RESUMEN
Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Piruvato Quinasa , Errores Innatos del Metabolismo del Piruvato , Sistema de Registros , Humanos , Piruvato Quinasa/deficiencia , Piruvato Quinasa/genética , Masculino , Femenino , Adulto , Niño , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/epidemiología , Errores Innatos del Metabolismo del Piruvato/genética , Errores Innatos del Metabolismo del Piruvato/epidemiología , Adolescente , Preescolar , Lactante , Comorbilidad , Persona de Mediana Edad , Esplenectomía , Adulto Joven , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/epidemiología , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/epidemiología , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/epidemiología , Recién NacidoRESUMEN
Triosephosphate isomerase deficiency (TPI Df) is a rare multisystem disorder with severe neuromuscular symptoms which arises exclusively from mutations within the TPI1 gene. Studies of TPI Df have been limited due to the absence of mammalian disease models and difficulties obtaining patient samples. Recently, we developed a novel murine model of TPI Df which models the most common disease-causing mutation in humans, TPI1E105D. Using our model in the present study, the underlying pathogenesis of neuromuscular symptoms has been elucidated. This is the first report detailing studies of neuromuscular pathology within a murine model of TPI Df. We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size. TPI Df mice also exhibited signs of cardiac pathology and displayed a deficit in vascular smooth muscle functionality. Together, these findings provide insight into pathogenesis of the neuromuscular symptoms in TPI Df and can guide the future development of therapeutics.
Asunto(s)
Modelos Animales de Enfermedad , Unión Neuromuscular , Triosa-Fosfato Isomerasa , Animales , Triosa-Fosfato Isomerasa/deficiencia , Triosa-Fosfato Isomerasa/genética , Triosa-Fosfato Isomerasa/metabolismo , Ratones , Unión Neuromuscular/patología , Unión Neuromuscular/metabolismo , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/patología , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/etiología , Errores Innatos del Metabolismo de los Carbohidratos/genética , Mutación , HumanosRESUMEN
Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Intrones , Piruvato Quinasa , Errores Innatos del Metabolismo del Piruvato , Humanos , Piruvato Quinasa/deficiencia , Piruvato Quinasa/genética , Masculino , Femenino , Errores Innatos del Metabolismo del Piruvato/genética , Niño , Preescolar , Anemia Hemolítica Congénita no Esferocítica/genética , Turquía , Lactante , Adolescente , MutaciónRESUMEN
Triosephosphate isomerase deficiency (TPI DF) is a severe multisystem degenerative disease, manifested clinically as hemolytic anemia, neuromuscular abnormalities, and susceptibility to infection, frequently leading to death within 5 years of onset. There is a lack of effective clinical treatment as the pathogenesis underlying TPI DF remains largely unknown. In this study, we generate a transgenic zebrafish line [Tg(Ubi:TPI1E105D-eGFP)] with the human TPI1E105D (hTPI1E105D) mutation, which is the most recurrent mutation in TPI DF patients. Overexpression of hTPI1E105D affects the development of erythroid and myeloid cells and leads to impaired neural and muscular development. In conclusion, we create a TPI DF zebrafish model to recapitulate the majority clinical features of TPI DF patients, providing a new animal model for pathogenesis study and drug screening of TPI DF.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Errores Innatos del Metabolismo de los Carbohidratos , Triosa-Fosfato Isomerasa/deficiencia , Pez Cebra , Animales , Humanos , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/patología , Triosa-Fosfato Isomerasa/genética , Modelos Animales de EnfermedadRESUMEN
Pyruvate kinase (PK) deficiency is a rare autosomal recessive disorder characterized by chronic hemolytic anemia of variable severity. Nine Polish patients with severe hemolytic anemia but normal PK activity were found to carry mutations in the PKLR gene encoding PK, five already known ones and one novel (c.178C > T). We characterized two of the known variants by molecular modeling (c.1058delAAG) and minigene splicing analysis (c.101-1G > A). The former gives a partially destabilized PK tetramer, likely of suboptimal activity, and the c.101-1G > A variant gives alternatively spliced mRNA carrying a premature stop codon, encoding a severely truncated PK and likely undergoing nonsense-mediated decay.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Mutación , Piruvato Quinasa , Errores Innatos del Metabolismo del Piruvato , Humanos , Piruvato Quinasa/genética , Piruvato Quinasa/deficiencia , Polonia , Errores Innatos del Metabolismo del Piruvato/genética , Masculino , Femenino , Anemia Hemolítica Congénita no Esferocítica/genética , Niño , Preescolar , Modelos Moleculares , Lactante , Adolescente , Codón sin Sentido , Empalme AlternativoRESUMEN
