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Peptides’ role in autism with emphasis on exorphins

Karl L. Reichelt, Dag Tveiten, Anne- Mari Knivsberg, Gunnar Brønstad

Problem: The nature of the peptides found increased in urine from autism needs verification of their structure, especially those that show opioid activity.
Methods: The peptides were separated on reverse phase C-18 HPLC in Trifluoroacetic acid acetonitril gradients. Peaks eluting where synthetic opioids appear, and peaks that are common to most autistic children were analyzed by mass spectrometry and fragmentation pattern on a quadropole mass-spectrometer.
Results: We could demonstrate exorphins in the urine from autistic children, and their length varied from one patient to the next.
Conclusion: Exorphins are found in urine of autistic children and may account for their symptoms.

Abstract

Problem: The nature of the peptides found increased in urine from autism needs verification of their structure, especially those that show opioid activity. Methods: The peptides were separated on reverse phase C-18 HPLC in Trifluoroacetic acidacetonitril gradients. Peaks eluting where synthetic opioids appear, and peaks that are common to most autistic children were analyzed by mass spectrometry and fragmentation pattern on a quadropole mass-spectrometer. Results: We could demonstrate exorphins in the urine from autistic children, and their length varied from one patient to the next. Conclusion: Exorphins are found in urine of autistic children and may account for their symptoms.

 
Citation: Microbial Ecology in Health & Disease 2012, 23: 18958
http://www.microbecolhealthdis.net/index.php/mehd/article/view/18958

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Cochrane Database Syst Rev. 2004;(2):CD003498. Links
Gluten- and casein-free diets for autistic spectrum disorder.

Millward C, Ferriter M, Calver S, Connell-Jones G.

BACKGROUND: It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of persons with autism. If this is the case, diets free of gluten and /or casein should reduce the symptoms associated with autism. OBJECTIVES: To determine the efficacy of gluten- and/or casein- free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. SEARCH STRATEGY: Electronic searching of abstracts from the Cochrane Library (Issue 3, 2003), PsycINFO (1971- May 2003), EMBASE (1974- May 2003), CINAHL (1982- May 2003), MEDLINE (1986- May 2003), ERIC (1965-2003), LILACS (to 2003) and the specialist register of the Cochrane Complementary Medicine Field (January 2004). Review bibliographies were also examined to identify potential trials. SELECTION CRITERIA: All randomised controlled trials involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with autistic spectrum disorder. DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. The authors independently selected the relevant studies from the reports identified in this way. As only one trial fitted the inclusion criteria, no meta-analysis is currently possible and data are presented in narrative form. MAIN RESULTS: The one trial included reported results on four outcomes. Unsurprisingly in such a small-scale study, the results for three of these outcomes (cognitive skills, linguistic ability and motor ability) had wide confidence intervals that spanned the line of nil effect. However, the fourth outcome, reduction in autistic traits, reported a significant beneficial treatment effect for the combined gluten- and casein- free diet. REVIEWERS' CONCLUSIONS: This is an important area of investigation and large scale, good quality randomised controlled trials are needed.

PMID: 15106205 [PubMed - indexed for MEDLINE]

 


 

Autism. 2006 Mar;10(2):189-97.
IgA antibodies in Rett syndrome.

Reichelt KL, Skjeldal O.
Institute of Pediatric Research, The National Hospital, University of Oslo, N-0027 Oslo, Norway. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

The level of IgA antibodies to gluten and gliadin proteins found in grains and to casein found in milk, as well as the level of IgG to gluten and gliadin, have been examined in 23 girls with Rett syndrome and 53 controls. Highly statistically significant increases were found for the Rett population compared to the controls. The reason for this remains unknown, but because IgA antibodies reflect the uptake of proteins and/or epitopes of proteins from the gut, this may be indicative of increased protein uptake.
PMID: 16613867 [PubMed - indexed for MEDLINE]

 


 

J Autism Dev Disord. 2006 Apr;36(3):413-20. Links
The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial.

Elder JH, Shankar M, Shuster J, Theriaque D, Burns S, Sherrill L.
College of Nursing, University of Florida, Gainesville, 32610, USA. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

This study tested the efficacy of a gluten-free and casein-free (GFCF) diet in treating autism using a randomized, double blind repeated measures crossover design. The sample included 15 children aged 2-16 years with autism spectrum disorder. Data on autistic symptoms and urinary peptide levels were collected in the subjects' homes over the 12 weeks that they were on the diet. Group data indicated no statistically significant findings even though several parents reported improvement in their children. Although preliminary, this study demonstrates how a controlled clinical trial of the GFCF diet can be conducted, and suggests directions for future research.

PMID: 16555138 [PubMed - indexed for MEDLINE]

Kommentar: 12 uker er for kort tid til å evaluere effekten av en utelukkelsesdiett, men foreldrene merket alikevel forbedringer.

