Original Article

Effectiveness of N,N-Dimethylglycine in and Pervasive

Janet K. Kern, PhD, RN; Van S. Miller, MD, PhD; Lawrence Cauller, PhD; Roger Kendall, PhD; Jyutika Mehta, DHMS, MS; Mary Dodd, MA

ABSTRACT

N,N-dimethylglycine, a dietary supplement, has been reported to be beneficial in children with autism and pervasive devel- opmental disorder. We examined the effectiveness of dimethylglycine in children with autism and pervasive developmental disorder in a double-blind, placebo-controlled study. Thirty-seven children between 3 and 11 years of age with a diagno- sis of autism and/or pervasive developmental disorder were gender and age matched and randomly assigned to receive either placebo or dimethylglycine for 4 weeks. All children were assessed before and after treatment on two behavioral measures, the Vineland Maladaptive Behavior Domain and the Aberrant Behavior Checklist. Standardized neurologic exam- inations before and after treatment on 33 children showed no change. An overall improvement on all behavioral measures was observed for both the placebo and the dimethylglycine groups. However, the improvement among the children who received dimethylglycine was not statistically different from the improvement observed among the children who received the placebo. The children who participated in this study were a heterogeneous group, and their apparent responses to the dimethylglycine varied. Some children appeared to respond positively to the dimethylglycine, and there was a smaller pro- portion of negative changes in the dimethylglycine group, but the quantitative changes in the dimethylglycine behavioral assessments were not significantly different from what was observed among children who received placebo. (J Child Neurol 2001;16:169-173).

Autism and pervasive developmental disorder of childhood lems in Korea~ suggest that dimethylglycine, a dietary sup- are common neurodevelopmental disorders estimated to plement, may be useful in children with autism/pervasive occur in more than 1 of every 1000 children.1,2 Diagnostic developmental disorder. In the Korean study on 39 chil- criteria for these disorders include impairment in social dren with autism, dimethylglycine was helpful in 80%, with interaction and communication and restricted, repetitive, and most notable improvements in the ability to talk, improved stereotyped patterns of behavior and activities.3,4 eating, toilet training, and &dquo;willingness.&dquo; Dimethylglycine, the Medical treatments in autism/pervasive developmental N,N-dimethylated derivative of the amino acid glycine, is disorder have been disappointing. Anecdotal reports and an found naturally in low levels in certain foods such as beans, unpublished study completed at the Center for Child Prob- cereal grains, and liver.6 Dimethylglycine is a normal con- stituent of the cell and is produced from choline via betaine by loss of a methyl group. Dimethylglycine is metabolized Received Dec 9, 1999. Accepted for publication June 15, 2000. in the liver into sarcosine (monomethylglycine) via an oxida- From the Department of Human Development (Drs Kern, Cauller, and Mehta tive demethylation. By this pathway, dimethylglycine can act and Ms Dodd), University of Texas at Dallas, Dallas, Department of Pediatric as an indirect methyl donor and provide both methyl groups Neurology (Dr Miller), University of Texas Southwestern Medical Center, via transfer to folate for synthesis of methionine from homo- Dallas, TX, and the Department of Biochemistry (Dr Kendall), University of Bridgeport, Bridgeport, CT. cysteine. Certain studies with dimethylglycine indicate that the nutrient can reduce lactic acid in the dur- The study was completed at the University of Texas at Dallas and was sup- build-up blood ported by FoodScience Corporation, Essex Junction, VT. ing times of stress,8,9 enhance oxygen use during times of Address correspondence to Dr Janet K. Kern, University of Texas hypoxia,8 and reduce seizure activity. 10-14 Extensive studies Southwestern Medical St. Paul Professional 5959 Center, Building I, Harry with have shown no adverse Hines Blvd., Suite 520, Dallas, TX 75235-9101. Tel: 214-648-1751; fax: 214- dimethylglycine significant 648-4278 ; e-mail: [email protected]. effects in humans or animals. 5,8-23 _

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We evaluated the effectiveness of dimethylglycine in a of age. Sensory defensiveness was reported to be a problem in 13 double-blind, placebo-controlled study of a heterogeneous of the children. Thirty-one of the children were normal in appear- population of children with diagnoses of autism and/or per- ance, whereas 8 had craniofacial and/or other physical anomalies. vasive developmental disorder. Standardized quantitative Seven children were on psychoactive medications (clonidine, thio- behavioral and neurologic assessments were completed ridazine, paroxetine, imipramine, methylphenidate, and fluoxe- before treatment and 4 weeks after the treatment began to tine) at the beginning of the study, but regimens were held constant measure the effects of dimethylglycine. for the duration of the study.

