Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to  -glutamylcysteine synthetase deficiency in a patient of Moroccan origin

Abstract

A previously undescribed mutation of hereditary γ γ-glutamylcysteine synthetase (GCS) deficiency was found in a 5 year old boy of Moroccan origin. He presented with chronic haemolytic anaemia, delayed psychomotor development and progressive motor sensitive neuropathy of lower extremities. The parents were third degree relatives. The activity of glycolytic enzymes were found to be normal in the propositus, his parents and a sister, but and a complete lack of GSH was found in the propositus. Accordingly, the measurement of de novo GSH synthetic enzymes was undertaken, and severe GCS deficiency was found in the propositus. Both parents and his sister presented GCS activity ranging from 69% to 90% of normal. GCS gene sequencing showed that the propositus was homozygous for a 1241C>T mutation in exon 11 and both parents and his sister were heterozygous. This mutation predicts a Pro414Leu amino acid substitution. Even though the homology between GCS and crystallographically solved, functionally related proteins is not very high, a three-dimensional model of GCS was derived using Modeller Software. GCS deficiency is a very rare autosomal recessive disorder reported so far in only 8 unrelated probands with severe haemolytic anaemia. In only 3 of these was the anaemia associated with severe neurological dysfunction. We report here the fourth case of GCS deficiency presenting neuropathy, giving further support to the eventual relationship between this enzymopathy and neurological damage Haematologica 2007; 92:e102-e105

Mechanistic Details of Glutathione Biosynthesis Revealed by Crystal Structures of Saccharomyces cerevisiae Glutamate Cysteine Ligase

“…In ScGCL, this lysine interacts via bridging water molecules with the ␤-phosphate of bound ADP. Further kinetic characterizations of the point mutants to confirm this assertion are needed as previous studies did not report K m(ATP) values for either enzyme (15,42).…”

“…Four single nucleotide mutations have been reported in hGCL deficiency, each leading to amino acid substitutions within the catalytic subunit of the enzyme: R127C, P158L, H370L, and P414L (15,41,42,57). Shown in Fig.…”

“…An anomalous difference map was calculated and examined (Fig. 3B) (41,42). However, comparison of these models with the ScGCL structure reported herein shows significant structural dissimilarities, revealing the limitations of models derived from such distant homologues.…”

Inborn errors in the metabolism of glutathione

“…Treatment with sulfonamide precipitated psychosis and pronounced hemolytic anemia in one of these siblings. One patient was reported to have learning disability with dyslexia and was also thought to be mentally retarded [5], and another had delayed psychomotor development and progressive sensory neuropathy of lower extremities, ataxia, hyperreflexia, dysarthria, and a peculiar gait suggestive of spinocerebellar degeneration [2]. Other symptoms found in patients with γ -glutamylcysteine synthetase deficiency are transient jaundice, reticulocytosis, and hepatosplenomegaly.…”

“…Four different mutations in the heavy subunit have been identified in four families affected by gamma-glutamylcysteine synthetase deficiency [1,2,4,5]. …”