article Rocchiccioli Francis, 2002
Dr. Francis Rocchiccioli, Laboratory of Biochemistry and INSERM U 561, Hôpital Cochin-Saint Vincent de Paul (University Rene Descartes), 82 avenue Denfert-Rochereau, 75674 Paris Cedex 14
There is no secrets that time does not reveal ...
Jean Racine, Britannicus, Act IV, Scene 4
Research on the Internet term autism (e) provides answers about 51,000 French and 568,000 in English, gluten-free diet gives 32,600, 315,000 mercury, mercury and mercury & autism 3,460,000 14,500. Very many anomalies are described ( http://www.autism.com/contents.htm the , http://www.panix.com / ~ Don Wiss / reichelt.html, http://www.healing-arts.org/children/autism-overview.htm ...). I confine myself in this statement voluntarily with urinary peptides related to the absorption of gluten and casein, fatty acid very long chain and polyunsaturated fats and heavy metals.
Autism is really a " disease " or syndrome or simply a term that encompasses some very heterogeneous population of children with behavioral disorders? It does not matter, the overriding issue is not there and multiple causes of the occurrence of behavioral problems have often been identified with a common effect, the absence of language related to an asocial. There is no statistical impact of French of autism, the Americans have seen an increase over five years (from 1993 to 1998) of over 500% in Maryland, with a current frequency of around 1 / 150, well above the " bar " rare diseases or orphan (1 / 2000 births) (http://orphanet. infobiogen.fr). Genetic studies have been undertaken to find the cause of autism; chromosomes 6, 7 and 15 are for example involved in the study PARIS (May 2001, Inserm), but the variation impressive 500% seems more reasonable bound to an environmental cause that a purely genetic cause where the frequency of occurrence of a given disease remains relatively constant despite successive generations.
It is currently in autism at the stage of validation of biomarkers. I do not want to show that autism is a metabolic disease or hereditary, although it can be considered as listening to other speakers of this Congress, but rather try to present the difficulty and caution needed to address this type of research. I briefly summarizes the time spent on exploration complete, the biological marker for gene therapy, the X-linked adrenoleukodystrophy (ALD-X), peroxisome disease for which I have specialized since 1984 in the laboratory diagnosis. The markers are the fatty acids to very long chain (≥ C 22 ) or VLCFA [1], prenatal diagnosis was quickly made on chorionic villi [2], the first marrow transplant performed in France in 1989 [3] The treatment "Lorenzo's oil " (erucic acid) advocated around 1990 [4], the location of gene (on X) in 1992 (Aubourg et al, Nature 1993), normalization of VLCFA by introducing the gene into the fibroblasts around 1994 [5], the animal model available in 1997 (ALDP KO mice), Standards and testing by gene transfection in mice KO (2001-2002) are still ongoing. Almost 20 years on! Despite the advance in knowledge of the genome, the time saved thanks to the Internet, some delays are still incompressible. I will only quote the Zellweger syndrome and Smith-Lemli-Opitz described clinically in 1964 and whose biomarkers were identified respectively 20 and 30 years later ...
Another difficulty is difficult to address in a disease not yet fully biologically targeted: the severity of clinical signs is often independent of the degree of accumulation of biological marker, thus making her even more specificity difficult to demonstrate in the case of a small increase in a marker in a new pathology. For the X-ALD, the brain changes and plasma markers compared to normal are "very low " (factor 4-5), although the disease often leads to demyelination central nervous system. External factors (environmental and / or food) that promotes the onset of the disease are also now in question. A deficit of E3 complex of pyruvate dehydrogenase (PDH) in neonatal statement, resulting in increased plasma lactate by a factor of 10 to 20, and paradoxically, alkaptonuria (homogentisate oxidase deficiency), where urinary homogentisic acid is increased by a factor of 1000 at least, will not affect clinical adulthood. The greatest caution is therefore required in selecting a marker to be applied characteristic. The choice is even more difficult as the number of disrupted pathways is impressive, without there being any obvious or apparent biochemical link between all these metabolisms.
