ZUSAMMENFASSUNG Mit dem nächsten Jahrzehnt kann sich die ambulante Pädiatrie im Rahmen eines tiefgreifenden Wandels auf gesellschaftliche und berufliche Veränderungen einstellen. Infektionskrankheiten behalten Ihre Bedeutung, gerade in den nächsten Jahren wird der Kinderarzt immer wieder mit den Folgeerkrankungen der Pandemie konfrontiert. Genetisch bedingte Erkrankungen von Migranten (Sichelzellkrankheiten, Thalassämien) werden weiter im Studium nicht ausreichend vermittelt, spielen aber in der Praxis eine zunehmende Rolle. Darüber hinaus sehen wir eine Zunahme von jungen Patienten mit chronischen Erkrankungen. Die Kinder- und Jugendärzte nehmen vermehrt eine Lotsen- und Beratungsfunktion ein und stehen der gesamten Familie bei Entscheidungen bei. Sozialpädiatrische Krankheitsbilder nehmen in der kinderärztlichen Praxis zu. Die notwendige interdisziplinäre Vernetzung von Allgemein- zu Spezialpädiatrie sowie zwischen ambulantem und stationärem Bereich gewinnt auch hier an Bedeutung. Telemedizin und künstliche Intelligenz (KI) verändern den Aufgabenbereich des Kinder- und Jugendarztes. Das spezifische Fachwissen kann durch künstliche Intelligenz teilweise geleistet werden. Der Kinderarzt muss entscheiden, welche Empfehlungen und Schlussfolgerungen der KI richtig sind und welche dem Patienten in seiner individuellen Situation am besten gerecht werden. Die Telemedizin beschleunigt den Fachaustausch von Expertenwissen des Schwerpunktpädiaters mit dem Erfahrungswissen des Allgemeinpädiaters. Um eine flächendeckende und bedarfsgerechte, patientenorientierte Versorgung gewährleisten zu können, müssen die medizinischen Ansprüche und die ärztlichen Kompetenzen schon in die Ausbildung integriert werden und die berufspolitischen Voraussetzungen für die Umsetzung gegeben sein.

