in triosephosphate isomerase deficiency.

Triosephosphate isomerase (TPI) deficiency is an autosomal recessive disorder of glycolysis characterized by multisystem disease and lethality in early childhood. Among seven unrelated Northern European kindreds with clinical TPI deficiency studied, a single missense mutation at codon 104 (GAG;Glu-->GAC;Asp) predominated, accounting for 11/14 (79%) mutant alleles. In three families molecular analysis revealed compound heterozygosity for Glu104Asp and novel missense mutations. In two cases the second mutation was a Cys to Tyr substitution at codon 41 (TGT-->TAT) and in one an Ile to Val substitution at codon 170(ATT-->GTT). The origin of the Glu104Asp mutation was defined by haplotype analysis using a novel G/A polymorphism at nucleotide 2898 of the TPI gene. Cosegregation of the low frequency 2898A allele with the G-->C base change at nucleotide 315 supports a single origin for the Glu104Asp mutation in a common ancestor.

Hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency: a prevalence study in Quebec (Canada).

Fifty-eight cases of hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency were collected from both laboratories that have performed the assay since 1972 and from attending physicians in the province of Quebec. Using the postal addresses of the probands, a prevalence map was constructed according to the administrative regions of the province of Quebec. The prevalence was found to be higher in eastern Quebec (1/81,838) than in western Quebec (1/139,086). Fifty probands were of French Canadian origin whereas the remaining 6 were recent immigrants.

G6PD Varadero. A new variant of glucose-6-phosphate dehydrogenase associated with congenital nonspherocytic hemolytic anemia.

A glucose-6-phosphate dehydrogenase (G6PD) variant was studied in a mulatto patient with chronic nonspherocytic hemolytic anemia. This variant has reduced activity, increased thermolability, a reduced Michaelis constant for glucose-6-phosphate, slightly increased electrophoretic mobility, a biphasic pH activity profile, high 2-deoxyglucose-6-phosphate utilization, normal diamino nicotinamide adenine dinucleotide phosphate utilization and a peak of elution profile after G6PD B. The electrophoretic, kinetic, and chromatographic properties of this erythrocyte G6PD variant allow the conclusion that G6PD Varadero is probably a new variant.