Autistic Syndromes and Diet : a Reasonable Connection

Autistic syndromes and diet : a reasonable connection

Author:

Dr KarlReichelt - University of Oslo, Norway
Dr Karl Reichelt, long-time professor at the University of Oslo, Norway, is a world authority on gluten and casein intolerance in autism. He has published many papers, including research showing evidence of abnormal peptides in the urine of people with autism. In 2004, he was visiting professor at the University of Newcastle, Australia

Abstract:

By KL Reichelt

Institute of Paediatric Research, University of Oslo, Rikshospitalet /Radiumhospitalet, N -0027 Oslo,Norway

The casein- and glute- free dietary intervention in autism is based on peptide increases and opioid activity, some of which are exogenous. Furthermore, opioids can explain many of the symptoms discovered, and dietary intervention has been found to be effective by several groups. Thephysiology involved in the demand for diet makes sense. Phenylketonuria is a reasonable model, where reducing the load of phenylalanineor pre-lesion of deficient enzyme prevents the genetic defect from becoming manifest. Many of the symptoms found in autism can be explained by the effects of the peptides. The diet has been proven safe when supplements such as calcium and vitamins and cod liver oil are taken.

Full Paper:

Biology

Since a genetic disposition to autism has been established with very high heritability (Bailey et al., 1995; Lathe 2006) in the autistic syndromes, there must be chemical changes. However, the probable large increase in ratesof autismover recent years indicates environmental factors, too. This is not surprising, because a genetic disposition must often be exposed to environmental /endocrine inputs or overload to become manifest.

A clearly genetic disorder like phenylketonuriacan be treated by decreasing themetabolic load presented by phenylalanine. Also, the polymorphic nature of most enzymes makes it possible to increase low activity enzymes by cofactor supplementation(Ames et al., 2002).

Increase in opioids in autism was measured as opioid binding activity increase (Gillberg et al., 1985) or antibody binding activity (Le Boyeret al., 1994). More specificdemonstrations of exorphins in urine from autistic childrenhave been described (Reichelt et al., 1990; Cade et al., 2000; Shanahan et al., 2000) as part of a more general peptide increase ( Shattock et al., 1990; Cade et al., 2000; Reichelt and Knivsberg, 2003 ).

High-functioningpatients with autismand Asperger's syndromedo not always show peptide increase,which is not surprising becauseurine overflow of peptides depends on peptide levelshigh enough to bypass reuptake mechanisms in the kidneys.(Sponheim et al., 2006).

That the urinary peptides are active in the central nervous system affecting behaviour and morphology has been extensively published (Hole et al., 1979; Drysdale et al., 1982; Idet et al., 1982; Sun et al., 1999; Sun and Cade 1999)
In recent years, release of inflammatory cytokines by casein and gliadin has been found (Jyonuchi et al., 2005; Ashwood et al., 2004),causing pan-enteric inflammation, and therefore increasing the uptake from the gut. Increased gut permeability has been found in autism (D’Eufemia et al., 1996). A general inflammatory activation has also been reported ( Croonenberghs et al., 2002).

How is this possible?

The normal gut takes uppeptides (Chabance et al., 1998: Gardner 1994) and peptide uptake is increased by preventing breakdown by peptidases, even without increased permeability (Mahe et al., 1989). Normally, intact proteins are also taken up( Paganelli andLevinsky, 1980; Kilshaw and Cant, 1984; Husby et al., 1984; Axelsson et al., 1986; Troncone et al., 1987;) and inflammation of the gut wall, as seen in cpeliac disease, is expected to increase both peptide uptake and urine excretion (Reichelt et al., 1998). Protein uptake expressed as increased IgA antibodies against food proteins in serum is also increased in coeliac diseaseand is also found in autistic children (Reichelt et al., 1990 and 1991; Lucarelli et al., 1995; Cade et al., 2000) In fact, intact proteinsfrom the food can be found in mothers' milk (Axelsson et al., 1986; Kilshaw and Cant ,1984; Stuart et al., 1984; Troncone et al., 1987 )

Rett syndrome, as part of CPDD (childhood onset pervasive developmental disorder) also shows peptide increases in more than 80 % of cases (Solaas et al., 1999) as well as IgA antibody increases (Reichelt and Skjeldal, 2006).

