Disorders of Purine and Pyrimidine Metabolism

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Chapter 83 Disorders of Purine and Pyrimidine Metabolism

The inherited disorders of purine and pyrimidine metabolism cover a broad spectrum of illnesses with various presentations. These include hyperuricemia, acute renal failure, renal stones, gout, unexplained neurologic deficits (seizures, muscle weakness, choreoathetoid and dystonic movements), developmental disability, intellectual disability, compulsive self-injury and aggression, autistic-like behavior, unexplained anemia, failure to thrive, susceptibility to recurrent infection (immune deficiency), and deafness. When such disorders are identified, all family members should be screened.

Purines are involved in all biologic processes; all cells require a balanced supply of purines for growth and survival. They provide the primary source of cellular energy through adenosine triphosphate (ATP) and, together with pyrimidines, provide the source for the RNA and DNA that stores, transcribes, and translates genetic information. Purines provide the basic coenzymes (NAD, NADH) for metabolic regulation and play a major role in signal transduction (GTP, cAMP, cGMP). Metabolically active nucleotides are formed from heterocyclic nitrogen-containing purine bases (guanine and adenine) and pyrimidine bases (cytosine, uridine, and thymine). The early steps in the biosynthesis of the purine ring are shown in Figure 83-1. Purines are primarily produced from endogenous sources and, in usual circumstances, dietary purines have a small role. The end product of purine metabolism in humans is uric acid (2,6,8-trioxypurine).

Uric acid is not a specific disease marker, so the cause of its elevation must be determined. The level of uric acid present at any time depends on the size of the purine nucleotide pool, which is derived from de novo purine synthesis, catabolism of tissue nucleic acids, and increased turnover of preformed purines. Uric acid is poorly soluble and must be excreted continuously to avoid toxic accumulations in the body. Its renal excretion involves the following components: (1) glomerular filtration, (2) reabsorption in the proximal convoluted tubule, (3) secretion near the terminus of the proximal tubule, and (4) limited reabsorption near these secretory sites. Thus, renal loss of uric acid is a result of renal tubular excretion and is a function of serum uric acid concentration and a homeostatic mechanism to avoid hyperuricemia. Because renal tubule excretion is greater in children than in adults, serum uric acid levels are a less reliable indicator of uric acid production in children than in adults, and consequently, measurement of the level in urine may be required to determine excessive production. Clearance of a smaller portion of uric acid is via the gastrointestinal tract (biliary and intestinal secretion). Owing to poor solubility of uric acid under normal circumstances, uric acid is near the maximal tolerable limits, and small alterations in production or solubility or changes in secretion may result in high serum levels. In renal insufficiency, urate excretion is increased by residual nephrons and by the gastrointestinal tract.

Increased production of uric acid is found in malignancy; Reye syndrome; Down syndrome; psoriasis; sickle cell anemia; cyanotic congenital heart disease; pancreatic enzyme replacement; glycogen storage disease types I, III, IV, and V; hereditary fructose intolerance; acyl coenzyme A dehydrogenase deficiency; and gout.

The metabolism of both purines and pyrimidines can be divided into 2 biosynthetic pathways and a catabolic pathway. The 1st, the de novo pathway, involves a multistep biosynthesis of phosphorylated ring structures from precursors such as CO2, glycine, and glutamine. Purine and pyrimidine nucleotides are produced from ribose-5-phosphate or carbamyl phosphate, respectively. The 2nd, a single-step salvage pathway, recovers purine and pyrimidine bases derived from either dietary intake or the catabolic pathway (Figs. 83-2 and 83-3; also see Fig. 83-1). In the de novo pathway, the nucleosides guanosine, adenosine, cytidine, uridine, and thymidine are formed by the addition of ribose-1-phosphate to the purine bases guanine or adenine, and to the pyrimidine bases cytosine, uracil, and thymine. The phosphorylation of these nucleosides produces monophosphate, diphosphate, and triphosphate nucleotides. Under usual circumstances, the salvage pathway predominates over the biosynthetic pathway. Synthesis is most active in tissues with high rates of cellular turnover, such as gut epithelium, skin, and bone marrow. The 3rd pathway is catabolism. The end product of the catabolic pathway of the purines is uric acid, whereas catabolism of pyrimidines produces citric acid cycle intermediates. Only a small fraction of the purines turned over each day are degraded and excreted.

Inborn errors in the synthesis of purine nucleotides include: (1) phosphoribosylpyrophosphate synthetase superactivity, (2) adenylosuccinase deficiency, and (3) 5-amino-4-imidazolecarboxamide (AICA) riboside deficiency (AICA-ribosiduria). Disorders resulting from abnormalities in purine catabolism include: (1) muscle adenosine monophosphate (AMP) deaminase deficiency, (2) adenosine deaminase deficiency, (3) purine nucleoside phosphorylase deficiency, and (4) xanthine oxidoreductase deficiency. Disorders resulting from the purine salvage pathway include: (1) hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, and (2) adenine phosphoribosyltransferase (APRT) deficiency.

