Chapter 9
Inborn Errors of Metabolism as Causes of Autism
By Dr. William Shaw


 Heavy Metals, Especially Mercury, Implicated in Autism and Learning Disabilities

Ted Page Ph.D. and Mary Coleman M.D. have established that abnormalities of purine and pyrimidine metabolism are common in children with autism and PDD. Although these abnormalities began to be reported over 30 years ago, progress has been hampered because only a very small number of research laboratories performed this kind of testing and only on a very sporadic basis. The children with these genetic diseases have many or all of the classic diseases of autism and therefore cannot easily be distinguished from “typical” children with autism. A critical finding of Drs. Page and Coleman is that two major subtypes of this disorder can be distinguished by a simple clinical test of urine, which is the content of uric acid in the urine.

Purines and pyrimidines are the building blocks or bases of nucleic acids DNA and RNA, which carry the genetic code for all living creatures. Purines and pyrimidines can be attached to a sugar, forming compounds called nucleosides. Compounds called nucleosides can have one or more phosphate groups attached to them, making them compounds called nucleotides. The names of these different compounds are given below:


Base

Nucleoside

Nucleotide

Uracil

Uridine

Uridylic acid

Thymine

Thymidine

Thymidylic acid

Cytosine

Cytidine

Cytidylic acid

Adenine

Adenosine

Adenylic acid

Guanine

Guanosine

Guanylic acid

 

 Dihydropyrimidine Dehydrogenase Deficiency

I became interested in the role of these compounds after noticing that a significant number of children with autism had high amounts of the compound uracil in the urine tested with the organic acid test in our laboratory. The upper limit of normal is 22 mmol/mol creatinine but we found that one child with autism had a value of 360 mmol/mol creatinine and perhaps 15% of all children with autism had elevated values to a lesser degree.  This was a very interesting finding since there is an inborn error of metabolism called dihydropyrimidine dehydrogenase deficiency in which both uracil and thymine are elevated in the urine. Some of the individuals with this disorder had autistic symptoms. However, the individuals tested by The Great Plains Laboratory, with the abnormal uracil levels, invariably had normal or very slightly elevated values for thymine in the urine.  As a result, I assumed that they did not have dihydropyrimidine dehydrogenase deficiency.  However, Ted Page suggested to me that these individuals might have a form of enzyme deficiency in which thymine could be processed by the enzyme but uracil could not.


 Low Urine Uric Acid and Elevated Nucleotidase in Autism
 A Subtype of Autism That Responds to Dietary Pyrimidine Supplementation

In the 1990’s Ted Page and his associate reported a biochemical abnormality in a group of patients with low urine uric acid. The syndrome is also associated with elevated levels of an enzyme that breaks down nucleotides called nucleotidase in the cells of skin samples. The symptoms of the patients included developmental delay, seizures, impaired fine motor control, distractibility, hyperactivity, abnormal social interaction, speech deficit, immune deficiency, and frequent infections. Treatment with pyrimidine nucleotides or nucleosides resulted in a marked improvement in symptoms in a double-blind placebo trial. The sugar ribose which combines with pyrimidines to form nucleosides was also therapeutically beneficial but to a degree lesser than the nucleosides. The exact frequency of this disorder is unknown since only a small number of children with autism have been tested for this abnormality.


 High Uric Acid and Autism
 A Subtype of Autism That Responds to Dietary Restriction of Purines and/or Allopurinol

Ted Page and Mary Coleman reported that there is a group of patients with autism (perhaps as high as 20% of all people with autism) with high amounts of uric acid in the urine with symptoms including:  lack of interest in social contact, impaired communication, stereotypical behavior consisting of repetitive motions, toe-walking, hand-flapping, increased auditory sensitivity, self-injurious behavior, and decreased sensitivity to pain. Of the 9 patients studied withthis subtype, 6 of them had seizure activity as well. Treatment with the drug allopurinol or a diet low in purines (that form uric acid) reduces symptoms. Ted Page reported at an autism conference in  St. Louis in 2001 that the use of the nucleotide uridine was also effective in this subtype of autism. The cause for this increase in uric acid is unknown but is probably due to a defect in the interconversion of purine compounds. The standard test for elevated uric acid in blood serum may not be abnormal in this disorder so the urine test is preferred.


