Purine Metabolism Paper

[Guest guest]

Hi -

Here is Ted Page's latest publication to give people an idea of his current

research as background especially for people attending the MN Conference. I

have the article in PDF and BMP in case someone wants the article with

footnotes. I deleted footnotes out of admitted laziness in converting them.

Maura

ELSEVIER

Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2001) 1-4

Metabolic treatment of hyperuricosuric autism

Theodore Pagea,*a, Moseleyb

aDepartment of Neurosciences. University of California, San Diego. 0624,

.9500 Oilman Drive. La Jolla, CA 92093-0624. USA

bClinical Studies. Washington. Falls Church, VA. USA

*Corresponding author.

Abstract ..

A single male subject with hyperuricosuric autism was treated for a period of

2 years with an oral dose of uridine, which increased from 50 to 500

fig/kg/day. This patient experienced dramatic social, cognitive, language,

and motor improvements. These improvement decreased within 72 h of the

discontinuation ofuridine, but reappeared when uridine supplementation was

resumed. Thus, it appears that patients with

hyperuricosuric autism benefit from metabolic therapy with oral uridine

therapy in a manner similar to that seen in other disorders of purine

metabolism in which there is autistic symptomatology.

Keywords: Autism; Hyperuricosuria; Metabolic disorders

Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate;

ASD, autistic spectrum disorder; ATP, adenosine triphosphate; GDP, guanine

diphosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate;

nucleotidaseassociated pervasive developmental disorder -.

1. Introduction

Autistic spectrum disorder (ASD) is a class of neuro-psychiatric disorders

(DSM-IV, 1994) that is known to arise from many different causes (Page, 2000;

Gillberg and , 2000). Some types of ASD are caused by metabolic

disorders in which an enzyme defect is known (page, 2000; Gillberg and

, 2000). In other cases, an abnormal amount of some metabolite is seen

in the body although no enzyme or gene defect has been identified (Page,

2000; Gillberg and , 2000). In one subclass of ASD, patients with all

the attributes of classic infantile autism (DSM-IV, 1994) have been found to

excrete an amount of uric acid that is > 2 S.D. above the normal mean

( et al., 1976). Although the enzyme defect responsible for this urate

overproduction has not yet been identified, several noteworthy metabolic

abnormalities have been identified in the cultured fibroblasts of these

hyper-hyperuricosuric autistic patients. De novo purine synthesis is elevated

approximately fourfold over normal control subjects (Page and , 2000).

The ratio of adenine to guanine nucleotides (i.e., [AMP + ADP + ATP]/[GMP +

GDP + GTP]) produced by de novo synthesis is also lower than that produced by

nonnal control cells (Page and , 2000). As such, hyperuricosuric

autism can be considered a disorder of purine nucleotide metabolism.

Although uric acid itself is not believed to be the cause of the autistic

symptoms (page and , 2000), patients with hyperuricosuric autism have

been noted to benefit from a low-purine diet (, 1989; et al.,

1976; Page and , 2000; Hooft et al., 1968). This dietary therapy (Land

grebe, 1976) both decreases uric acid excretion and brings about improvement

in learning, attention, and social interaction, which are thought to be

causally related.

In another ASD in which there is a disorder of purine nucleotide metabolism,

patients have been found to have a 6- to 10-fold increase in cytosolic

5'-nucleotidase activity in their cultured skin fibroblasts (page et al.,

1997). These nucleotidase-associated pervasive developmental delay activity,

impulsiveness, absent or greatly delayed speech, abnormal social interaction,

seizures, ataxia, and frequent infections. Although NAPDD patients excrete

reduced, rather than increased, uric acid, these patients have also been

noted to benefit from a low-purine diet. This diet was associated with

decreased hyperactivity and reduced seizure activity. The fact that both

disorders benefit from the low-purine diet suggests the possibility that the

meta- bolic abnormality underlying the autistic symptoms might be similar.

NAPDD patients have been found to benefit greatly from oral uridine therapy

(Page et al., 1997). Dramatic reductions in hyperactivity, impulsiveness, and

seizures were noted; speech and social behavior also improved; and infections

became less frequent. Due to the similar response of these two disorders to

the low-purine diet and the suggestion of a similar biochemical etiology, a

trial with oral undine was initiated in a patient with hyperuricosuric autism.

2. Case

The patient, a left-handed Caucasian male, was first studied at age 9 years

for speech, behavior, motor, and cognitive abnormalities. His birth and

neonatal period were unremarkable. As a small child, he began head banging,

crib rocking, hand flapping, and toe walking, and these were present at his

examination at age 9. His balance and fine motor control were found to be

poor. Speech was dysarthric

and dyslexic. Cognitively, auditory perception was found to be " almost nil, "

and he had great difficulty reading. Behaviorally, he was hyperactive,

impulsive, had a short

attention span, and rarely made eye contact. He " tuned out " when alone but

became hysterical in groups. A number of these symptoms, especially

hyperactivity, were found to improve somewhat on the low-purine diet. Despite

these difficulties, he was said to be of above average intelligence and was

particularly talented in music and mathematics. He was able to graduate from

the normal secondary school

system and attend junior college.