 


 

J Pediatr. 2005 May;146(5):605-10.
Comment in: J Pediatr. 2005 May;146(5):582-4.
Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders

Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B.
Department of Pediatrics, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases, New Jersey Medical School/UMDNJ, 185 South Orange Avenue, Newark, NJ 07101-1709, USA. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.

PMID: 15870662 [PubMed - indexed for MEDLINE]

 


 

Nutr Neurosci. 2004 Jun;7(3):151-61.
Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism.

Vojdani A, O'Bryan T, Green JA, Mccandless J, Woeller KN, Vojdani E, Nourian AA, Cooper EL.
Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Ste. 200, Beverly Hills, California 90211, USA. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

The mechanisms behind autoimmune reaction to nervous system antigens in autism are not understood. We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously. For examining cross-reaction between dietary proteins and cerebellar antigens, antibodies were prepared in rabbits, and binding of rabbit anti-gliadin, anti-cerebellar peptides, anti-MBP, anti-milk, anti-egg, anti-soy and anti-corn to either gliadin- or cerebellar-antigen-coated wells was measured. In comparison to anti-gliadin peptide binding to gliadin peptide at 100%, the reaction of anti-cerebellar peptide to gliadin peptide was 22%, whereas the binding of anti-myelin basic protein (MBP), anti-milk, anti-egg and anti-soy to gliadin was less than 10%. Further examination of rabbit anti-gliadin (EQVPLVQQ) and anti-cerebellar (EDVPLLED) 8 amino acid (AA) peptides with human serum albumin (HSA) and an unrelated peptide showed no binding, but the reaction of these antibodies with both the cerebellar and gliadin peptides was greater than 60%. This cross-reaction was further confirmed by DOT-immunoblot and inhibition studies. We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.

PMID: 15526989 [PubMed - indexed for MEDLINE]



Nutr Neurosci. 2003 Feb;6(1):19-28.
Can the pathophysiology of autism be explained by the nature of the discovered urine peptides?

Reichelt KL, Knivsberg AM.
Institute of Pediatric Research, Univ of Oslo, Rikshospitalet, N-0027, Oslo, Norway. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Opioid peptides derived from food proteins (exorphins) have been found in urine of autistic patients. Based on the work of several groups, we try to show that exorphins and serotonin uptake stimulating factors may explain many of the signs and symptoms seen in autistic disorders. The individual symptoms ought to be explainable by the properties and behavioural effects of the found peptides. The data presented form the basis of an autism model, where we suggest that exorphins and serotonin uptake modulators are key mediators for the development of autism. This may be due to a genetically based peptidase deficiency in at least two or more peptidases and, or of peptidase regulating proteins made manifest by a dietary overload of exorphin precursors such as by increased gut uptake.

PMID: 12608733 [PubMed - indexed for MEDLINE]


Nutr Neurosci. 2002 Sep;5(4):251-61.
A randomised, controlled study of dietary intervention in autistic syndromes.

Knivsberg AM, Reichelt KL, Hoien T, Nodland M.
Center for Reading Research, Stavanger University College, Norway. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Impaired social interaction, communication and imaginative skills characterize autistic syndromes. In these syndromes urinary peptide abnormalities, derived from gluten, gliadin, and casein, are reported. They reflect processes with opioid effect. The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected diet and control group with 10 children in each group participated. Observations and tests were done before and after a period of 1 year. The development for the group of children on diet was significantly better than for the controls.

PMID: 12168688 [PubMed - indexed for MEDLINE]


J Hum Nutr Diet. 2002 Apr;15(2):141-4.
An audit of referrals of children with autistic spectrum disorder to the dietetic service.

Bowers L. Llanfrechfa Grange Hospital, Gwent Healthcare NHS Trust, Cwmbran, UK. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.

Autistic spectrum disorder (ASD) is a developing area for dietetic referrals. There is little published data on current dietetic practice. Some children with ASD are referred for gluten/casein free diet. The theory is that abnormal metabolites in the urine may be a result of incomplete breakdown of gluten and casein in the gut. There are some published open studies that support the efficiency of such a diet [Knivsberg et al. (1995) Scand. J. Educ. Res.39: 223; Lucarelli et al. (1995) Panminerva Med.37: 137; Whiteley et al. (1999) Int. J. Res. Practice 3: 45] and also that there are many anecdotal reports that the diet helps some children. AIMS AND OBJECTIVES: This study aimed to audit the types of referral made to the dietetic service to identify key dietetic issues and to describe factors which may influence outcome/disease management. METHODS: Dietetic records were used to audit the referrals to the dietetic service over a 3-month period. Seven-day diet histories were assessed using computer food composition tables and topics of interest recorded against a draft protocol agreed within the profession. RESULTS: Requests for gluten-free and casein-free dietetic advice, and/or the management of food selectivity and dysfunctional feeding behaviour constituted the majority of referrals. In many cases, child's environment was rarely simple. CONCLUSIONS: Despite the limitations of this small study, the findings suggest that the management of these referrals is highly complex. A dietitian's input should ensure that the nutritional adequacy of the diet is maintained or restored.