The exorphins are furthermore taken up through the blood-brain barrier (Ermisch et al., 1983; Nyberg et al.,1989) and thesehave behavioural and trophic effects(Reichelt and Knivsberg ,2003)

The gutto brainrelationship has been considerably strengthened by the effectof food in chronic bowel inflammation (Geissler et al.,1995; Hart et al., 1998). In these papers, food intake resulted in white matter perivascular oedmea seen on NMR (almost hives-like). EEG changes in ADHD (hyperkinetic) kids with food intolerance has likewise been foundon exposure to mostly casein and gluten(Uhlig et al., 1997). Also, incoeliac disease, long-standing EEG changes in children could be induced by provocation caused exposure to gluten/gliadin (Paul et al., 1985).

Behavioural and neurological effects of untreated celiac disease (Pynnönen et al 2002; Hadjivassiliou et al 1998; Paul et al 1985; Gobbi et al 1992; Hallert et al 1982; Chapmann et al 1978 ).

These effects range from epilepsies to severe mental symptoms and developmental delays, and cerebellar lesions. Likewise, irritable bowel syndrome or inflammation can cause psychiatric disorders such as depression (Svedlund et al., 1985; Masandet al., 1995; Pynnünen et al., 2005; Hauget al., 2002) This is also the case for animal models (Welch et al., 2005), where brain areasinvolved in the autistic state are influenced by chronic gut irritation. It may reasonably be concluded that what happens in the gut affects the brain(Murch 2005)

Dietary evidence

Because of the dietary origin of some of the peptides, dietary intervention has been tried (Reichelt et al.,1990, Reichelt et al., 1991, Lucarelli et al., 1995, Knivsberg et al., 1995, Whiteley et al., 1999, Cade et al., 2000; Kniker et al., 2002, Knivsberg et al., 2002). The intervention by diet in small serieshas p values on the promille level of significance after one year, and decrease in peptidesconfirms the dietary origin of this peptide increase. The diet must be strict, as one molecule of glutenin has 16 opioid residues. Especially older autistic children tend actively to seek gluten/casein-containing foods from almost any source (addiction).

An Internet survey of a large number of autistic children on the diet (Klavness and Bigam, 2002) demonstrates that the individual improvements ranged from very fast to excruciatingly slow rates, and a trend for younger children to respond faster.

A 2002 paired and randomly assigned controlled, single blind paper (Knivsberg et al., 2002) has received a Cochrane rating. A relationship f gluten to behavioural problemshas been described earlier (Daynes 1956)

Based on the laws of mass action(Guldberg and Waage), supplying cofactors (trace minerals and vitamins) in excess of usual intake but below toxic levels can force polymorphically insufficient enzymes to higher activity(Ames et al., 2002). This has been demonstrated for phenylketonuria.

Other elementswhich ought to be critical

Learning programmes: Man is a learning 'animal' and therefore correcting the physiologymust be followed by a planned training programme. ABA or instrumental learning initiatedby Lovaas inLos Angeles has, byusing repetition and reward systematically as well aslittle input signalling, shown improvements(Sallows and Graupner, 2005). It makes sense that combining biomedical treatment with a systematic training would be a useful type of intervention.

Nutritional inputs: Omega 3 and 6 unsaturated fatty acids easily obtained throughcod liver oilproduce more flexible membranesand permit greater flexibility of membrane-bound proteins like receptors, increasing their efficiency (Heron et al.,1980). Vitamins and trace minerals with or without chelation, depending onheavy metal contamination (Nataf et al., 2006) would likewise have a reasonable place and could increase desired enzyme activities (Ames et al., 2002).

Hypothesis: Is that there is a genetic disposition in several loci.?