OBJECTIVE: Glucose-6-phosphate isomerase (GPI) deficiency is a rare hereditary nonspherocytic hemolytic anemia caused by GPI gene variants. This disorder exhibits wide heterogeneity in its clinical manifestations and molecular characteristics, often posing challenges for precise diagnoses using conventional methods. To this end, this study aimed to identify the novel variants responsible for GPI deficiency in a Chinese family. METHODS: The clinical manifestations of the patient were summarized and analyzed for GPI deficiency phenotype diagnosis. Novel compound heterozygous variants of the GPI gene, c.174C>A (p.Asn58Lys) and c.1538G>T (p.Trp513Leu), were identified using whole-exome and Sanger sequencing. The AlphaFold program and Chimera software were used to analyze the effects of compound heterozygous variants on GPI structure. RESULTS: By characterizing 53 GPI missense/nonsense variants from previous literature and two novel missense variants identified in this study, we found that most variants were located in exons 3, 4, 12, and 18, with a few localized in exons 8, 9, and 14. This study identified novel compound heterozygous variants associated with GPI deficiency. These pathogenic variants disrupt hydrogen bonds formed by highly conserved GPI amino acids. CONCLUSION: Early family-based sequencing analyses, especially for patients with congenital anemia, can help increase diagnostic accuracy for GPI deficiency, improve child healthcare, and enable genetic counseling.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia Hemolítica , Niño , Humanos , Glucosa-6-Fosfato Isomerasa/genética , Glucosa-6-Fosfato Isomerasa/química , Anemia Hemolítica/genética , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Mutación Missense , ExonesRESUMEN
BACKGROUND: Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death. CASE PRESENTATION: This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically. CONCLUSIONS: Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia Hemolítica , Adulto , Femenino , Humanos , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Glucosa , Glucosa-6-Fosfato Isomerasa/genética , FosfatosRESUMEN
The hexokinase (HK) enzyme plays a key role in red blood cell energy production. Hereditary non-spherocytic haemolytic anaemia (HNSHA) caused by HK deficiency is a rare disorder with only 12 different disease-associated variants identified. Here, we describe the clinical features and genotypes of four previously unreported patients with hexokinase 1 (HK1)-related HNSHA, yielding two novel truncating HK1 variants. The patients' phenotypes varied from mild chronic haemolytic anaemia to severe infantile-onset transfusion-dependent anaemia. Three of the patients had mild haemolytic disease caused by the common HK1 promoter c.-193A>G variant combined with an intragenic HK1 variant, emphasizing the importance of including this promoter variant in the haemolytic disease gene panels. HK activity was normal in a severely affected patient with a homozygous HK1 c.2599C>T, p.(His867Tyr) variant, but the affinity for ATP was reduced, hampering the HK function. In cases of HNSHA, kinetic studies should be considered in the functional studies of HK. We reviewed the literature of previously published patients to provide better insight into this rare disease and add to the understanding of genotype-phenotype correlation.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Hexoquinasa , Regiones Promotoras Genéticas , Humanos , Hexoquinasa/genética , Hexoquinasa/deficiencia , Femenino , Masculino , Anemia Hemolítica Congénita no Esferocítica/genética , Lactante , Alelos , Preescolar , Fenotipo , Niño , GenotipoRESUMEN
Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia with wide-ranging clinical symptoms and complications associated with significant morbidity and reduced health-related quality of life in both children and adults. The management of patients with PK deficiency has been historically challenging due to difficulties in the diagnostic evaluation, heterogeneity of clinical manifestations, and treatment options limited to supportive care with transfusions and splenectomy. An oral allosteric PK activator, mitapivat, is now a clinically available disease-modifying treatment for adults with PK deficiency. Phase 2 and 3 clinical trials of mitapivat have demonstrated sustained improvements in hemolytic anemia, hematopoiesis, and quality of life in many adults with PK deficiency and a generally reassuring safety profile with continued dosing. Additional long-term benefits include rapid and ongoing reduction in iron overload and potential stabilization of bone health. Clinical trials of treatment with mitapivat in children with PK deficiency are ongoing. In addition to disease-modifying treatment with PK activators, gene therapy is a potentially curative treatment currently under evaluation in clinical trials. With the availability of disease-targeted therapies, accurately diagnosing PK deficiency in patients with chronic hemolytic anemia is critical. PK activation and gene therapy have the potential to change the natural history of PK deficiency by improving clinical manifestations and patient quality of life and decreasing the risk of long-term complications.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia Hemolítica , Adulto , Niño , Humanos , Piruvato Quinasa/genética , Calidad de Vida , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/terapia , Anemia Hemolítica Congénita no Esferocítica/diagnósticoRESUMEN
