Mental retardation purine metabolism

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

A condition known as Lesch-Nyhan syndrome is one of the primary causes of gout. An X-linked recessive trait occurring in males, this condition involves a tremendous overproduction of uric acid due to a deficiency of one of the enzymes involved in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Other abnormalites lead to mental retardation and aggressive behavior. An obvious symptom of the condition is self-mutilation. 

HGPRT is responsible for the conversion of guanine to guanylic acid and hypoxanthine to inosinic acid. These two conversions require PRPP as the cosubstrate and are important reutilization reactions involved in the synthesis of nucleic acids. A deficiency in the HGPRT enzyme leads to increased metabolism of guanine and hypoxanthine to uric acid, and more PRPP to interact with glutamine in the first step of the purine pathway." Complete absence of HGPRT results in the childhood Lesch-Nyhan syndrome, characterized by choreoathetosis, spasticity, mental retardation, and markedly excessive production of uric acid. A partial deficiency of the enzyme may be responsible for marked hyperuricemia in otherwise normal, healthy individuals. 

Lesch-Nyhan disease is an X-linked recessive disorder characterized by hyperuricemia, physical and mental retardation, choreo-athetosis, and compulsive self-mutilation. The disease is associated with absence of activity of an enzyme involved in purine metabolism, namely hypoxanthlne guanine phosphoribosyl transferase (HGPRT), and is believed to affect male only. We present here, however, an unusual case of a girl with the Lesch-Nyhan syndrome, whose mother is not heterozygous for a deficiency of the enzyme. 

The pathogenesis of the neuro-behavioral abnormalities associated with the Lesch-Nyhan syndrome remains obscure despite recent reports of neurotransmitter abnormalities in these patients. Many attempts to correct the characteristic manifestations of spasticity, mental retardation, choreoathetosis, and compulsive self-mutilation have been reported but none have reported sustained clinical efficacy. Many pathogenic mechanisms have been proposed over the past two decades to explain the relationship between the known aberration in purine metabolism and the observed neurologic dysfunction. One of these proposed mechanisms is that the absence of the purine salvage pathway in the central nervous system (CNS) results in (1) the accumulation of oxy-purines in the spinal fluid which then may act as toxic endogenous mediators and (2) the depletion of guanine and adenine nucleotides that are important to normal CNS function. Supplementation of purine intermediates with dietary adenine, guanosine, inosine, and GMP have not altered the clinical course of the disease. 

Inherited disorders of purine and pyrimidine metabolism exhibit a wide variety of clinical symptoms, including anemia, immunodeficiency, kidney stones, seizures, mental retardation, autism and growth retardation. Refer to Chap. 23 and ref. 7 for further details. 

Measurement of apparent activities of enzymes of purine metabolism have been made in mixed blood leukocytes from more than 100 patients with severe mental retardation of unknown etiology, but in which a hereditary element is possible. About 10% showed... 

The clinical picture of the Lesch-Nyhan syndrome shows besides massive hyperuricemia mental retardation and spasticity (later choreoathetosis and self mutilation in the behavior) ( ) The disturbance of purine metabolism is based on the deficiency of hypoxanthine-guanine phosphoribosyltransferase activity (HG-PRT) (2) ... 

This condition is a rare X-linked disorder of purine metabolism that usually kills in early childhood it causes kidney stones, arthritis, spasticity and mental retardation... 

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