Pyruvate kinase deficiency (PKD) is an autosomal recessive enzymopathy in erythrocytes caused by mutations in the PKLR gene. The clinical phenotype of the disease is nonspherocytic hemolytic anemia, characterized by both anemia- and treatment-related complications, including extramedullary hematopoiesis, iron overload, thrombosis, and pulmonary hypertension. Current management includes mainly supportive care interventions, notably chronic transfusions. Other disease-modifying therapies are currently in clinical trials, and show potential to reduce symptoms and prevent treatment-related complications.1,2

In a review article published in Blood, Rachael F. Grace, MD, of the department of pediatrics at Dana-Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center in Massachusetts and Wilma Barcellini, MD, of Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Italy, summarized current literature surrounding the treatment of PKD. They also reviewed novel agents currently in clinical development.

Epidemiology and Diagnosis

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The estimated prevalence of PKD is 3 to 8 cases per 1,000,000; however, this frequency may be underestimated due to underdiagnosis, likely attributable to the rarity of the disease, variable clinical presentation, and challenges with diagnosis. Heterozygous carriers of PKD are usually asymptomatic, which adds to the complexity of estimating prevalence, but is anticipated to range from 0.15% to 6%.1

The diagnosis of PKD is established on the basis of suspected clinical signs and symptoms related to chronic hemolytic anemia, which include jaundice, splenomegaly, and gallstones, as well as associated laboratory markers, such indirect hyperbilirubinemia, mild hyperferritinemia, and elevated reticulocytes. Given the autosomal recessive inheritance pattern, family history is typically of limited utility for establishing diagnosis, with the exception of affected siblings and miscarriages. Common differential diagnoses include both acquired and congenital hemolytic disorders.1

While the clinical presentation of the disease is highly variable, patients will often present within the first month after birth, but diagnoses in adulthood do occur, especially among patients with mild anemia or compensated hemolysis.1

Clinical Management in Newborns

In utero complications of newborns with PKD include prematurity, hydrops fetalis, and intrauterine growth retardation. In rare cases, infants may be very ill at the time of birth, presenting with signs and symptoms of pulmonary hypertension and/or stroke. Hepatic failure may also occur, and infants with this complication have a significant mortality rate; however, some cases have been successfully treated with liver transplant. Neonatal jaundice may also occur, with infants experiencing severe indirect hyperbilirubinemia, often warranting use of phototherapy.1