A new disorder of purine metabolism with behavioral manifestations

doi:10.1016/S0022-3476(69)80004-1

The Journal of Pediatrics

Volume 74, Issue 1, January 1969, Pages 20-27

https://doi.org/10.1016/S0022-3476(69)80004-1 Get rights and content

Hyperuricemia has been observed in a 3-year-old boy with mental retardation, dysplastic teeth, failure to cry with tears, absence of speech, and unusual, autistic behavior. Increased synthesis of purines de novo was documented by a rate of conversion of glycine to uric acid that was seven times that of control. The activity of the enzyme hypoxanthine guanine phosphoribosyl transferase was normal, while that of adenine phosphoribosyl transferase was increased. These observations are interpreted to reflect a distinct disease productive of hyperuricemia very early in life.

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There are more references available in the full text version of this article.

Cited by (58)

Purines and pyrimidines
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1
Lesch–Nyhan disease results from mutations in the gene for hypoxanthine quinine phosphoribosyltransferase hypoxanthine guanine phosphoribosyltransferase. Patients have varying degrees of diminished activity of the enzyme, but a majority with the complete syndrome have essentially zero activity. Patients have crystalluria, hematuria, and renal stone disease. Neurologic development is severe; patients do not walk or sit alone. Involuntary movements are characteristic. Self-injurious behavior includes characteristic biting injury, which may lead to loss of tissue about the mouth or fingers. Treatment with allopurinol prevents hyperuricemia and its consequences, but it has no effect on the neurology or the behavior. Phosphoribosylpyrophosphate syntheses deficiency leads also to clinical gout and urolithiasis. The disease is transmitted as an X-linked dominant; so females are clinically affected.
Antipurinergic therapy for autism—An in-depth review
2018, Mitochondrion
Citation Excerpt :
To answer this question, researchers had to weave together several apparently unrelated threads. These threads included research on mitochondria and healing (Naviaux et al., 2009), genetic forms of mitochondrial dysfunction in autism (Graf et al., 2000), genetic forms of autism associated with increased purine metabolism (Nyhan et al., 1969), and the paradoxical improvement with fever that proved that the core behaviors of autism could be dynamically regulated by metabolism (Curran et al., 2007). The author hypothesized that the root cause of pathological persistence of the CDR was continued excessive or unbalanced purinergic signaling, called hyperpurinergia (Naviaux et al., 2013), and dyspurinergia, respectively.
Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A small clinical trial published in 2017 suggests this is possible. Based on a new unifying theory of pathogenesis for autism called the cell danger response (CDR) hypothesis, this study of 10 boys, ages 5–14 years, showed that all 5 boys who received antipurinergic therapy (APT) with a single intravenous dose of suramin experienced improvements in all the core symptoms of autism that lasted for 5–8 weeks. Language, social interaction, restricted interests, and repetitive movements all improved. Two children who were non-verbal spoke their first sentences. None of these improvements were observed in the placebo group. Larger and longer studies are needed to confirm this promising discovery. This review introduces the concept of M2 (anti-inflammatory) and M1 (pro-inflammatory) mitochondria that are polarized along a functional continuum according to cell stress. The pathophysiology of the CDR, the complementary functions of M1 and M2 mitochondria, relevant gene-environment interactions, and the metabolic underpinnings of behavior are discussed as foundation stones for understanding the improvements in ASD behaviors produced by antipurinergic therapy in this small clinical trial.
Disorders of Purine Metabolism
2014, Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth Edition
Inherited defects of purine and pyrimidine metabolism have been well documented in 11 different syndromes, many of which are associated with neurologic abnormalities. Lesch–Nyhan disease is the most common and best studied of these disorders. The defect is a lack of activity of the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT).
Affected patients have an enormous overproduction of purines, hyperuricemia, uricosuria and all of the complications of gout, including arthritis, tophi, renal calculi, and renal failure resulting from the deposition of urate in renal parenchyma. The neurologic disease has often been diagnosed as cerebral palsy; patients are spastic and hyperreflexic, and they are impressively dystonic. The movement disorder may also be choreic or athetoid. The behavior has been classified as a behavioral phenotype. Its most striking characteristic is self-injury, particularly through biting. Partial amputations have been seen.
Phosphoribosylpyrophosphate synthetase abnormality is another hyperuricemic disorder coded for by a gene on the X chromosome. In this situation, the abnormal enzyme is overactive. Sensorineural deafness is another characteristic. Some patients have been mentally retarded, but our patient was thought to be retarded until it was realized he was deaf.
The hyperuricemic features of both diseases are effectively treated by xanthine oxidase inhibitors.
Metabolic features of the cell danger response
2014, Mitochondrion
Citation Excerpt :
Dr. Nyhan published the first example of an inherited defect in purine metabolism that profoundly altered behavior known as Lesch–Nyhan Disease (Lesch and Nyhan, 1964). Just a few years later he published the first example of a child with autism-like behaviors resulting from an inherited increase in purine synthesis known as phosphoribosylpyrophosphate synthase (PRPPS) super activity syndrome (Nyhan et al., 1969). Both disorders resulted in a profound increase in de novo purine biosynthesis.
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
Purine metabolism in the pathogenesis of hyperuricemia and inborn errors of purine metabolism associated with disease
2012, Gout and Other Crystal Arthropathies
Purine metabolism in the pathogenesis of hyperuricemia and inborn errors of purine metabolism associated with disease
2011, Gout and Other Crystal Arthropathies: Expert Consult: Online and Print

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^*: This investigation was supported by United States Public Health Service Research Grants No. HD 02609 from the National Institute of Child Health and Human Development and No. FR 00261 from the General Clinical Research Centers Branch, Division of Research Facilities and Resources, National Institutes of Health, and by Public Health Service Training Grant No. T1 HD 76 from the National Institute of Child Health and Human Development, National Institutes of Health.

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Original articleA new disorder of purine metabolism with behavioral manifestations*

Am. J. Med.

J. Pediat.

Biochim. et biophys. acta

Genetics of an X-linked disorder of uric acid metabolism and cerebral function

Pediat. Res.

Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis

Science

Original article
A new disorder of purine metabolism with behavioral manifestations*