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

Introduction: Pyruvate kinase (PK) deficiency is a rare, congenital, hemolytic anemia caused by mutations in the PKLR gene. Patients, including those never managed with blood transfusions, experience iron overload and other disease-related complications. In 2024, the first international expert guidelines for PK deficiency were published and included monitoring recommendations for patients never transfused (NT). Aim: Todescribe the reasons provided by clinicians for not transfusing patients with PK deficiency who were NT and the disease monitoring activities in these patients, using data from two real-world studies: Peak Registry (NCT03481738) and PK deficiency Natural History Study (NHS; NCT02053480). Methods: Both NHS and Peak were designed as global, longitudinal, observational studies enrolling patients with PK deficiency (NHS 2014-2017, Peak 2018-ongoing [data cut-off date: 15May2023]). This descriptive analysis used merged data from both studies and included patients aged ≥18 years, with a confirmed diagnosis of PK deficiency who were NT (defined as no lifetime history of blood transfusions before/during study follow-up). A subgroup analysis of patients with ≥12 months of retrospective data was performed to ensure adequate time for monitoring to occur. Results were evaluated relative to pertinent recommendations from the PK deficiency international expert guidelines. Results: A total of 55 adult NT patients were included in the analysis. Median age (min-max) at the last visit was 39 years (18-81), 43.6% were female, 86.0% were White, 10.2% were Hispanic/Latino. Most patients resided in Southern Europe (43.6%), followed by North America (18.2%), Northern Europe (18.2%), Asia (12.7%), and Central Europe (7.3%). Overall, 18.9% (10/53; 2 unknown) had previously undergone splenectomy. PKLR genotype distribution was 62.3% missense/missense, 34.0% missense/non-missense, and 3.8% non-missense/non-missense. Median (min-max) lab results at patients' last visit included hemoglobin 11.4 g/dL (6.8-18.3), reticulocytes 6.6% (2.6-63.0), and ferritin 312.0 ng/mL (16.6-6208.0). The most common reason for not being transfused was “anemia not very severe” (71.1%), followed by “anemia not symptomatic” (20.0%), “iron-overload risks” (11.1%), “patient objection” (4.4%), “immune-associated risks” (2.2%), and “injection-related risks” (2.2%); rationale was only captured in Peak (n=45) and multiple response options were allowed. Among the 42 NT patients with ≥12 months of retrospective data, clinical monitoring received during registry participation (and recent pre-baseline history) included lab assessments for hemoglobin (97.6%), reticulocytes (85.7%), and ferritin (95.2%). Bone health was monitored via 25-hydroxyvitamin D (23.8%, 10/42) and Dexa scan (12.9%, 4/31). Cardiovascular monitoring occurred in 37.5% and 19.4% of NHS and Peak participants, respectively. MRI for iron assessment (liver and/or cardiac) was performed for 20.8% of NHS patients and 25.0% of Peak patients. Among 5 patients with ongoing chelation therapy, all had registry documentation of ferritin monitoring, and none had a liver iron concentration evaluation via MRI. Complications among the 42 NT patients with ≥12 months of retrospective data included iron overload (40.0%), osteoporosis (12.1%), extramedullary hematopoiesis (8.6%), left ventricular hypertrophy (7.4%), diabetes (5.7%), thromboembolic events (4.3%), hepatic cirrhosis (2.8%), and arrhythmia (2.7%). These complications, except for hepatic cirrhosis, were also observed in the subgroup reporting anemia not very severe and/or not symptomatic. Conclusion: Among NT patients with PK deficiency, observed medical monitoring practices fall short of evidence-based recommendations in recently published guidelines. NT patients are at risk for complications, such as iron overload and osteoporosis, that require routine monitoring. Even patients classified as “not being very severe” and/or “not symptomatic” experienced disease complications. These findings emphasize the need for evidence-based disease monitoring to be consistently implemented for all patients with PK deficiency, enabling early detection and management of complications. Guidelines recommend annual screening for iron overload irrespective of transfusion status, highlighting that chelation therapy can potentially avoid further complications.

Background: Pyruvate Kinase Deficiency (PKD) drastically reduces the lifespan of erythrocytes resulting in, inter alia, jaundice, hypersplenism and dependency on regular blood transfusions due to hemolysis. Splenectomy and blood transfusions do not guarantee an improvement of clinical symptoms and cause severe side effects such as iron overload and risk of infection. Procedure: Treatment with EPO was introduced two months after birth and commenced with a dosage of < 200.0 U/kg subcutaneously twice per week. Results: Hemoglobin concentration (Hb) remained stable at 8.0 g/dl at the age of 12 months and reached a peak of 11.0 g/dl at 20 moths. No further transfusions were necessary since the effect of EPO set in. Mean corpuscular volume (MCV) showed a slower increase than the number of reticulocytes proving that treatment with EPO improved the maturation of reticulocytes to adult erythrocytes thereby overcoming ineffective erythropoiesis. Iron overload due to prior transfusions was reduced, hypersplenism and compromised liver function were not present at any time. The child’s health and neurological development were in line with its age always. Conclusions: Treatment with EPO overcomes ineffective erythropoiesis in patients with a measurable residual activity of PK preventing the risks and side effects of current standard treatment strategies