Inborn errors of pyrimidine metabolism include disorders of pyrimidine synthesis and of pyrimidine nucleotide degradation. Disorders include: (1) hereditary orotic aciduria (uridine monophosphate synthase deficiency), (2) dihydropyrimidine dehydrogenase (DPD) deficiency, (3) dihydropyrimidinase (DPH) deficiency, (4) β-ureidopropionase deficiency, (5) UMPH-1 deficiency (previously pyrimidine 5′-nucleotidase deficiency), (6) pyrimidine nucleoside depletion and overactive cytosolic 5′-nucleotidase, (7) thymidine kinase 2 deficiency, and (8) thymidine phosphorylase deficiency.


Gout presents with hyperuricemia, uric acid nephrolithiasis, and acute inflammatory arthritis. Gouty arthritis is due to monosodium urate crystal deposits that result in inflammation in joints and surrounding tissues. The presentation is most commonly monoarticular, typically in the metatarsophalangeal joint of the big toe. Tophi, deposits of monosodium urate crystals, may occur over points of insertion of tendons at the elbows, knees, and feet or over the helix of the ears. Primary gout, ordinarily occurring in middle-aged men, results from overproduction of uric acid, decreased renal excretion of uric acid, or both. The biochemical etiology of gout is unknown for most of those affected, and it is considered to be a polygenic trait. When hyperuricemia and gout occur in childhood, it is most often secondary gout, the result of another disorder in which there is rapid tissue breakdown or cellular turnover leading to increased production or decreased excretion of uric acid. Gout occurs in any condition that leads to reduced clearance of uric acid: during therapy for malignancy or with dehydration, lactic acidosis, ketoacidosis, starvation, diuretic therapy, and renal shutdown. Excessive purine, alcohol, or carbohydrate ingestion may increase uric acid levels.

Gout is associated with hereditary disorders in three different enzyme disorders that result in hyperuricemia. These include the severe form of HPRT deficiency (Lesch-Nyhan disease) and partial HPRT deficiency, superactivity of PP-ribose-P synthetase, and glycogen storage disease type I (glucose-6-phosphatase deficiency) (Chapter 81.1). In the 1st two, the basis of hyperuricemia is purine nucleotide and uric acid overproduction, whereas in the 3rd, it is both excessive uric acid production and diminished renal excretion of urate. Glycogen storage disease types III, V, and VII are associated with exercise-induced hyperuricemia, the consequence of rapid ATP utilization and failure to regenerate it effectively during exercise (Chapter 81.1). Autosomal dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are proposed to be allelic and can result from uromodulin (UMOD) mutations; the term uromodulin-associated kidney disease (UAKD) has been proposed. Unlike the three inherited purine disorders that are X-linked and the recessively inherited glycogen storage disease, these are autosomal dominant conditions. Familial juvenile gout or familial juvenile hyperuricemic nephropathy is associated with severe renal hypoexcretion of uric acid. Although it most commonly presents from puberty up to the 3rd decade, it has been reported in infancy. It is characterized by early onset, hyperuricemia, gout, familial renal disease, and low urate clearance relative to glomerular filtration rate. It occurs in both males and females and is frequently associated with a rapid decline in renal function that may lead to death unless diagnosed and treated early. Once FJHN is recognized, presymptomatic detection is of critical importance to identify asymptomatic family members with hyperuricemia and to begin treatment, when indicated, to prevent nephropathy.

Treatment of hyperuricemia involves the combination of allopurinol (a xanthine oxidase inhibitor) to decrease uric acid production, probenecid to increase uric acid clearance in those with normal renal function, alkalinization of the urine to increase the solubility of uric acid, and increased fluid intake to reduce the concentration of uric acid. A low-purine diet, weight reduction, and reduced alcohol intake are recommended.

Abnormalities in Purine Salvage

Lesch-Nyhan Disease (LND)

LND is a rare X-linked disorder of purine metabolism that results from HPRT deficiency. This enzyme is normally present in each cell in the body, but its highest concentration is in the brain, especially in the basal ganglia.