Another difficulty arises for such diseases linked to the ingestion of gluten. Celiac disease is well known and all the specialists are based primarily on blood antibodies (anti-gliadin, endomysial, anti-transglutaminase, IgA, IgE, IgG ....) And histology (intestinal biopsy). This is one reason why I have developed since 1993 a test of intestinal permeability to mannitol differential and lactitol as a diagnostic tool in Gastroenterology, the test assesses the state of the intestinal membrane and to avoid, if the result is normal, a biopsy [6]. Urinary peptides, which just spoke to Professor Reichelt, gastroenterologists are often ignored by adults. The normality of the different antibody blood aforementioned does not necessarily allow to exclude with certainty a particular response or sensitivity to gluten proteins, many examples show the effect of urinary peptide profiles dominated by the gluten and its degradation products, and especially a significant improvement and rapid recovery of weight in some of these patients after starting a gluten exclusion diet (SG).
I approached biologically behavior problems in late 1999 to a little boy, David, about 2 years with autistic disorder and has miraculously improved (normal for now) thanks to the persistence of his mother that put him against any medical advice free diet gluten and casein (MSLP) ... Since I had the opportunity to participate Exploration metabolic approximately 320 patients, mostly boys but also girls and some adults, about half from the proper recruitment of Madame Arod (elke@hyperactif.org). The diet change has often been proposed with vitamin supplementation, many people were put on a diet MSLP, many have changed considerably ... so they are almost all set to grow, mostly to talk (or talk) and very few people for whom this type of diet had no effect ... Among children become normal, I will cite only three examples of significant behavioral disorders causing immediate relapse after a "food gap " the powerful incentive to go on a diet as strict as possible when it is introduced: casein for David, homeopathic medicine (lactose) for Steven and pancakes for Karl. It is however likely that this food sensitivity diminishes gradually over the years, although the treatment is typically for life for celiac disease.
Without exhaustively explored all genetic diseases most frequently found in disorders of behavior, it was possible for me on these 320 patients did highlight eight genetically proven disease : David has a disease X-linked, Soledad has Rett syndrome, Nicolas has a Rett syndrome (her mother is heterozygous), Paul and Philip have Duchenne muscular dystrophy and Becker, William has thalassemia, Anthony C has a disorder of purine metabolism, and possibly Anthony L Wilson disease (to be confirmed by finding a mutation on chromosome 13). This list includes only one girl and seven boys (87.5%), thus close the number stated above 80% of boys in the autistic population, and four X-linked diseases in boys ... It's very little in total (2.5%) and very diverse, and probably the value is obtained it by default because of the lack of systematic research, but close to the value provided by Professor Fombonne officially during a symposium on autism at the end of 1999 Defence where he announced 6-7% ...
Two previous patients, and Nicolas Guillaume, had to undergo involuntary massive exposure to mercury. William underwent general anesthesia the installation of eight amalgam in a Parisian hospital in October 2000 and a dynamic test at ASD has recently demonstrated a clear mercury poisoning. As for Nicolas, it was his mother who was heavily intoxicated accident before his birth ... In addition, thimerosal, present in many vaccines, is implicated in neurite growth by having a toxic effect on tubulin and actin. But the list grows progressively proven cases of poisoning by heavy metals determination in various matrices: plasma, red blood cells, urine, hair and feces. Administration ASD, DMSA or EDTA is often necessary to highlight intoxication old. It is likely that heavy metals and peptides from gluten and casein have also a synergistic effect and further aggravate the mental condition of autism: advances in MSLP regime are often spectacular cleanliness (especially SC), the contact, growth and language, but sometimes they can be magnified by taking ASD still used with great caution because it can also complex with the metabolism of essential elements like calcium, magnesium or zinc.
Being specialist biochemical diagnosis of diseases of peroxisome (ALD-X, Zellweger syndrome and related diseases), I studied in fifty small VLCFA the autism as well as globular plasma by isotope dilution without ever finding any damage, contrary to what some Americans argue that talk of default functionalization peroxisome (?) . Moreover, being also specializes in the diagnosis of mitochondrial diseases, we must take with the utmost caution any defect in the Krebs cycle (also stated by some Americans) without being validated by a biological disturbance of lactate, pyruvate, NADH / NAD ratio, and other energy substrates.
