ABSTRACT
BACKGROUND: Pyruvate kinase deficiency (PKD) is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. The disease shows a marked variability in clinical expression. We studied the molecular features of nine unrelated Argentinian patients with congenital hemolytic anemia associated with erythrocyte pyruvate kinase deficiency. DESIGN AND METHODS: Routine hematologic investigations were performed to rule out other causes of chronic hemolytic anemia. Sanger sequencing and in-sílico analysis were carried out to identify and characterize the genetics variants. RESULTS: Six different novel missense variants were detected among the 18 studied alleles: c.661 G > C (Asp221His), c.956 G > T (Gly319Val), c.1595 G > C (Arg532Pro), c.347 G > A (Arg116Gln), c.1232 G > T (Gly411Val), c.1021G > A (Gly341Ser). Structural implications of amino-acid substitutions were correlated with the clinical phenotypes seen in the probands. CONCLUSIONS: This is the first comprehensive report on molecular characterization of pyruvate kinase deficiency in Argentina and the second from South America that would contribute to our knowledge on the distribution and frequency of PKLR variants in our population but also offer new insights into the interpretation of the effect of PKLR variants and phenotype.
Subject(s)
Alleles , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Mutation, Missense , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/genetics , Adolescent , Adult , Amino Acid Substitution , Argentina , Child , Child, Preschool , Female , Humans , Infant , Male , Pyruvate Kinase/geneticsABSTRACT
A comatose male newborn infant with congenital lactic acidosis caused by pyruvate decarboxylase deficiency was treated with dichloroacetate (DCA), which stimulated an 88% drop in serum lactate concentration and reversed his coma. The response to DCA was temporary and the lactic acidosis worsened until his death, but DCA may confer more lasting benefit in less severely affected infants.
Subject(s)
Acidosis, Lactic/congenital , Acidosis, Lactic/drug therapy , Dichloroacetic Acid/therapeutic use , Pyruvate Decarboxylase/deficiency , Pyruvate Metabolism, Inborn Errors/drug therapy , Acidosis, Lactic/etiology , Humans , Infant, Newborn , Male , Pyruvate Metabolism, Inborn Errors/complicationsABSTRACT
The two first homozygous (or double heterozygous) cases of pyruvate kinase (PK) deficiency found in a Costa Rica family with no signs of consanguinity are reported. The clinical manifestations of the deficiency were present in both cases, these being enhanced in one of them by pregnancy. The family study performed showed the heterozygous character of the PK deficiency in all cases, plus the demonstration in two instances (father and brother) of a heterozygous haemoglobin C disease. The importance of the PK/HK quotient in the identification of the PK deficiency heterozygous is stressed, especially when the enzyme activity registered from haemolysates falls within the normal range.