Glutathionuria

A number sign (#) is used with this entry because of evidence that glutathionuria is caused by homozygous deletion/insertion in the GGT1 gene (612346) on chromosome 22q11. One such family has been reported.

Clinical Features

Gamma-glutamyltranspeptidase (see GGT1; 612346) acts as a glutathionase and catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. This enzyme is located on the outer surface of the cell membrane. It is widely distributed in mammalian tissues involved in absorption and secretion. In humans, hepatic GGT activity is elevated in some liver diseases. GGT is released into the bloodstream after liver damage, and an elevated level of the enzyme may be a useful early sign of hepatocellular carcinoma. Schulman et al. (1975) described a mildly retarded adult male with glutathionemia and marked glutathionuria, whose cultured skin fibroblasts showed very low activity of the transpeptidase. Since several studies have suggested that the transpeptidase may play a role in cellular amino acid transport, the lack of amino aciduria and amino acidemia was noteworthy. O'Daley (1968) may have described the same condition.

Hammond et al. (1995) reported sisters with GGT deficiency. The elder of the 2 sibs was detected during the course of a population screening on infants at 6 weeks of age using ascending paper chromatography of urine, which revealed a migration spot similar to that of cystine. Her growth and development were normal. During the second year, easy bruising was noted. Asthma was diagnosed at 2.5 years but was never a major problem. At 10 years of age, she began having attacks of absence and an EEG showed typical 3-Hz spike and wave activity. Seizures were controlled by valproate medication. At age 21 years, she had no significant health problems, had a good secretarial position, and was pursuing a course at technical college. The younger sister was somewhat hypotonic and inactive at birth and had a dislocated hip and mild bilateral equinovarus. Tube feeding was required for the first 4 months. Problems noted later included strabismus, easy bruising, poor coordination, and some dysmorphic features. A diagnosis of Prader-Willi syndrome (PWS; 176270) was confirmed by demonstration of an interstitial deletion of 15q11-q13. Both sisters had normal red cell glutathione and no Heinz bodies. Clearly there were no specific clinical indicators for GGT deficiency, which in the younger sister was unrelated to PWS.

Darin et al. (2018) reviewed 6 previously reported patients from 4 families. Most patients presented with involvement of central nervous system in the form of mild to moderate mental retardation, behavioral disturbances, and in 1 case, seizures. Marfanoid features were reported in 2 sibs. The age of diagnosis ranged from the second to the sixth decade of life. Darin et al. (2018) described 2 previously unreported sibs born to consanguineous Turkish parents. The brother was diagnosed at 10 years of age. In addition to the previously reported features, he had hypertelorism and low-set ears. The sister was diagnosed at 25 years of age with mild mental retardation, a mild tremor, and mild hyperreflexia. The brother's MRI showed agenesis of the corpus callosum and multiple cortical heterotopias. The girl's MRI was normal. Both sibs had increased glutathionuria and markedly decreased plasma gamma-GT activity of less than 0.05 microKAT per liter (normal range 0.15-0.75).

Molecular Genetics

In 2 Turkish sibs with glutathionuria, Darin et al. (2018) identified a homozygous 16,993-bp deletion combined with a 13-bp insertion (612346.0001) in the GGT1 gene that removed the first coding exon and several noncoding exons in all isoforms of GGT1. Both parents were heterozygous for this deletion. Both breakpoints for the deletion were located in Alu elements.