Metabolic data for this patient had been reported previously (page and

, 2000). Measurement of a urinary uric acid gave a value of 18.1

mg/kg/dayat age 9

years. This is nearly 5 S.D. above the normal mean of 8.3:+/- 2.0 for this

age group. The average of three analyses of de novo purine synthesis in his

cultured skin fibroblasts gave a value of 34.4 nmoVIOO nmoV24 h, a value

nearly four times greater than the normal mean of 8.97+/- 1.56. The

adenine/guanine nucleotide ratio for this patient was found to be 4.65, with

the normal mean value of 7.15+/- 0.73. Thus, all the metabolic abnormalities

reported earlier for the hyperoricosunc autistic patients (Page and ,

2000) were present.

The patient began treatment with oral undine at age 32. His condition prior

to treatment is summarized in Table I. He suffered from a number of speech,

cognitive, social, and motor abnormalities. He began with 50 mg/kg/day

uridine and this dose was increased to 100 mg/kg/day after I week. At this

time, he began to notice improvements in his ability to concentrate, his

ability to un...derstand spoken language, and in his motor coordination.

After 3 weeks, the dose was again increased to 200 mg/kg/day. At this dose,

his speech improved greatly, with much clearer pronunciation and correct

syntax. The patient noted that his ability to read improved at this time as

well. After approximately 2 months, the dose was again increased to 500

mg/kg/day and he continued to improve in all areas. Maximum improvement was

seen at approximately 6 months after the initiation of therapy and is

described in Table I. Dramatic improvement was noted in virtually every area

of deficit. His awkward, shuffiing gait had become smooth and normal. His

fine motor control improved to the point where he could use a screwdriver,

scissors, and other hand tools. Whereas he had previously relied on " talking

books, " he could now read highly technical material with good comprehension.

His comprehension of language improved to where he no longer required

numerous repetitions. He could, for the first time, speak in clear and

grammatical sentences. This combination of improved perceptive and expressive

language function resulted in a newfound ability to engage in normal

conversation.

Withdrawal of uridine for more than 72 h caused some regression. He noted

that he had difficulty concentrating and his speech, gait, and fine motor

control appeared to deteriorate. Resumption of uridine restored the benefits

he had gained over the course of the trial. At present, the patient has been

taking oral uridine for more a 2 years. No adverse effects have been noted

dunng this time. It is notable that the absence of.adverse drug effects

includes several episodes of reduction/cessation of dosage and return to use

of uridine with uniformly good results.

3. Discussion

The magnitude of the improvement accompanying uridine appears to be similar

to that seen in the treatment of NAPDD with uridine (Page et al., 1997). It

is likely that

both hyperuricosunic autism and NAPDD represent disorders of purine

nucleotide metabolism despite the fact that the enzyme defect and uric acid

excretion are different. The mechanism of the beneficial effect of uridine in

both disorders may be due to thee preservation of purine nucleotides through

inhibition of 5' -nucleotidase by large amounts of uridine monophosphate.

The enzyme defect in hyperuricosuric autism is thus far unknown, but it is

likely to be one of the enzymes of purine nucleotide interconversion.

Experimental models of defects in purine nucleotide interconversion are known

to produce increased de novo purine synthesis, increased excretion of

purines, and an abnormal ratio of nucleotide synthesis (Ullman, 1984; Willis

and Seegmiller, 1980). A defect in AMP deaminase, an enzyme of purine

nucleotide interconversion, was found to be the cause of clinical gout in one

case (Van Den Berghe and Hers, 1980). Another defect in purine nucleotide

interconversion, adenylosuccinate lyase deficIency, is known to be the cause

of one type of autism (Van Den Berghe et al., 1997). Some success in the

treatment of this disorder with oral uridine has been reported recently

(Salerno et al., 2000).

Several population studies have placed the prevalence of the hyperuricosuric

subclass at 11-28% of the auttstic population ( et al., 1976 ;

Rosenberger-

Debiesse and , 1986; Nowell et al., 1990). If the majority of these

individuals have the same enzyme defect as the subject in this report and

undine proves to be a similarly effective treatment, then the population of

individuals who might benefit may be quite large.

WhIle this report is of Iimited scope due to its sing!e-case, uncontrolled

status, It is notable that the trial of uridine was instituted due to the

absence of an effective treatment for the moderately severe, life-long

disability widely known to be a manifestation of adult expression of ASD. The

rationale for the use of uridine was provided by the experience with the

NAPDD patients that led to the prediction on theoretical grounds that uridine

would be beneficial for this subpopulation of ASD. It is believed the

combination of beneficial effects and absence of adverse effects argues

strongly for large controlled clinical trials of uridine in the

hyperuricosuric subpopulation of ASD.

4. Conclusion

From this limited clinical trial, it appears that patients with

hyperuricosunc autism benefit from metabolic therapy with oral undine therapy

in a manner similar to that seen in NAPDD and, to a lesser extent,

adenylosuccinate lyase deficiency. All of these disorders involve

abnormalities of purine nucleotide metabolism, and uridine may act to correct

this abnormality.

(FOOTNOTES DELETED)