 Abnormal Succinylpurines and Autism

Researchers in Belgium first reported the presence of a genetic abnormality implicated as a probable cause of autism. Furthermore, they stated that this abnormality might not be rare (1). However, this abnormality is almost never tested in children with autism, even in those who undergo extensive biochemical testing at the time of initial evaluation. The biochemical reactions that result in the elevated succinylpurines (adenylosuccinate and succinylaminoimidazole carboxamide) are indicated below.

The case reports indicate that these three children with autism are not significantly different than many other children with autism. A description of symptoms in the children is useful:

Child one: The first girl evaluated had low muscle tone, a symptom prevalent in almost all children with autism. She had impaired development and motor skills. She had no readily apparent physical abnormalities. She would not maintain eye contact and she spent hours repetitively manipulating toys and grimacing. She cried incessantly and ground her teeth and bit herself. She was found to have striking autistic symptoms. Interestingly, a brain scan (CT) detected an underdeveloped cerebellum, an abnormality that has been reported, by Eric Corchesne, to be present in many individuals with autism.

Child two: The second patient was a boy who had impaired development and motor skills and the parents both noticed autistic behaviors when the child was a few months old. The child still had no speech at 3 years 8 months, lacked eye contact, and spent hours handling the same object and laughing to himself. He had tantrums without cause and spent excessive time with eye stimming and hand clapping. Like the first child, he also had a significantly underdeveloped cerebellum determined by a brain scan.

Child three. The third child was the sister of child two. She had the same autistic features as her brother and a brain scan also detected an underdeveloped cerebellum.

All three of the children had markedly elevated amounts of incompletely made purine compounds called succinylpurines in their urine samples, which include adenylosuccinate and succinylaminoimidazole carboxamide ribonucleotide. Children with this disorder have markedly low amounts of the enzyme adenylosuccinate lyase in certain tissues of the body but normal amounts in other tissues. Purines are necessary for virtually all living creatures from viruses to whales so an inability to produce purines is a significant biochemical abnormality. Ted Page reported at a conference in St Louis that supplementation with nucleosides or ribose appears to be effective in the treatment of this disorder as well.  Such compounds are available throughout the world. Nucleotides are essential for the production of RNA, which is needed for the production of all proteins and they have many other functions as well.


Figure 1
Biochemical Pathways Blocked in Succinylpurine Excess Subtype of Autism
Figure-2

 

 Testing

  • The standard organic acid test from The Great Plains Laboratory includes testing for uracil and thymine. Although there is no current treatment, new DNA biotechnology might be available as a treatment in the future.
  • Uric acid in urine will be available as a screening test at The Great Plains Laboratory using the enzymatic uricase method using first morning urine. To get the most accurate screening for high uric acid autism and low uric acid autism, a 24-hour urine collection is necessary.

References

  1. Page T and Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim et Biophys Acta 1500: 291-296, 2000.
  2. Jacken J and Van Den Berghe G. An infantile autistic syndrome characterized by the presence of succinyl purines in the body fluids. Lancet 2: 1058-1061, 1984.
  3. Berger R et al. Dihydropyrimidine dehydrogenase deficiency leading to thymine uraciluria. An inborn error of pyrimidine metabolism. Clin Chim Acta 141 227-234, 1984.
  4. Page T. et al. Developmental disorder associated with increased cellular nucleotidase activity.
  5. Langrede M. The restricted purine diet. In: M. Coleman, editor, The autistic syndromes, Elsevier, NY, 1976, Appendix IV-B.
  6. Coleman M et al. Purine autism. Hyperuricosuria in autistic children: does this identify a subgroup of autism?  In: M. Coleman, editor, The autistic syndromes, Elsevier, NY, 1976, pp. 183.
  7. Coleman M et al. Progressive seizures with hyperuricosuria reversed by allopurinol. Arch Neurol. 31:238-242,1974.
  8. Kaufman J et al. Urine uric acid to creatinine ratio-a screening test for inherited disorders of purine metabolism. J Pediatrics 73: 583-592, 1968.