A rare G6PD variant (c.383T>G; p.128Leu>Arg) with a molecular pathophysiological mechanism similar to that of G6PD A- (68Val>Met, 126Asn>Asp).

We report the second documented observation of a rare class-III variant, we named G6PD Pyrgos, [c.383 T>G, p.128Leu>Arg] found in a Greek family. A 3-dimensional structure model for the enzyme shows that the region modified by the substitution is identical to that modified in G6PD A(-) (68Val>Met, 126Asn>Asp), suggesting a common underlying pathophysiological mechanism. Observation of this mutation in different Mediterranean regions suggests that it might be more widespread that initially supposed and, in the absence of molecular characterization, could be confused with other frequent variants.

Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations.

Pyruvate kinase (PK) deficiency is the most common enzyme defect affecting the glycolytic pathway of the erythrocyte. Usually, it is clinically silent in heterozygotes but serious disorders are described at birth in homozygotes or compound heterozygotes. Including the mutants herein reported, more than 180 mutations of the PK-LR gene have now been identified. This 3-year study was carried out to detect mutations associated with disease-affecting families. Haematological indices, erythrocyte PK and glucose-6-phosphate dehydrogenase activities were measured. Molecular characterisation of the PK gene mutations included restriction enzyme analysis, mutation scanning and gene sequencing. Among the 56 families studied, nine homozygous cases and 41 different mutations were found. Eight mutations involved a splice site, 31 missense mutations were located in crucial domains of the molecule (catalytic site, cleft between the A and C domains, A/A' interface) and two cases of insertion-deletion were found. In total, 20 new mutations modifying the structure of the enzyme and seven affecting a splice site are reported. PK deficiency is an under diagnosed disease. However, deficiency could be life threatening in perinatal period and we report two lethal cases. These results support the characterisation of PK mutations, and show that prenatal diagnosis can identify affected infants and prepare safer conditions for the birth.