Mitapivat (Pyrukynd®), an oral, allosteric activator of pyruvate kinase (PK), is approved in the USA for the treatment of haemolytic anaemia in adults with PK deficiency and in the EU and UK for the treatment of PK deficiency in adults. Mitapivat acts by restoring activity of the red blood cell (RBC) PK enzyme, which is dysfunctional due to genetic mutations in the PKLR gene in patients with PK deficiency. In the double-blind placebo-controlled phase III ACTIVATE trial in adults with PK deficiency who were not regularly RBC transfused, mitapivat was superior to placebo in improving haemoglobin levels. In the single-arm phase III ACTIVATE-T trial in adults with PK deficiency who were regularly RBC transfused, a reduction in RBC transfusion burden was observed with mitapivat. In both trials, mitapivat improved other clinical parameters of haemolysis and patient-reported health-related quality of life. At the approved twice-daily dosage range, mitapivat was generally well tolerated, with adverse events generally being mild to moderate in severity. Results from an ongoing extension study in previously enrolled phase III trial patients will be of interest. Currently available data indicate that mitapivat, the first approved disease-modifying drug for PK deficiency in adults, is a valuable treatment option for this rare disease.
Pyruvate kinase (PK) deficiency is a rare hereditary disease caused by mutations affecting the function of the PK enzyme in red blood cells (RBCs) and is characterized by chronic haemolytic anaemia. Treatment options for adults with PK deficiency have historically been limited to supportive care and are themselves associated with potentially serious complications. Oral mitapivat (Pyrukynd®) is the first disease-modifying drug to be approved for use in adults with PK deficiency and acts by restoring activity of the dysfunctional RBC PK enzyme. Based on findings from two phase III clinical trials, twice-daily oral mitapivat provided clinical benefit in adults with PK deficiency, both in patients not requiring, and requiring, regular RBC transfusions. Improvements in disease-specific health-related quality of life were observed in adults with PK deficiency treated with mitapivat. Mitapivat was generally well tolerated, with most adverse events being mild to moderate in severity. In conclusion, current evidence indicates that mitapivat is a valuable treatment option for adults with PK deficiency.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Piruvato Quinasa , Humanos , Adulto , Piruvato Quinasa/genética , Calidad de Vida , Anemia Hemolítica Congénita no Esferocítica/tratamiento farmacológico , Anemia Hemolítica Congénita no Esferocítica/genética , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Pyruvate kinase deficiency (PKD) is a rare congenital hemolytic anemia. Here, we summarized the clinical features and laboratory examinations of four Chinese children with PKD and analyze genomic mutations. METHOD: Collected and analyzed the clinical data of all children and their parents and completed the relevant laboratory examinations of all children. Analyzed the sequences of related genes in children by second-generation sequencing technology and verified the suspected mutations in children's family by Sanger sequencing method or second-generation sequencing technology. RESULTS: A total of six mutations in gene PKLR were detected in four cases. Except for c.1510C>T (P1) and c.941T>C (P2 and P4), which had been reported in previous studies, the other four novel gene mutations were reported for the first time, including a rare homozygous mutation with large fragment deletion. All those gene mutations cause changes in the amino acids encoded by the gene, as well as subsequent changes in protein structure or loss of function. CONCLUSION: Compound heterozygous or homozygous mutations in the coding region of PKLR gene are the causes of PKD in these four Chinese children. The second-generation sequencing technology is an effective means to diagnose PKD. The mutations of c.457-c.462delATCGCC, c.1297T>C, c.1096C>T and Exon4-10del of PKLR reported in this article have not been included in the Thousand Genome Database, dbSNP(v138) and ExAC Database. The PKLR gene mutations found in these children with PKD can provide references for further research of the genetic characteristics of PKD and subsequent gene therapy.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Pueblos del Este de Asia , Humanos , Niño , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , HomocigotoRESUMEN
