The symptoms found in the autistic spectrum vary in quality and quantity (1).Very few patients demonstrate all the symptoms and no chemical change is found in absolutely all autistic patients suggesting that autism is a heterogeneous disorder.
Changes in monoamine metabolism have been found such as increased serotonin in blood platelets (2) , increased CSF HVA (homovanillic acid) indicating increased dopamine metabolism and decreased 5HIAA(5hydroxy indolacetic acid ) in CSF (2,3).Such changes may be regulated by peptides such as a serotonin uptake stimulatory peptide ( 4 5 )found in autistic urines and dialysis fluid. Furthermore exorphins like casomorphin (5) have been found as part of a general hyperpeptiduria and peptidemia (6-8.). Opioids may activate the dopaminergic system as has been shown also for noradrenaline ( 9). We think that the demonstrated peptides may be central to the aetiology of the disease. Exorphins not only increase social isolation in animal models(10) and reduce separation distress vocalisation in puppies(11) , but may cause CNS inhibition of maturation (12). By acting as kindling agents opioids may cause epilepsy . The frequency of epilepsy in autistic patients increases with age , and is found in almost 114 at the age of 25.(13)
Hyperpeptidemia and hyperpeptiduria may be caused by peptidase defects (14-17),and/or fauits in peptide metabolising enzymes (18,19). However, excessive uptake from the gut as peptides (20,21) or excess of intact proteins taken up (22) could lead to the same increases in peptides in blood and urine, especially if combined with peptidase defects. Decreased sulphation of glycosoaminoglycans in the gut could increase uptake across the mucosa (23-25) Evidence for decreased sulphation' of paracetamol has been found (23).It can be seen from table 1 that the ratio of sulphation to glucuronidation is very significantly altered due to increased glucoronidation and reduced sulphation ( 23). Similarly a decrease in plasma sulphate combined with an increase in plasma cysteine has also been found (table l). A defect in sulphation could by damage to the formation of the sulphated mucoproteins (glycosaminoglycans) lining the gut wall and thereby increase the uptake across the mucosa .(23,24)Because cysteine is an excitotoxin ,increased levels may be damaging on their own accord by acting on the NMDA sub-type of glutamate receptors.
Table l: Synopsis of data on sulphation in autism(23)
| RATIO | AUTISM | CHILD CONTROLS | ADULT CONTROLS |
|---|---|---|---|
| N=46 | N=21 | N=28 | |
| (Sulphation / Glucoronidation) of paracetamol | 0.9+/-0.8* (0.6-6.0) | 2.1+/-2.7 (1.8-9.3) | 1.8+/-2.2 (0.4-2.4) |
| N=14 | N=18 | N=30 | |
| Cysteine / Sulphate | 115+/-889** (136-2988) | 65.2+/-44 (7-171) | 94.6+/-62.5 (15-280) |
Peptides are furthermore found to be increased in urine and dialysis fluid over normal age matched controls in 80-90% of the patients(5) but with considerable variation in quantity and pattern. This enormous quantitative difference is illustrated by the scatter diagram for the three different main subtypes found and normal in fig 1. In fig 2 the P2 geliltration patterns before and after one year of diet are seen when the peptides are fractionated on P2 gels after removing amino acids ,salts and urea ( 26). Note the difference in V max values indicating different chain lengths of the isolated peptides Because opioid activity notably casomorphins of bovine type (5) and a serotonin uptake stimulator (27) are found the peptides are probably relevant to the disease. Also their general levels and specific level decreases after dietary intervention (5,28)and correlates with the improvement of particularly social ability.(28). Several of the opioids show belishaped dose response curves and we think this is why some people find increased levels of opioids in autism using the opioid receptor assay (29 ) while others do not. Furthermore this typical peptide dose response relationship implies that naltrexone treatment(30) would be controversias and must be titrated out individually. A possible aetiological hypothesis :because a genetic defect in at least two genes is probable ( 31 ) we think that the above mentioned data and the heterogeneity may be explained by:
a) A defect in at least two peptidases;or b) An increased uptake from the gut (due to sulphation defects ?) combined with a peptidase defect,