title: Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin.
abstract: A previously undescribed mutation of hereditary gamma-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.
authors.affiliation: Red Cell Pathology Unit, CDB-IDIBAPS, Hospital Clinic i Provincial, University of Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Mañú Pereira
authors.forename: T
authors.initials: T
authors.lastname: Gelbart
authors.forename: E
authors.initials: E
authors.lastname: Ristoff
authors.forename: K C
authors.initials: KC
authors.lastname: Crain
authors.forename: J M
authors.initials: JM
authors.lastname: Bergua
authors.forename: A
authors.initials: A
authors.lastname: López Lafuente
authors.forename: S G
authors.initials: SG
authors.lastname: Kalko
authors.forename: E
authors.initials: E
authors.lastname: García Mateos
authors.forename: E
authors.initials: E
authors.lastname: Beutler
authors.forename: J L
authors.initials: JL
authors.lastname: Vives Corrons
mesh_terms: D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000150:complications* / Q000235:genetics; D002675:Child, Preschool; D005192:Family Health; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D009018:Morocco; D009422:Nervous System Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D017354:Point Mutation
chemical_list: D005721:Glutamate-Cysteine Ligase