Familial Spinocerebellar Degeneration, Hemolytic Anemia, and Glutathione Deficiency

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

“…The responsible mutation, a 379C>T leading to an Arg127Cys amino acid change, was identified in 2003. 12 After this first description of two cases of GCS deficiency in 1974, 6,7 six new cases have been reported, two unrelated patients by Beutler et al in 1990 8 and in 1999, 10 respectively, two other cases by Hirono et al in 1996 9 and another two by Ristoff et al in 2000. 11 In most of these cases, a moderate to severe haemolytic anaemia appeared during neonatal period or in the early childhood that persisted during all the life or compensated haemolysis with sporadic recurring bouts of anaemia and jaundice.…”

“…Hereditary deficiency of GCS is a very rare autosomal recessive enzymopathy so far reported in only 8 unrelated families. [6][7][8][9][10][11] The common clinical manifestation of GCS deficiency is recurring bouts of anaemia and jaundice but it has been found to be associated with severe neurological abnormalities in two cases 6,12 and mental retardation in one. 10 In the two most recently reported cases of GCS deficiency [9][10][11] single-point mutations in the coding sequence of GCS gene have been identified as the underlying molecular cause of the condition.…”

A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production

“…Each patient went on to develop neurologic disease including ataxia and myopathy, thought to be due to spinocerebellar degeneration. 27 Because these were the first case reports of ␥-GCS deficiency, it was believed that neurologic disease was part of the disorder, but this has not been seen in any further case reports. The putative catalytic site of human ␥-GCSH from the molecular dynamic-refined ␥-GCSH-BSO complex.…”

“…Although the number of reports of GSH synthetase deficiency are numerous, [33][34][35] there are only 8 published reports of ␥-GCS deficiency. [7][8][9][10][11]27 Deficiency of either enzyme results in hemolytic anemia and jaundice, but patients with GSH synthetase deficiency present with a broader clinical picture, owing to differences in tissue distribution. Those with mild and moderate cases demonstrate GSH deficiency in the red cell compartment and suffer with hemolytic anemia and metabolic acidosis, whereas many of those with severe disease, in which the deficiency is more generalized, die in the neonatal period, suffering with neurologic symptoms, convulsions, and psychomotor development retardation.…”

Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of γ-glutamylcysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5’ untranslated region

“…Deficiency of GCS is rare but has been described in several individuals. In two sibs, GCS deficiency was associated with hemolytic anemia, spinocerebellar degeneration, peripheral neuropathy, myopathy, and aminoaciduria (Richards et al, 1974). More recently, an individual with GCS deficiency who exhibited only hemolytic anemia was described (Beutler et al, 1990).…”