ZUSAMMENFASSUNG Anämien sind heterogen und vielfältig, daher werden besonders seltene Anämieformen häufig unterdiagnostiziert. Eine ausführliche Diagnostik im klinischen Alltag ist deshalb notwendig. Zum Ausschluss häufiger Anämieursachen sollten immer eine eingehende klinische Anamnese und Diagnostik mit der Suche nach Infektionen oder Tumoren, Hämolysezeichen und Coombs-Test erfolgen. Als Differenzialdiagnose bei verändertem Blutbild muss auch an ein malignes Geschehen gedacht werden. Nur durch das Ausschließen zahlreicher Differenzialdiagnosen lassen sich seltene Anämien detektieren und adäquat behandeln. Die Eisenmangelanämie ist die häufigste Anämieform, die sich mit einer mikrozytären, hypochromen Anämie im Blutbild präsentiert. Ursache ist entweder eine zu geringe Zufuhr, eine schwache Absorption (zum Beispiel bei Zöliakie) oder eine vermehrte Ausscheidung von Eisen. Therapeutisch kann eine orale Therapie mit Fe2+ (Ferrosanol-Tropfen/Kapseln) eingeleitet werden und bei schwerer, therapieresistenter Eisenmangelanämie sollte eine Eisentransfusion in Erwägung gezogen werden. Bei der Sichelzellerkrankung kommt es zu mehr oder weniger schweren Gefäßverschlüssen, chronischer Hämolyse und Infektbereitschaft durch funktionelle Asplenie. Eine Prophylaxe mit Hydroxycarbamid kann Sichelzellkrisen vorbeugen, die einzig kausale Therapie ist die allogene Stammzellentransplantation. Die hereditäre Sphärozytose und der Pyruvatkinase-Mangel sind in Mitteleuropa die häufigsten, genetisch bedingten chronischen hämolytischen Anämien. Bei diesen beiden Erkrankungen ist durch einfache hämatologische Untersuchungen eine Unterteilung in verschiedene Schweregrade der Erkrankung möglich. Diese Einteilung erlaubt eine prognostische Aussage über den zu erwartenden klinischen Verlauf und die Einleitung einer adäquaten Therapie. Als erste kongenitale hämolytische Anämie kann der Pyruvatkinase-Mangel molekular durch Mitapivat behandelt werden. Dieser Therapieversuch sollte vor der Splenektomie erfolgen. Bei der Sphärozytose sollte eine nahezu totale Splenektomie (NTS) der vollständigen Splenektomie vorgezogen werden, da dadurch die immunologische Milzfunktion erhalte werden kann. Weitere wichtige Anämien sind die Autoimmunhämolytischen Anämien (AIHA). Sie werden durch eine Bildung von Antikörpern gegen Antigene auf autologen Erythrozyten charakterisiert. Die zwei häufigsten Vertreter sind die durch Wärme- und Kälteantikörper ausgelösten AIHA. Therapeutisch können Steroide und bei Steroidresistenz Immunsuppressiva angewandt werden. Renale Anämien sind sehr selten und treten bei Kindern mit chronischem Nierenversagen, meist als Folge kongenitaler Nephropathien, auf. Es sollten einerseits die Verbesserung der Nierenfunktion, andererseits die Stimulation der Erythropoese als therapeutische Ansätze erwogen werden.

Erythrocyte membrane and enzyme defects are the most common cause of congenital hemolytic anemias in the Central European population. Diagnostics include erythrocyte morphology, special biochemical tests such as osmotic fragility (AGLT) and EMA. For enzymopenic hemolytic anemias, cost-effective biochemical analysis remains the gold standard, supplemented by molecular genetic diagnostics when appropriate. Therapeutically, near complete splenectomy reduces hemolysis significantly for spherocytosis. The residual spleen at least provides a considerable phagocytic function and better response to immunisation and by inference possibly better protection against severe post-splenectomy infection. For pyruvate kinase deficiency, which is not so rare, a new molecular therapy (Mitapivat) is currently being introduced. In G6PD deficiency, there are very few drugs that cause hemolytic crisis. Sudden onset of hemoglobinuria is an early important hallmark of severe hemolytic crisis in G6PD deficiency and these patients should be hospitalized. Aplastic crises in the setting of parvovirus B19 infection occur in all congenital hemolytic anemias. Transfusion is not preventable in most cases. Iron-excreting treatment is required in the rare patients in need of chronic transfusion.

