The Purine Research Society


What We Learn About Metabolic Disease Will Benefit Each and Every One of Us

The Purine Research Society was formed in 1986 by parents of children with autism who excrete too much uric acid in their urine. Each family contributed a significant amount of money to fund M.D./Ph.D. researchers to find out why their children with autism were excreting excess uric acid, the end product of purines. Several researchers have studied the problem, and there continues to be significant progress. One of the accomplishments of the Society has been to produce a pamphlet explaining metabolic diseases in general and purine metabolic diseases in autism, as well as other diseases with excess uric acid, such as gout.


Every day of our lives, starting with the day we were born, we have been consuming food. We start with milk and gradually progress to cereals, fruits and vegetables, and meats. As we grow older, we may develop a preference for chocolate, salsa, or caviar. Indeed, the ability to satisfy our nutritional needs with a wide variety of foodstuffs is a distinct advantage. And yet, the skin, bones, hair, and muscle which make up our bodies are obviously very different from these foodstuffs. How is it that we are able to convert these foods into the materials which compose our bodies and use them to produce the energy we need to survive and function?

The excessive uric acid production during the childhood of children with autism greatly diminishes or disappears at puberty.


Metabolism is the body's answer to this question. Our bodies are like individual chemical factories. In the cells that make up our bodies, thousands of different chemical reactions which keep us alive are constantly taking place. Together, these reactions make up our metabolism, converting the wide variety of chemical compounds that we consume into the chemical compounds that we need.

Each chemical reaction is helped along by a specific protein catalyst called an enzyme. As catalysts, enzymes increase the rate at which specific chemical reactions take place. But in the process, the enzyme itself remains unaltered. Enzyme catalysts are amazingly specific and efficient. Enzymes catalyze thousands of reactions at the same time, in the same place (a cell in your body), and with virtually a 100% yield. Compare that with a chemist attempting to synthesize a particular compound in the laboratory. The chemist is limited to producing no more than one compound at a time in the same place (the test tube), and with a yield which is usually considerably less than 100%.

When our bodies convert a typical food molecule such as sucrose (sugar) into a very different molecule, such as a fat molecule for energy storage, many small steps are required. Each step is catalyzed by a specific enzyme. The sequence of steps by which one molecule is converted to another is known as a metabolic pathway.


How do our bodies produce so many individual, unique enzymes? The explanation lies in the study of genetics, the scientific study of heredity.

The structure of each enzyme is determined by a specific gene, part of the hereditary material which exists in every cell in our bodies. In most of us, our genes work to produce enzymes that function flawlessly. But in one out of every 100 live births, a defective enzyme gene occurs, resulting in a partially or completely non-functioning enzyme. (In rare cases, a defective gene results in an enzyme with too much activity.) Then, like traffic backed up behind a washed-out bridge, the molecule normally converted by that enzyme (the substrate) builds up; the molecule normally produced by that enzyme (the product) becomes scarce. Two important consequences result:



Distress to the body resulting from the production of too much of a toxic substance or too little of an essential one is referred to as a metabolic disease.

Metabolic diseases are inherited and are present from birth, although the disease may first manifest itself at any age. The resultant metabolic diseases, which can occur in any area of human metabolism, could affect our lives or the life of someone close to us. Most of us have heard of these more familiar metabolic diseases:

Some other diseases are obviously inherited metabolic disorders, but researchers have not yet identified the defective enzyme.


The class of chemical compounds known as purines was first encountered in a waste product of metabolism known as uric acid, which causes gout. "Purine," coined by chemist Emil Fischer in the 19th century, comes from the Latin PURUS (pure, clean) and New Latin URICUS (uric acid, from urine). All purines share the basic nine-membered ring structure shown below.

Figure 1. The Purine Nucleus. All naturally occurring purine compounds are a variation on this structure.


Different metabolic pathways, shown below, exist for: (1) making purines (the synthetic pathways); (2) converting purine compounds (the conversion pathways); (3) reusing purines consumed in the diet (the reuse pathways); and (4) disposing of excess purines (the disposal pathways).

