Pathways

Homocarnosinosis is caused by an inherited defect in serum carnosinase, which converts homocarnosine to GABA (gamma aminobutyric acid). A defect in serum carnosinase causes accumulation of the brain specific dipeptide homocarnosine (Hca), in the CSF and brain. Symptoms include hypotonia, mental retardation, retinitis pigmentosa and spastic diplegia/quadriplegia.

Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.

Glutathione Synthetase Deficiency (5-Oxoprolinuria; Pyroglutamic Aciduria; GSD) is a rare inborn error of metabolism (IEM) which arises from a disfunctional gene called GSS. This gene is responsible for glutathione synthetase. Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. A defect in this enzyme results in accumulation of pyroglutamic acid and gamma-glutamylcysteine in urine and blood; decrease level of glutathione in erythrocytes; increase urinary excretion of 5-oxoproline. GSD is typically distinguished by three levels of severity. Those levels naturally being mild, moderate and severe. Being with the former, mild GSD can lead to a harmful condition known as hemolytic anemia. This occurs when red blood cells are destroyed. Although not as common, it is also possible for patients affected with GSD to excrete in their urine elevated quantities of 5-oxoproline (hence the other name for this condition shown in the first sentence of this description). The accumulation of high levels of 5-oxoproline (and hence the elevated level of secretion of this compound) is a direct consequence of glutathione being improperly processed by the body. Turning now to the second level of severity, moderate, it is typical to see affected patients experience experience the two symptoms described above, in addition to metabolic acidosis. The latter condition being the consequence of high acidity levels in the blood as well as other tissues. Finally, individuals with severe GSD may suffer from a wide variety of neurological symptoms. This could include anything from ataxia and slowed reactions, to psychomotor retardation, mental retardation and seizures.

5-Oxoprolinuria (5-Oxoprolinase deficiency) is a result of a defect in the gamma-glutamyl cycle due to either 5-oxoprolinase or glutathione synthetase deficiency. In the case of glutathione synthetase deficiency, the glycine is not incorporated into gamma-glutamylcysteine. In the case of 5-oxoprolinase, however, pyroglutamic acid accumulates. Symptoms include anemia, mental retardation, metabolic acidosis, respiratory distress and urolithiasis.

Adenosine deaminiase deficiency (immunodeficiency) is an autosomal recessive disease caused by a muation in the ADA gene which codes for adenosine deaminase. A deficiency in this enzyme results in immunodeficiency and a decreased concentration of lymphocytes in blood. Symptoms include diarrhea, severe or recurrent infections, vomiting and early onset in children, infants and newborns. Treatment includes bone-marrow transplants and enzyme replacement therapy.

Adenylosuccinate Lyase Deficiency. (Adenylosuccinase Deficiency ; Adenylosuccinate monophosphate lyase deficiency) is a rare autosomal recessive disease caused by a mutation in the ADSL gene which codes for adenylosuccinate lyase. A deficiency in this enzyme results in accumulation of succinyladenosine in plasma, spinal fluid, and urine. Symptoms, which present at birth, include hyptonia, seizures, mental retardation, and encephalopathy. Treatment includes allopurinol.

Gout, also called Kelley-Seegmiller syndrome, is a condition that is hereditary and causes an excess in the production of uric acid in the body. It is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. When working properly, this enzyme works to restore purines. These purines are salvaged from degraded DNA and are used towards purine synthesis. When uric acid builds up as it is being overproduced, needle-like crystals are formed and can provoke sudden attacks of pain in the joints, the big toe and in other places around the body. Unlike Lesch-Nyhan syndrome, this condition does not present neurological conditions and can be treated with medication.

Lesch-Nyhan Syndrome is a syndrome identified through its neurological, behavioural metabolic impact. It is characterized by a mental deficit and self-mutilation, accompanied with an overproduction of uric acid. A mutation of the HPRT1 gene are responsible for this condition, as they cause the enzyme hypoxanthine phosphoribosyltransferase 1 to be present in extremely low levels or absent altogether. This causes an overproduction of uric acid as the purines are not recycled, but only broken down. This gene is also connected to dopamine production, which a lack of causes smooth muscle function to suffer, resulting in dystonia, ballismus and chorea. Patients are usually unable to walk, and the connection between a lack of hypoxanthine phosphoribosyltransferase 1 and the behavioural abnormalities associated with this condition are unknown.

Molybdenium cofactor deficiency (Sulfite oxidase deficiency) is caused by mutations in the genes MOCS1 and MOCS2 in the formation of molybdenum cofactor. A molybdenum-containing cofactor is essential to the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Xanthine dehydrogenase is a molybdenum-containing hydroxylase involved in the oxidative metabolism of purines. Defects in this enzyme cause accumulation of hypoxanthine,, s-s-sulfocysteine, taurine, and xanthine in the urine. Symptoms include hemorrhage, cerebral atrophy, encephalopathy, lactic acidosis, nystagmus, spastic diplegia/quadriplegia, and vomiting.

The rare genetic disorder, Xanthinuria (also referred to as xanthine oxidase deficiency) results from a deficiency of the enzyme xanthine oxidase. This enzyme deficiency causes the accumulation of: xanthine in the plasma, uric acid in serum or hypoxanthine, uric acid and xanthine in the urine. The disorder has symptoms including arthralgia, hematuria, mental retardation, stomatisis, and urolithiasis.