The HPRT gene has been localized to the long arm of the X chromosome (q26-q27). The complete amino acid sequence for HPRT is known (≈44 kb; 9 exons). The disorder appears in males; occurrence in females is extremely rare and ascribed to nonrandom inactivation of the normal X chromosome. Absence of HPRT prevents the normal metabolism of hypoxanthine resulting in excessive uric acid production and manifestations of gout, necessitating specific drug treatment (allopurinol). Because of the enzyme deficiency, hypoxanthine accumulates in the cerebrospinal fluid, but uric acid does not; uric acid is not produced in the brain and does not cross the blood-brain barrier. The behavior disorder is not caused by hyperuricemia or excess hypoxanthine because patients with partial HPRT deficiency, the variants with hyperuricemia, do not self-injure and infants having isolated hyperuricemia from birth do not develop self-injurious behavior.

The mechanism whereby HPRT leads to the neurologic and behavioral symptoms is unknown. Both hypoxanthine and guanine metabolism is affected; guanosine triphosphate (GTP) and adenosine have substantial effects on neural tissues. There is a functional link between purine nucleotides and the dopamine system that involves guanine, the precursor of GTP. Dopamine binding to its receptor results in either an activation (D1 receptor) or an inhibition (D2 receptor) of adenylcyclase. Both receptor effects are mediated by G proteins (GTP-binding proteins) dependent on guanosine diphosphate (GDP) in the GDP/GTP exchange for cellular activation. Dopamine and adenosine systems are also linked through the role of adenosine as a neuroprotective agent in preventing neurotoxicity. Adenosine agonists mimic the biochemical and behavioral actions of dopamine antagonists, whereas adenosine receptor antagonists act as functional dopamine agonists. Dopamine reduction in brain is documented in HPRT-deficient strains of mutant mice.

Clinical Manifestations

LND is characterized by hyperuricemia, intellectual disability, dystonic movement disorder that may be accompanied by choreoathetosis and spasticity, dysarthric speech, and compulsive self-biting, usually beginning with the eruption of teeth. There are several clinical presentations of HPRT deficiency. HPRT levels are related to the extent of motor symptoms, to the presence or absence of self-injury, and possibly to the level of cognitive function. The majority of individuals with classic LND have low or undetectable levels of the HPRT enzyme. Partial deficiency in HPRT (Kelley-Seegmiller syndrome) with >1.5-2.0% enzyme is associated with hyperuricemia and variable neurologic dysfunction (neurologic HPRT deficiency). HPRT deficiency with levels ≥8% leads to a severe form of gout, with apparently normal cerebral functioning (HPRT-related hyperuricemia) although cognitive deficits may occur. Qualitatively similar cognitive deficit profiles have been reported in both LND and variant cases. Variants produced scores that are intermediate between those of patients with LND and normal controls on nearly every neuropsychologic measure tested.

At birth, infants with LND have no apparent neurologic dysfunction. After several months, developmental delay, intellectual disability, and neurologic signs become apparent. Before the age of 4 mo, hypotonia, recurrent vomiting, and difficulty with secretions may be noted. By about 8-12 mo, extrapyramidal signs appear, primarily dystonic movements. In some cases, spasticity may become apparent at this time or, in some instances, later in life.

Cognitive function is usually reported to be in the mild-to-moderate range of intellectual disability, although some individuals test in the low normal range. Because test scores may be influenced by difficulty in testing the subjects owing to their movement disorder and dysarthric speech, overall intelligence may be underestimated.

The age of onset of self-injury may be as early as 1 yr and, occasionally, as late as the teens. Self-injury occurs, although all sensory modalities, including pain, are intact. The self-injurious behavior usually begins with self-biting, although other patterns of self-injurious behavior emerge with time. Most characteristically, the fingers, mouth, and buccal mucosa are mutilated. Self-biting is intense and causes tissue damage and may result in the amputation of fingers and substantial loss of tissue around the lips (Fig. 83-4). Extraction of primary teeth may be required. The biting pattern can be asymmetric, with preferential mutilation of the left or right side of the body. The type of behavior is different from that seen in other intellectual disability syndromes involving self-injury; self-hitting and head banging are the most common initial presentations in other syndromes. The intensity of the self-injurious behavior generally requires that the patient be restrained. When restraints are removed, the individual with LND may appear terrified, and stereotypically place a finger in the mouth. The patient may ask for restraints to prevent elbow movement; when the restraints are placed or replaced, the patient may appear relaxed and better humored. Dysarthric speech may cause interpersonal communication problems; the higher-functioning children can express themselves fully and participate in verbal therapy.

The self-mutilation presents as a compulsive behavior that the child tries to control but frequently is unable to resist. Older individuals may enlist the help of others and notify them when they are comfortable enough to have restraints removed. In some instances, the behavior may lead to deliberate self-harm. Individuals with LND may also show compulsive aggression and inflict injury to others through pinching, grabbing, or hitting or by using verbal forms of aggression. Afterwards they may apologize, stating that their behavior was out of their control. Other maladaptive behaviors include head or limb banging, eye poking, and psychogenic vomiting.