Five patients with gamma glutamyl transpeptidase deficiency have been reported or are under investigation. Three of them have CNS involvement, though two siblings have apparently no signs of CNS damage.
This may reflect the fact that the first three patients were identified by screening for amino acid defects in populations of mentally retarded patients.
The patients have increased glutathione concentrations in plasma and urine, butthe cellular levels are normal. In addition to glutathionuria, urinary levels of gamma glutamyl cysteine and cysteine are also increased.
The patients are often identified by urinary screening for amino acid disorders using thin layer or paper chromatography and ninhydrine detection. This reveals glutathionuria (up to 1g per day). Decreased activity of gamma glutamyl transpeptidase can be demonstrated in leukocytes or cultured skin fibroblasts, but not in erythrocytes, which lack this enzyme under normal conditions.
No specific treatment has been postulated. The prognosis must be considered as serious if the patients presents with psychiatric or neurologic symptoms. On the other hand, two siblings aged 11 and 13 years so far have no signs of CNS involvement.
The gamma glutamyl cycle involves six and zymes. The biosynthesis of glutathione is catalyzed by gamma glutamyl cysteine synthetase and glutathione synthetase. The break down of the tripeptide is mediated by four enzymes. The initial step is catalyzed by gamma glutamyl transpeptidase. The gamma glutamyl residue is then released as 5-oxoproline, which is converted to glutamic by 5-oxoprolinase. The biosythesis of glutathione is feedback regulated, i.e., glutathione acts as an inhibitor to gamma glutamyl cysteine synthetase.
Glutathione has been postulated to participate in several fundamental functions, such as free radical scavenging, redox reactions, formation of deoxyribonucleotides, xenobiotic metabolism, and amino acid transport. Patients with genetic defects in the metabolism of glutathione are therefore likely to exhibit a variety of symptoms.
In diagnostic work it is essential to remember that erythrocytes contain an incomplete gamma glutamyl cycle gamma glutamyl transpeptidase, they lack both and 5-oxoprolinase.
Kvittingen et al. first described patients with cerebral atrophy and leukodystrophy with N-acetylaspartic aciduria. It was the merit of Matalon et al and divry et al. to link this disorder with Canavan disease.
The diagnosis of Canavan disease can be suggested by clinical features including leukodystrophy, megaloencephaly, mental retardation, and optic atrophy. Death usually occurs in the first decade of life. Computed Tomography (CT) scan or magnetic resonanceimaging (MRI) show white matter attenuation. Brain histopathology shows spongy degeneration of the myelin, astrocytic swelling, and elongated mitochondria; neurons are normal. Three clinical variants of the disease have been described:
• A congenital form in which the disease is apparent from birth
• An infantile form, which is the most common and which becomes manifest after the first 6 months of life (this form is frequently seen among Jewish patients)
• A juvenile form in which symptoms appear after the first 5 years of life.
The key feature is accumulation of N-acetylaspartic acid in the body fluids, levels in the CSF being much higher than in the serum. The enzymatic defect can be confirmed by assay of aspartoacylase in fibroblasts. Aspartoacylase is also deficient in Brain, liver, and kidney.
N-acetylaspartic acid is abundant in Brain, where its concentration is second only to glutamic acid in the free amino acid pool and is higher than that of GABA Brain is the only organ where biosynthesis of N-acetylaspartic acid has been demonstrated. Its normal function is not well understood. It has been reffered to as an essential component in a series of reactions required for the conversion of lignoceric acid to cerebronic acid, a component of myelin, and the formation of glutamic acid and has been assigned a possible role in neurotransmission and in the production of N-acetylaspartylglutamate. It may also serve as a chemical compartment so that aspartate is released only by the action of aspartoacylase and the released aspartate may be channeled to form arginine.
The diagnosis is based on gas chromatography mass spectrometry(GCMS) of urine or other body fluids showing increased N-acetylaspartic acid levels and is confirmed by aspartoacylase assay on cultured fibroblasts and/or by restriction fragment length polymorphism (RFLP) or mutation analysis of DNA. For prenatal diagnosis the measurement of aspartoacylase in fresh chorionic villi samples or the quantitation of N-acetylaspartic acid in amniotic fluid supernatant are the methods of choice. Obviously, molecular diagnosis using RFLP or mutation analysis within given families will provide prenatal diagnostic facilities and carrier detection in at risk populations in the near future.
It has been proposed that N-acetylaspartic acid serves as a transporter of acetyl groups from mitochondria to the cytosol for lipogenesis. Therefore, in an attempt to supply alternative substrate for lipogenesis in the brain, a ketogenic diet was given to one patient for 5 months. No improvement was seen. No other treatment is available. Progressive deterioration leads to a decorticate condition and death within a few years.
Genetictransmission is autosomal recessive. The human aspartoacylase gene is localized on chromosome 17 p13-ter. A full-length human cDNA for aspartoacylase has been isolated and a predominant point mutation 856 A>C was identified in Jewish patients.