Abbreviations are names of purine compounds Reaction Pathways have numbers for each enzyme

Figure 2. The Pathways of Purine Metabolism

Purines play many important roles in the life process:


When we consider the many different roles purines play in our metabolism, it is not surprising that the diseases of purine metabolism are as varied, ranging from asymptomatic conditions, which are only discovered accidentally, to disorders with severe neurological abnormalities, which are ultimately fatal. As with other metabolic diseases, each disorder is caused by a defective gene which results in an enzyme with too little or too much catalytic activity. The numbered enzymes referred to below are shown in Figure 2. Purine metabolic diseases include:

Gout. The most common defect of purine metabolism is one of the oldest known metabolic diseases. Gout was known to the ancient Egyptians, and was extensively studied by the Roman physician Galen (A.D. 131-200). We now know that gout is caused by overproduction of uric acid, with a consequent depositing of uric acid crystals in the joints. Several different enzyme defects cause gout, notably deficiency of HPRT (enzyme 21). Gout can be treated successfully by limiting purines in the diet and by using drugs which inhibit xanthine oxidase (enzyme 27) and, thereby, the production of uric acid.

Lesch-Nyhan Syndrome. One of the better known diseases of purine metabolism is caused by a deficiency of HPRT (enzyme 21). Symptoms include very severe gout, poor muscular control (patients are wheelchair-bound), and moderate mental retardation. The most unusual feature of Lesch-Nyhan syndrome is compulsive self-injury, including chewing of the tongue, lips, and fingers. Targeted treatment of symptoms is available, but overall therapy remains unknown.

Adenosine Deaminase (ADA) and Purine Nucleoside Phosphorylase (PNP) Deficiency. A deficiency of either ADA (enzyme 24) or PNP (enzyme 25) causes a moderate to complete lack of immune function. Affected children cannot survive outside a sterile environment. They may also have moderate neurological problems, including partial paralysis of the limbs. When a compatible donor can be found, bone marrow transplant is an effective treatment. Recently, some experimental therapies have also been successful.

Adenylosuccinate Lyase Deficiency. A deficiency of enzymes 9 and 12 results in mental retardation, seizures, and autistic behavior. No successful treatment has been established to date.

Myoadenylate Deaminase Deficiency. A deficiency of enzyme 13 impairs the ability of muscles to regulate energy during exercise. The most prominent symptoms are muscle fatigue and cramps after normal activities, such as climbing stairs. Several experimental therapies appear to be helpful.

5' Nucleotidase Defect. The most recently described and most unusual defect of purine metabolism is caused by excessive activity of the enzyme 5' nucleotidase (enzyme 23). Symptoms include constant infections, seizures, skin rashes, and very unusual behavior, characterized by extreme hyperactivity, short attention span, lack of speech, and poor social interaction. This disease appears to be fully treatable by diets which restore the compounds that are consumed by the excessive enzyme activity.

Phosphoribosyl Pyrophosphate (PRPP) Synthetase Defects. Two distinct defects are associated with enzyme 1. Enzyme deficiency results in convulsions, autistic behavior, anemia, and severe mental retardation. Excessive enzyme activity causes gout, along with various neurological symptoms, such as deafness. Aside from the treatment of gout, no treatment for the symptoms of these diseases is available at this time.

Xanthinuria and Adenine Phosphoribosyltransferase (APRT) Deficiency. A deficiency of either xanthine oxidase (enzyme 27) or APRT (enzyme 20) causes accumulation of xanthine or 2,8 dihydroxyadenine, respectively. Often this causes no symptoms at all, and patients are discovered accidentally during some other kind of medical test. In other cases, these compounds accumulate and crystallize in the joints, causing a gout-like condition. No effective treatment is known, though reduction in dietary purines is often helpful.


