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 Purine Autism (autistic children 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.

WHY WE AREN'T WHAT WE EAT

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?

Purine Autism is One of the More Frequent Forms of Autism.

THE BODY'S ANSWER --- METABOLISM

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.

THE IMPORTANCE OF GENETICS

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:

 

THE BAD NEWS --- METABOLIC DISEASES

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.

WHERE DO PURINES FIT IN?

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).

Compound Abbreviations Enzyme Names and Reaction Pathways

Figure 2. The Pathways of Purine Metabolism

Purines play many important roles in the life process:

RECOGNIZING PURINE METABOLIC DISEASES

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. Though many experimental therapies have been tried, no effective treatment is known for this disease.

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.

Purine Autism. A number of cases have been reported in medical literature in which classic autistic symptoms (a lack of social interaction and repetitive behaviors) are combined with an overproduction of purine compounds. This almost certainly represents some defect of purine metabolism, although no specific enzyme defect has been identified. Research is ongoing to identify the defect, and to explore possible therapies.

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.

THE GOOD NEWS --- UNLOCKING THE SECRETS OF PURINE METABOLISM

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.

WHAT LIES AHEAD FOR PURINE RESEARCH?

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. Some current projects funded by the PRS include:

Several surveys have shown that up to 25% of the autistic population may overproduce purines. The first step in providing a useful understanding of this disease is to identify the defective enzyme responsible for purine overproduction. This enzyme defect is likely to be the cause of the autistic symptoms as well. Many of these patients have very specific dietary sensitivities, and their symptoms may be greatly worsened if they eat certain foods. Because of these observations, researchers feel that once the enzyme defect is identified, the resulting metabolic aberration can be explained, and a dietary treatment devised.

Children receiving treatment for this unusual disease are able to attend normal schools and lead otherwise normal lives, as the enzyme defect has been identified, and a treatment has been devised. However, the current diagnostic test is extremely expensive and labor-intensive, and therefore, not useful for screening populations of children. Researchers are now investigating the neurochemical mechanism through which a defect in purine metabolism causes specific psychiatric abnormalities. The long-term goal is to produce a simpler and less expensive treatment, as well as a simpler screening test.

One of the better known diseases of purine metabolism is still without any effective treatment. Researchers continue to focus on how the enzyme defect affects purine production in brain cells, and how this might lead to abnormal brain development. They are also exploring approaches to correcting the metabolic defect.

Professional Advisory Board

 

E-Mail: purine@erols.com

 

FROM AUTISM IN CHILDREN TO GOUT IN ADULTS, RESEARCH ON PURINE DISEASES IS LEADING TO EVENTUAL TREATMENTS.

For a restricted purine diet for gout or high uric acid, e-mail: purine@erols.com.

For a copy of a restricted purine cookbook go to http://www.gout-haters.com.

Last Updated: November 24, 2004