PMID: 11972743 [PubMed - indexed for MEDLINE]


Autism. 2002 Sep;6(3):315-28.
Urinary peptides in Rett syndrome.

Solaas KM, Skjeldal O, Gardner ML, Kase FB, Reichelt KL.
Institute of Pediatric Research, The National Hospital, University of Oslo, Norway.


Rett syndrome is a neuro-developmental disorder related to autistic behavior. Persons with autism have previously been found to have hyperpeptiduria. We here report a significantly higher level of peptides in the first fasting morning urine from 53 girls with Rett syndrome (both classical and congenital) compared with 53 healthy girls. This elevation in urinary peptides was similar to that in 35 girls with infantile autism. As in persons with autism, the individual levels of urinary peptides in the Rett syndrome group varied, and about a fifth were within the normal range. Levels of peptides were lower in girls with classic Rett syndrome than in girls with congenital Rett syndrome. This may be due to different etiological causes or to active and stagnant phases of the disease. Urine from girls with Rett syndrome was found to have higher frequency and higher levels of some urinary peptides that may cause inhibition of brain maturation and epilepsy

PMID: 12212921 [PubMed - indexed for MEDLINE]



Nutr Neurosci. 2001;4(1):25-37.
Reports on dietary intervention in autistic disorders.

Knivsber AM, Reichelt KL, Nodland M.
Center for Reading Research, Stavanger College, Norway. Denne e-postadressen er beskyttet mot programmer som samler e-postadresser. Du må aktivere javaskript for å kunne se den.


Autism is a developmental disorder for which no cure currently exists. Gluten and/or casein free diet has been implemented to reduce autistic behaviour, in addition to special education, since early in the eighties. Over the last twelve years various studies on this dietary intervention have been published in addition to anecdotal, parental reports. The scientific studies include both groups of participants as well as single cases, and beneficial results are reported in all, but one study. While some studies are based on urinary peptide abnormalities, others are not. The reported results are, however, more or less identical; reduction of autistic behaviour, increased social and communicative skills, and reappearance of autistic traits after the diet has been broken.

PMID: 11842874 [PubMed - indexed for MEDLINE]



1: Encephale. 1993 Mar-Apr;19(2):95-102.Links
[Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone][Article in French]

Leboyer M, Bouvard MP, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M. Service de Psychiatrie Adulte, Hôpital Pitié-Salpêtrière, Paris.

The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). This hypothesis has now received strong support and is currently based on three types of arguments: (1) similarity between autistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agent naltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexone has been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8275903 [PubMed - indexed for MEDLINE]



Revied:
1: Arch Gen Psychiatry. 1995 Sep;52(9):766-73.Links
Failure of naltrexone hydrochloride to reduce self-injurious and autistic behavior in mentally retarded adults. Double-blind placebo-controlled studies.

Willemsen-Swinkels SH, Buitelaar JK, Nijhof GJ, van England H.
Department of Child Psychiatry, Rudolf Magnus Institute for Neurosciences, University of Utrecht, The Netherlands.

BACKGROUND: It is hypothesized that self-injurious behavior (SIB) and symptoms of autism may be due to overactivity in some opioid systems in the brain. We examined the efficacy and safety of naltrexone hydrochloride, an opioid antagonist, in the treatment of SIB and autism in mentally retarded adults. METHOD: Thirty-three mentally retarded adults with autism and/or SIB participated in double-blind, placebo-controlled crossover studies. Active treatment was first a single 100-mg dose of naltrexone hydrochloride. Subsequently, 19 subjects were treated with 50 mg/d and 14 with 150 mg/d of naltrexone hydrochloride for 4 weeks. The outcome was assessed by means of direct observations (n = 11) and on the basis of scores on a list of target behaviors, the Aberrant Behavior Checklist, and the Clinical Global Impression Scale. RESULTS: Thirty-two subjects (seven with autism, 16 with autism and SIB, and nine with SIB) completed the trial. Naltrexone treatment failed to have therapeutic effects on SIB and autism. On the contrary, naltrexone increased the incidence of stereotypic behavior on the Aberrant Behavior Checklist, and the care staff evaluated the effect of the 50-mg/d treatment as being significantly worse than that of the placebo treatment as measured by the Clinical Global Impression Scale. CONCLUSION: Our findings suggest that naltrexone has no clinical value for a broad group of mentally retarded subjects with SIB and/or autism.

PMID: 7654128 [PubMed - indexed for MEDLINE]


Kommentar: Etter 3 uker vil normalt abstinens-perioden starte. Det kalles withdrawal-syndrome, og arter seg tilsvarende som for annen opiatavhengighetsabstinens. Vist i studier på autister som starter utelukkelsesdiett.  Aggresjon er en vanlig reaksjon under abstinensperioden.

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