PKLR – Pyruvate Kinase Deficiency of Red Cells

Pyruvate kinase deficiency of red cells is an autosomal recessive enzyme disorder caused by biallelic pathogenic variants in the PKLR gene, leading to chronic nonspherocytic hemolytic anemia, hyperbilirubinemia, splenomegaly, and related complications. Onset ranges from fetal hydrops to compensated adult anemia, with neonatal hyperbilirubinemia and transfusion‐dependence in severe cases. Genetic diagnosis informs prognosis, family planning, and emerging therapies such as allosteric activators.

Extensive genetic studies have identified over 250 unique PKLR variants in 257 unrelated patients, including 84 missense, 20 stop-gain, 11 splice, five large deletions, four in‐frame indels, and three promoter mutations ([PMID:32043619]). The most frequent allele, c.1529G>A (p.Arg510Gln), accounts for 23% of mutant alleles and recurs in diverse populations ([PMID:8483951]). Recurrent founder variants such as p.Arg486Trp (c.1456C>T) and deep‐intronic or regulatory alleles (e.g., promoter −83G>C) further illustrate the allelic heterogeneity and population specificity.

Inheritance is autosomal recessive, with segregation demonstrated in consanguineous families. For example, a Pakistani pedigree showed three affected siblings homozygous for p.Asp339Asn and fully cosegregating with severe transfusion‐dependent anemia in all born to consanguineous parents ([PMID:35168679]). Case series and family studies have reported segregation in multiplex kindreds (affected_relatives: 3).

Functional assays support haploinsufficiency and loss of function. Promoter‐reporter studies in K562 cells confirmed that the −83G>C promoter mutation abrogates erythroid‐specific PKLR transcription ([PMID:12393511]). Splicing analyses of IVS5+1G>A and c.1436G>A (p.Arg479His) donor‐site mutations revealed exon skipping and leaky transcripts correlating with absent protein in erythroid precursors ([PMID:15059150]). Moreover, erythroid progenitors express compensatory PKM2 but insufficiently to prevent hemolysis in null PKLR alleles ([PMID:28295642]).

Therapeutic interventions guided by genetic diagnosis include splenectomy, transfusion management, chelation, and curative options such as allogeneic stem cell transplantation. The recent approval of mitapivat for select missense genotypes underscores the need for precise genotype‐phenotype mapping to optimize personalized treatment.

Key take‐home: Definitive association of AR PKLR variants with pyruvate kinase deficiency enables reliable molecular diagnosis, family counselling, and targeted therapeutic strategies.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1993 • Analysis of pyruvate kinase‐deficiency mutations that produce nonspherocytic hemolytic anemia. PMID:8483951
• American journal of hematology • 2020 • Genotype‐phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency. PMID:32043619
• Journal of medical case reports • 2022 • A novel homozygous missense variant p.D339N in the PKLR gene correlates with pyruvate kinase deficiency in a Pakistani family: a case report. PMID:35168679
• Blood • 2003 • Disruption of a novel regulatory element in the erythroid‐specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. PMID:12393511
• British journal of haematology • 2004 • Ex vivo analysis of aberrant splicing induced by two donor site mutations in PKLR of a patient with severe pyruvate kinase deficiency. PMID:15059150
• European journal of haematology • 2017 • Residual pyruvate kinase activity in PKLR‐deficient erythroid precursors of a patient suffering from severe haemolytic anaemia. PMID:28295642

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