The mutant allele frequency of the Pyruvate kinase (PK) gene has been investigated mostly in pure breed cats. We investigated the PK mutant gene in stray and animal hoarding mongrel cats in Hokkaido, Japan. We also investigated the kinship of individuals carrying the mutant gene. Genotyping was conducted using the previously reported real-time PCR method. Fourteen microsatellite markers were used to identify the parents and offspring of cats carrying the PK mutant gene, and some kinship such as parent-offspring and siblings was observed. Some stray and animal hoarding cats carried the PK mutation gene and that consanguinity was confirmed among these cats indicated that the PK mutation gene was spread by unregulated interbreeding.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Enfermedades de los Gatos , Acaparamiento , Gatos/genética , Animales , Piruvato Quinasa/genética , Japón/epidemiología , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/veterinaria , Enfermedades de los Gatos/epidemiología , Enfermedades de los Gatos/genéticaRESUMEN
Thrombocytopenia is a common laboratory abnormality encountered in critically ill neonates. The broad differential for thrombocytopenia, and its association with potentially severe neonatal pathology, often presents a diagnostic dilemma prompting extensive evaluation. Hemolysis due to red cell enzymopathies is a rare cause of neonatal thrombocytopenia that is typically brief and self-limiting. Here, we present a case of thrombocytopenia, refractory to transfusion, associated with anemia and hyperbilirubinemia in a neonate with pyruvate kinase deficiency (PKD) arising from compound heterozygous PKLR mutations. The nature of the thrombocytopenia in this patient created considerable diagnostic uncertainty, which was ultimately resolved by whole-exome sequencing. This case emphasizes that inherited red cell defects, such as PKD, are important to consider in cases of neonatal thrombocytopenia.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia , Enfermedades del Recién Nacido , Errores Innatos del Metabolismo del Piruvato , Trombocitopenia Neonatal Aloinmune , Recién Nacido , Humanos , Anemia Hemolítica Congénita no Esferocítica/complicaciones , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Errores Innatos del Metabolismo del Piruvato/diagnóstico , Errores Innatos del Metabolismo del Piruvato/genética , Errores Innatos del Metabolismo del Piruvato/complicaciones , Piruvato Quinasa/genéticaRESUMEN
BACKGROUND AND AIMS: Glucose phosphate isomerase (GPI) deficiency is an extremely rare autosomal recessive disorder caused by mutations in the GPI gene. In this research, the proband displaying typical manifestations of haemolytic anaemia and his family members were recruited to analyse the pathogenicity of the detected variants. METHODS: Peripheral blood samples were collected from the family members and genomic DNA was extracted and targeted for capture and sequencing. The effect of the candidate pathogenic variants on splicing was further investigated using the minigene splicing system. The computer simulation was also used for further analysis of the detected data. RESULTS: The proband carried the compound heterozygous variants c.633 + 3 A > G and c.295G > T in the GPI gene, which have never been reported before. In the genealogy, co-segregation of the mutant genotype with the phenotype was established. The minigene study showed that intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the two aberrant transcripts: r.546_633del and r.633 + 1_633 + 2insGT were transcribed by the minigene plasmid expressing the c.633 + 3 A > G variant. The missense mutation c.295G > T in exon 3 resulted in altering glycine at codon 87 to cysteine which was predicted to be pathogenic in an in silico analysis. Deeper analyses revealed that the Gly87Cys missense mutation led to steric hindrance. Compared to the wild-type, the mutation G87C led to a significant increase in intermolecular forces. CONCLUSION: Overall, the novel compound heterozygous variants in the GPI gene contributed to the etiology of the disease. Genetic testing can assist in the diagnosis. The novel gene variants identified in the present study has further expanded the mutational spectrum of GPI deficiency, which can better guide family counselling.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Enfermedades Metabólicas , Humanos , Simulación por Computador , Pueblos del Este de Asia , Virulencia , Glucosa-6-Fosfato Isomerasa/genética , Anemia Hemolítica Congénita no Esferocítica/genéticaRESUMEN
Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Errores Innatos del Metabolismo del Piruvato , Adulto , Humanos , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismo , Calidad de Vida , Anemia Hemolítica Congénita no Esferocítica/genética , Anemia Hemolítica Congénita no Esferocítica/terapia , Errores Innatos del Metabolismo del Piruvato/genética , Errores Innatos del Metabolismo del Piruvato/terapiaRESUMEN
INTRODUCTION: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry. METHODS AND ANALYSIS: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations. ETHICS AND DISSEMINATION: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications. TRIAL REGISTRATION NUMBER: NCT03481738.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Errores Innatos del Metabolismo del Piruvato , Adulto , Humanos , Niño , Piruvato Quinasa/genética , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Errores Innatos del Metabolismo del Piruvato/genética , HomocigotoRESUMEN