It is with the utmost caution must be taken into account the nature, structure and impact of a urinary metabolite specific: I only mention the phénylpropionylglycine (PPG) that I was first described [7, 8] as a marker of mitochondrial enzyme deficiency, acyl-CoA dehydrogenase medium chain (MCAD). The result of its accumulation in urinary actually quite complex because it corresponds to a catabolism " cross " between human and bacterial metabolism. Phenylpropionic acid (PPA) can come only from phenylalanine and the action of a bacterial ammonio-lyase (not found in humans), conversely, man can degrade the APP MCAD benzoic acid by b-oxidation (not found in bacteria). MCAD deficiency will therefore result in an accumulation of APP, which is subsequently conjugated with glycine in the liver PPG excreted unchanged in urine. This peculiarity has been taken up by other teams as a diagnostic tool [9] and as a challenge test for APP detection of MCAD deficiency [10].
erythrocyte polyunsaturated fatty acids are also an interesting research direction to follow. A very important deficiency in essential fatty acids of the w3 series has indeed been observed in the population of young adults with autism and a study is currently underway on the rate differential distribution of fatty acids between phospholipids and triglycerides (plasma and blood cells ) to better identify the causes This deficiency related to food and the environment. Again great care is needed because we are probably all more or less deficient w 3 but have no behavioral problems ...
The task is difficult and professional specialists metabolism must take made primarily of clinical improvement of young patients especially as I have already spoken with the regime MSLP, and partner with psychiatrists and psychologists to define a PEP to objectify the progress observed in MSLP regime. Also certain parameters (urinary peptides, erythrocyte fatty acids, acids dysbiosis ...) are not yet realized in a hospital, but only in private laboratories.
I already mentioned the mercury, but it could be a major cause of autism, as " link" between all disturbed metabolism with a particular connotation for bacterial metabolism and / or fungal dysbiosis and acids that are often disrupted. The report 261 of the French Senate ( http://www.senat.fr/rap/100-261/100-261.html) is also extremely informative about the precautions for the disposal of mercury, used extensively in some industries that discharge large quantities in the atmosphere ...
The parents' motivation is obviously legitimate autism and exemplary, and I can only hope that the gathering in the congress of scientists interested in metabolic problems of autism (First Congress of French inspiration DAN) advances the knowledge and treatment of Autism same way as have parents made Lorenzo's small for X-ALD ...
References
1. Aubourg P Bougnères PF Rocchiccioli F. Capillary gas-liquid chromatography mass spectrometric measurement of very long chain (C 22 to C 26) fatty acids in Microliter samples of plasma. J Lipid Res 26, 263-7 (1985).
2. Rocchiccioli F, Aubourg P, Choiset A. Immediate prenatal diagnosis of Zellweger syndrome by direct measurement of very long chain fatty acids in chorionic villus cells. Prenat diagn 7 , 349-54 (1987).
3. Aubourg P, Blanche S, Jambaqué I, Rocchiccioli F, Kalifa G, Naud-Saudreau C, Rolland MO, Debré M, Chaussain JL, Griscelli C, Fischer A, Bougnères PF. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med 322, 1860-6 (1990).
4. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Jambaqué I, Jakobezak C, Lemaitre A, Boureau F, Wolf C, Bougnères PF. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy. N Engl J Med 329 , 745-52 (1993).
5. Cartier N, Lopez J, Moullier P, Rocchiccioli F, Rolland MO, Jorge P, Mosser J, Mandel JL, Bougnères PF, Danos O, Aubourg P. Retroviral-mediated gene transfer corrects very-long-chain fatty acid metabolism in adrenoleukodystrophy fibroblasts. Proc Nat Acad Sci USA 92 , 1674-8 (1995).
6. Kalach N, Rocchiccioli F, de Boissieu D, Benhamou PH, Dupont C. Intestinal permeability in children: variation with age and reliability in the diagnosis of cow's milk allergy. Acta Paediatr 90 , 499-504 (2001).
7. Rocchiccioli F, Cartier PH, Bougnères PF. Mass spectrometric identification of abnormal aromatic compounds in the urine of a child with Reye's like syndrome. Biomed Mass Spectrom 11 , 127-31 (1984).
8. Bougnères PF, Rocchiccioli F, Kolvraa S, Hadchouel M, Lalau-Keraly J, Chaussain JL, Wadman SK, Gregersen N. Medium-chain acyl-CoA dehydrogenase deficiency in two siblings with a Reye-like syndrome. J Pediatr 106, 918-21 (1985).
9. http://www.icondata.com/health/pedbase/files/MCADDEFI.HTM
10. Seakins JWT, Rumsby G. The use of phenylpropionic acid as a loading test for medium-chain acyl-CoA dehydrogenase deficiency. J Inher Metab Dis 11 (Suppl. 2) 221-4 (1988).
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