Erythrocyte membrane and enzyme defects are the most common cause of congenital hemolytic anemias in the Central European population. Diagnostics include erythrocyte morphology, special biochemical tests such as osmotic fragility (AGLT) and EMA. For enzymopenic hemolytic anemias, cost-effective biochemical analysis remains the gold standard, supplemented by molecular genetic diagnostics when appropriate. Therapeutically, near complete splenectomy reduces hemolysis significantly for spherocytosis. The residual spleen at least provides a considerable phagocytic function and better response to immunisation and by inference possibly better protection against severe post-splenectomy infection. For pyruvate kinase deficiency, which is not so rare, a new molecular therapy (Mitapivat) is currently being introduced. In G6PD deficiency, there are very few drugs that cause hemolytic crisis. Sudden onset of hemoglobinuria is an early important hallmark of severe hemolytic crisis in G6PD deficiency and these patients should be hospitalized. Aplastic crises in the setting of parvovirus B19 infection occur in all congenital hemolytic anemias. Transfusion is not preventable in most cases. Iron-excreting treatment is required in the rare patients in need of chronic transfusion.

Anämien sind in der Bevölkerung weit verbreitet. Besonders im Kindes- und Jugendalter ist die Wahrscheinlichkeit hoch, an einer erworbenen Anämie zu erkranken. Die Basisdiagnostik und erweiterte Diagnostik und das Erkennen der unterschiedlichen Anämieformen sind essenziell für die richtige Therapieentscheidung. Insbesondere transfusionsbedürftige Kinder müssen rechtzeitig erkannt werden, um richtig handeln zu können.

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Although recognition of the disease spectrum has recently expanded, data describing its impact on health-related quality of life (HRQoL) are limited. In this prospective international cohort of 254 patients (131 adults and 123 children) with PKD, we used validated measures to assess the impact of disease on HRQoL (EuroQol 5-Dimension Questionnaire, Pediatric Quality of Life Inventory Generic Core Scale version 4.0, and Functional Assessment of Cancer Therapy-Anemia) and fatigue (Patient Reported Outcomes Measurement Information System Fatigue and Pediatric Functional Assessment of Chronic Illness Therapy-Fatigue). Significant variability in HRQoL and fatigue was reported for adults and children, although individual scores were stable over a 2-year interval. Although adults who were regularly transfused reported worse HRQoL and fatigue compared with those who were not (EuroQol-visual analog scale, 58 vs 80; P = .01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. HRQoL and fatigue significantly differed in children by genotype, with the worst scores in those with 2 severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. Additionally, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. Although current treatments for PKD are limited to supportive care, new therapies are in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having >4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064]) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Red blood cell pyruvate kinase deficiency (PKD) is an autosomal recessive disease caused by mutations in the PKLR gene causing a hereditary non-spherocytic hemolytic anemia. The PKLR gene is responsible for coding the red blood cell pyruvate kinase (PK-R), which is the last enzyme of the anaerobic glycolysis in erythrocytes. This article presents the clinical, biochemical and molecular characteristics of patients with PKD in Germany. Medical data of 28 patients with PKD were retrospectively collected and prospectively analyzed for a period of 2 years. The data were collected using standardized questionnaires. All patients participated in the international PKD Natural History Study, being the biggest cohort study of PKD patients, so far. These data highlight the clinical and molecular variability of this rare disease. The study focuses on analyzing the genotype-phenotype association and the quality of life of patients with PKD. The objective of this article is to highlight the clinical and molecular variability of this rare disease in order to diagnose PKD earlier and treat according to the modern medical standards.

Background Pyruvate kinase deficiency (PKD) is a rare, autosomal recessive red blood cell enzyme disorder, which leads to lifelong hemolytic anemia and associated complications from the disease and its management. Methods An international, multicenter registry enrolled 124 individuals younger than 18 years old with molecularly confirmed PKD from 29 centers. Retrospective and prospective clinical data were collected. Results There was a wide range in the age at diagnosis from 0 to 16 years. Presentation in the newborn period ranged from asymptomatic to neonatal jaundice to fulminant presentations of fetal distress, myocardial depression, and/or liver failure. Children 12 to <18 years (53% vs. 14%, p = .0006), which correlated with the timing of splenectomy. Regular transfusions were most common in children with two severe PKLR variants. In regularly transfused children, the nadir hemoglobin goal varied considerably. Impact on quality of life was a common reason for treatment with regular blood transfusions and splenectomy. Splenectomy increased the hemoglobin and decreased transfusion burden in most children but was associated with infection or sepsis (12%) and thrombosis (1.3%) even during childhood. Complication rates were high, including iron overload (48%), perinatal complications (31%), and gallstones (20%). Conclusions There is a high burden of disease in children with PKD, with wide practice variation in monitoring and treatment. Clinicians must recognize the spectrum of the manifestations of PKD for early diagnostic testing, close monitoring, and management to avoid serious complications in childhood.