Pyruvate kinase deficiency (PKD) is an autosomal recessive condition, caused due to homozygous or compound heterozygous mutation in the PKLR gene resulting in non-spherocytic hereditary hemolytic anemia. Clinical manifestations in PKD patients vary from moderate to severe lifelong hemolytic anemia either requiring neonatal exchange transfusion or blood transfusion support. Measuring PK enzyme activity is the gold standard approach for diagnosis but residual activity must be related to the increased reticulocyte count. The confirmatory diagnosis is provided by PKLR gene sequencing by conventional as well as targeted next-generation sequencing involving genes associated with enzymopathies, membranopathies, hemoglobinopathies, and bone marrow failure disorders. In this study, we report the mutational landscape of 45 unrelated PK deficiency cases from India. The genetic sequencing of PKLR revealed 40 variants comprising 34 Missense Mutations (MM), 2 Nonsense Mutations (NM), 1 Splice site, 1 Intronic, 1 Insertion, and 1 Large Base Deletion. The 17 novel variants identified in this study are A115E, R116P, A423G, K313I, E315G, E318K, L327P, M377L, A423E, R449G, H507Q, E538K, G563S, c.507 + 1 G > C, c.801_802 ins A (p.Asp268ArgfsTer48), IVS9dsA-T + 3, and one large base deletion. In combination with previous reports on PK deficiency, we suggest c.880G > A, c.943G > A, c.994G > A, c.1456C > T, c.1529G > A are the most frequently observed mutations in India. This study expands the phenotypic and molecular spectrum of PKLR gene disorders and also emphasizes the importance of combining both targeted next-generation sequencing with bioinformatics analysis and detailed clinical evaluation to elaborate a more accurate diagnosis and correct diagnosis for transfusion dependant hemolytic anemia in a cohort of the Indian population.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia Hemolítica , Humanos , Recién Nacido , Anemia Hemolítica/genética , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Piruvato Quinasa/genéticaRESUMEN
BACKGROUND: Pyruvate kinase (PK) deficiency is the most common enzyme abnormality in the glycolytic pathway. Here, we describe two siblings with PK deficiency that mimicked congenital dyserythropoietic anemia (CDA) type I. CASE: The siblings were referred to our hospital for evaluation of anemia when they were newborns. Their PK enzyme activities were normal. Their bone marrow aspirations and electron microscopies showed CDA-like findings. A CDA panel with next-generation sequencing showed no mutation. Though their PK enzyme levels were normal, a molecular study of the PKLR gene showed a homozygous variant c.1623G > C (p.Lys541Asn) in exon 12 of our patients. CONCLUSIONS: Although the diagnosis of pyruvate kinase deficiency is difficult, it can be confused with many other diagnoses. Bone marrow findings of these cases are similar to congenital dyserythropoietic anemia. In patients with normal pyruvate kinase enzyme levels, the diagnosis cannot be excluded and genetic analysis is required.
Asunto(s)
Anemia Diseritropoyética Congénita , Anemia Hemolítica Congénita no Esferocítica , Errores Innatos del Metabolismo del Piruvato , Humanos , Recién Nacido , Piruvato Quinasa/genética , Anemia Diseritropoyética Congénita/diagnóstico , Anemia Diseritropoyética Congénita/genética , Errores Innatos del Metabolismo del Piruvato/diagnóstico , Errores Innatos del Metabolismo del Piruvato/genética , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/genéticaRESUMEN
INTRODUCTION: Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Until recently, treatment had been limited to supportive management including red blood cell transfusions, splenectomy, and management of chronic disease complications such as iron overload and decreased bone mineral density. AREAS COVERED: We discuss preclinical data and phase 1, 2, and 3 clinical studies evaluating mitapivat for adult patients with hemolytic anemia secondary to PKD. Mitapivat has been shown to offer early and durable improvement in hemoglobin with reduction in transfusion burden, and preliminary data suggest it can induce a negative iron balance in many patients without the use of dedicated iron chelators. EXPERT OPINION: Mitapivat is a first-in-class allosteric activator of pyruvate kinase and the first FDA-approved disease directed therapy for PKD. It has a favorable safety profile and clear clinical efficacy. Given the considerable genetic heterogeneity of PKD and the rapid effect on improving hemoglobin and reducing hemolysis, a therapeutic trial of mitapivat should be considered in all patients with PKD who are not homozygous for the PKLR R479H mutation. Further investigations are needed regarding long-term safety and efficacy profiles and whether long-term PKD-associated complications can be reduced or even reversed.