Enzyme polymorphism ranging from inactive to slightly active

With low-activity variants of enzymes by exposure to various factors such as mercury, gut inflammation leads to increased peptide /protein uptake because of decreased peptide breakdown. Pan-enteric gut inflammatory states (Ashwood et al., 2004 ) would further increase uptakeandalso increase gut irritation, because digestive enzymes would be hypofunctional due to the inflammation. Damage to the blood-brain barrier could, even with normal peptide levels, produce behavioural effects by gaining access to thecentral nervous system.The peptide effects may be direct, such as those seen for opioids, or indirect by peptide inhibition of peptide breakdown (La Bella et al.,1985). Depending on the constitution, different sub-syndromes are seen, just as a dammed river can form many different shapes of lake upriver from the dam.

Can the peptides explain some of the symptoms of autism?

Social Isolation/indifference

Opioids inhibit social bonding (Panksepp et al., 1978) and abrogate the separation distress calls ofnew-born animals (Panksepp et al.,1984). Because oxytocin (formed by peptidases like convertase) apparently hasa social bonding effect (Kirsch et al., 2005), it may be low in autism.A combined effect would indeed be deadly to social bonding.

Slow habituation

The palmar conductancemeasured in autistic children shows exaggerated response to auditory stimulation and poor habituation (Bernal and Miller, 1971). Increased sensory arousaland insufficient reactive inhibtion (lack of habituation) would cause avoidance of new inputs andproduce a preference for the status quo and rituals (Mednick et al., 1974). A peptide candidate for this is the serotonin uptake stimulator, pyroglu-trp-glyNH2 (Pedersen et al., 1999). It is well established that low serotonin in the synaptic cleft causes sensory - especially auditiory -hypersensitivity, poor habituation and sleep problems, as seen in carcinoid tumours where tryptophan is sequestered into the carinoid tumour, thus reducing the precursor available for thebrain.

Language problems

Social indifference would, by itself, cause language problems, but with poor habituation,the necessary cortical inhibition of one word to the next toenable sentence formation would not be expected to be present. As one treated autistic girl explained: 'All the words came tumbling mixed up like Irish stew.'

Sleep problems

Many, not all, CPDD children show a peculiar sleep disturbance. They go to sleep and, after a short while, wake up apparently completely rested. Decreased serotonin in the synaptic cleft, as seen in carcinoid tumours, causes a similar sleep pattern. The peptide Pyroglu-trp-glyNH2 was found to be increased in many autistic children andincreases serotonin uptake into platelets and synaptosomes (Pedersen et al., 1999) and could explain such a state.

Decreased pain sensitivity

Analgaesia would be explained by the increase in opioids, as would the fluctuatinganalgaesiaby exorphins from the digestion (Hole et al., 1978; Cade et al 2000).

Trophic changes in the brain

Opiods affect brain maturation as growth factors (Hauser et al., 1989) and Fos antigen isinduced in key nuclei of the brain (Sun et al., 1999), as would be expected in autism and schizophrenia. Such nuclei as nucleus accumbens and amygdala etc showed highly significant statistical changes.
In thefirstfive years, a tendency to macrocrania and excess brain growth had been found in children with autism (Courchesne et al., 2004) and growth factors (Nelson et al., 2002)which would be expected from inhibition of breakdown by accumulating peptides (La Bella et al., 1985). For details, see Reichelt and Knivsberg 2003.

Increased rate of epilepsy with age is found in autism (Deykin and MacMahon 1979). In coeliac disease, increased rates of epilepsy have been reported (Chapman et al., 1978; Gobbi et al., 1992). Opioids have a biphasic (hormetic dose) response and, at certain concentrations, are quite epileptogenic in the limbic brain (Siggins et al., 1986). We have seen substantial decrease in seizures in autistic children while on diet, which fits this background.

Conclusion

Since some of the peptides found to be increasedare of dietary origin, and can explain the symptoms of CPDD, this should be a fruitful lead to follow (Murch 2005). The many reported positive effects of diet likewise reinforce this view. However, as with most syndromes, other subgroups than those already known are likely to surface. Fragile X and tuberous sclerosis, which can cause autistic syndromes, do not show peptide increase.

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