Der Pyruvatkinase(PK)-Mangel der Erythrozyten wird autosomal-rezessiv vererbt und durch Mutationen im PKLR-Gen verursacht. Das Gen kodiert für das letzte Enzym der anaeroben Glykolyse der Erythrozyten, die Pyruvatkinase (PK-R [Pyruvatkinase-R-Isoform]). Die Folge ist eine nichtautoimmunvermittelte, nichtsphärozytäre hämolytische Anämie. Dieser Beitrag beleuchtet die klinischen, laborchemischen und molekulargenetischen Charakteristika von Patienten mit PK-Mangel in Deutschland. Mithilfe von standardisierten Fragebogen wurden von den 28 deutschen Patienten mit PK-Mangel, die alle an der PKD Natural History Study teilnahmen, retrospektiv Daten erhoben. Die Patienten wurden außerdem prospektiv über einen Zeitraum von 2 Jahren beobachtet. Besondere Schwerpunkte wurden auf die Genotyp-Phänotyp-Korrelation sowie die Analyse der Lebensqualität der Patienten mit PK-Mangel gelegt. Ziel dieses Beitrags ist es, die vielfältigen klinischen und molekulargenetischen Eigenschaften dieser seltenen Erkrankung darzustellen, um durch eine erhöhte Wachsamkeit die Erkrankung früher zu diagnostizieren und adäquat zu behandeln.

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p<0.0001), have received chelation therapy (90% vs. 42%, p<0.0001), and had more lifetime transfusions (median: 77 versus 15, p<0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year. Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Ernährungsbedingte Anämien (durch Eisen- oder Vitamin-B12-Mangel) sind im Kindesalter kein seltenes Problem. Oft liegt der Ursprung der Anämie in der mütterlichen Vitaminversorgung, insbesondere während der Schwangerschaft. Ein Eisenmangel sowie Vitamin-B12-Mangel sollten ausgeglichen werden, um irreversible Schäden wie Entwicklungsstörungen zu vermeiden. Dafür stehen orale sowie parenterale Wirkstoffe zur Verfügung.

Hereditary spherocytosis (HS) is characterised by increased osmotic fragility and enhanced membrane loss of red blood cells (RBC) due to defective membrane protein complexes. In our diagnostic laboratory, we observed that pyruvate kinase (PK) activity in HS was merely slightly elevated with respect to the amount of reticulocytosis. In order to evaluate whether impaired PK activity is a feature of HS, we retrospectively analysed laboratory data sets from 172 unrelated patients with HS, hereditary elliptocytosis (HE), glucose-6-phosphate dehydrogenase (G6PD) or PK deficiency, sickle cell or haemoglobin C disease, or β-thalassaemia minor. Results from linear regression analysis provided proof that PK activity decreases with rising reticulocyte counts in HS (R2  = 0·15; slope = 9·09) and, less significantly, in HE (R2  = 0·021; slope = 8·92) when compared with other haemolytic disorders (R2  ≥ 0·65; slopes ≥ 78·6). Reticulocyte-adjusted erythrocyte PK activity levels were significantly lower in HS and even declined with increasing reticulocytes (R2  = 0·48; slope = -9·74). In this report, we describe a novel association between HS and decreased PK activity that is apparently caused by loss of membrane-bound PK due to impaired structural integrity of the RBC membrane and may aggravate severity of haemolysis in HS.