Historically, research in purine metabolism has always been at the forefront of medical investigation. Owing to the importance of purines in metabolism, this research has consistently led to significant advances in other areas. Among the most noteworthy:

1942 In testing synthetic purine compounds to inhibit the growth of bacteria, Hitchings and Elion hit on the "antimetabolite" concept. According to this concept, a synthetic compound which sticks to an enzyme and prevents reaction with a natural substrate can be used to selectively "turn off" an enzyme. For their pioneering work, these two researchers were awarded the Nobel Prize in 1988. This concept has been employed in the design of many modern drugs, including those for the treatment of cancer, AIDS, and bacterial infections.

1967 The first psychiatric abnormality which could be attributed to a specific enzyme defect, Lesch-Nyhan syndrome, was described. Although the extent to which genes can influence behavior is still very controversial, this was the first demonstration that a gene defect could cause a specific behavior (i.e., compulsive self-injury). More recently, researchers have tentatively identified genes linked to depression, alcoholism, and schizophrenia in some families.

1980 The first human disease shown to be caused by excessive (rather than deficient) enzyme activity, PRPP synthetase superactivity, was described. Discovery of the mechanism through which excessive enzyme activity causes a disease has led to greater understanding of metabolic regulation.

1982 The first gene for a human enzyme, HPRT (enzyme 21), was artificially produced in the laboratory, or cloned. Today, more than 200 human enzyme genes have been cloned, helping us not only to understand the precise molecular events which cause genetic diseases, but also to detect carriers of these disorders.

1992 The first successful use of gene therapy, the insertion of a normal, functioning gene into cells which contain abnormal, nonfunctioning genes, was achieved with adenosine deaminase. Patients previously confined to germ-free enclosures were now able to venture outdoors. This is perhaps the most important advance in medical research in decades, and may produce treatments for everything from cancer to baldness.


The Purine Research Society (PRS) was founded to support research aimed at furnishing a biochemical explanation for the mechanism through which enzyme defects result in clinical diseases. Researchers believe this to be the most direct route to providing diagnostic capabilities and identifying potentially useful treatments.

Three surveys have shown that between 11% to 28% of children with autism excrete excessive uric acid during their childhood years, a phenomenon that diminishes or disappears with the onset of puberty. There also are a number of single case reports of hyperuricosuria in children with autism in the literature. In spite of extensive research, how hyperuricosuria relates to autistic symptoms has never been established. One study suggested that this temporary phenomenon may be due to a defect in purine nucleotide interconversion, as shown by an abnormal ratio of adenine to guanine nucleotides. Further research is needed to determine the meaning of why this secondary lab abnormality is found in several types of autism.

A single study has described four unrelated children with a developmental disorder with low levels of uric acid in the urine due to increased enzyme activity related to pyrimidine salvage. A double blind study indicated that the children’s symptoms could be reversed by uridine. However the current diagnostic test is expensive and labor-intensive, not suitable for screening. Duplication of this study and development of an inexpensive screening test is needed.

One of the better known diseases of purine metabolism is still without effective treatment for self-mutilation. This is the Lesch-Nyhan syndrome, an X-linked recessive disorder caused by a deficiency in a purine salvage enzyme. Although more than 300 disease-associated mutations in the HPRT1 gene have been identified, at present treatments remain merely symptomatic.

Adenylosuccinate Lyase deficiency is an autosomal recessive disorder of de novo purine synthesis which results in accumulation of succinylpurines in body fluids. Half of these children have autistic features; 80% have seizures. Currently there is no established therapy, but trials of research drugs are underway.


Professional Advisory Board


Bruce Barshop, M.D., Ph.D. University of California, San Diego
Mary Coleman, M.D., Emeritus Georgetown University, Washington, D.C.
James C. Harris, M.D. Johns Hopkins University, Baltimore
Jaak Jaeken, M.D., Ph.D. Universitaire Ziekenhuisen, Belgium
William Nyhan, M.D., Ph.D. University of California, San Diego
Phillip Pearl, M.D. Georgetown University, Washington, D.C
J.E. Seegmiller, M.D. University of California, San Diego
H. Anne Simmonds, Ph.D. Guy's Hospital, London
Georges van den Berghe, M.D. University of Leuven, Belgium