METHODS Setting and behavioral assessments were completed at the ... ’&dquo; Neurologic Subject Selection and Participation University of Texas at Dallas in the childcare room, a large, child- Patients were recruited from local autism societies, schools, doc- friendly room with toys and activity centers. A variety of items were tors, and the Internet (by posting on an autism site). Thirty-nine available to use during the behavioral observations, such as wooden children, 3 to 11 years of age, with a diagnosis of autism/pervasive blocks, crayons, pencils, paper, and balls. Patients were accom- developmental disorder were enrolled in the study. The study was panied by their parents/guardians, who remained present during approved by the institutional review boards of the University of the assessments. Texas at Dallas and the University of Texas Southwestern Medical School. Informed consent was obtained from the parents. Each child Behavioral Assessments met the diagnostic criteria for autism or pervasive developmental Behavioral assessments were completed using two assessment disorder, according to the Diagnostic and Statistical Manual of tools, the Vineland Maladaptive Behavior Domain, a section of Mental Disorders-IV (DSM-IV) criteria,&dquo;3 confirmed independently the Vineland Adaptive Behavior Scales Survey Form,24 and the by the authors. The children who participated in this study were Aberrant Behavior Checklist, Subscales I to V. 25 These measures heterogeneous, although all had either autism or pervasive devel- were obtained immediately before treatment (week 0) and 4 weeks opmental disorder. Because dimethylglycine may be beneficial after the treatment began (week 4). The assessment tools were com- only in certain subtypes of autism we did not attempt to limit par- pleted by the examiner (J.K.K.). The Maladaptive Behavior Domain ticipation to strictly defined subtypes of patients. The children was completed by interviewing the parent/guardian. The Aberrant were randomly assigned to receive either dimethylglycine or Behavior Checklist was completed by both observing the child and placebo by the research pharmacists at the Children’s Medical obtaining input from the parent/guardian. Both the examiner and Center of Dallas. The groups were matched for gender and age. the parent/guardian were blinded as to the child’s group assignment. Group assignments were made by the pharmacist, who assisted with All assessments were videotaped and were later reviewed to ensure the study without knowledge of the diagnostic status, severity, or the accuracy of the changes noted during the assessments. behavioral characteristics of the patients. The Maladaptive Behavior Domain was chosen because it Thirty-nine children began the study, and 37 children completed assesses several features relevant to autism (eg, eye contact, prob- the study (19 in the placebo group and 18 in the treatment group). lems with eating or sleeping, attention, concentration, aggres- One child discontinued the study due to negative behavioral effects siveness, peculiar occupations, peculiar mannerisms or habits, of the dimethylglycine (hyperactivity and increased agitation), self-injurious behavior, awareness of environment, bizarre speech, and another child discontinued due to damage to the foil wrappers rocking). The Vineland Adaptive Behavior Scales have been used around the tablets. Four of the children were not examined by the in other recent biomedical treatment studies for children with neurologist at the post-test because of scheduling conflicts. autism.26 The Maladaptive Behavior Domain is a parent interview Children in this study displayed a wide range and variety of format containing 36 items, of which 16 are specifically relevant autistic features and soft neurologic findings common in such to autism/pervasive developmental disorder. Such items include &dquo;has children. For example, delays in gross and/or fine motor skills excessive or peculiar preoccupations with objects or activities,&dquo; were noted in 26 of the children. Problems with smooth ocular pur- &dquo;is unaware of what is happening in immediate surroundings,&dquo; &dquo; suit were noted in 4 of the children, and 4 children had obvious bal- and &dquo;rocks back and forth when sitting or standing.&dquo; ance problems. Poor muscle tone was noted in 5 of the children. The Aberrant Behavior Checklist was chosen because it is a Ten children were completely nonverbal, 12 were echolalic, and 4 scale for rating inappropriate and maladaptive behavior. The Aber- had only slightly limited verbal skills. The children ranged in social rant Behavior Checklist was designed to monitor the behavioral skills from friendly to completely asocial (even with family mem- effects of psychotropic drugs. This same Aberrant Behavior Check- bers). Whereas some were quiet and/or passive, others were vio- list assessment was used in a recent Taiwanese study on the effec- lent and/or aggressive. Sixteen children had difficulty sleeping, tiveness of dimethylglycine in children with autism/pervasive which ranged from waking up several times per night to having to developmental disorder (Bernard Rimland, PhD, personal com- be medicated to sleep. Eating disorders were described by the par- munication, January 1998). The Aberrant Behavior Checklist con- ents in 16 of the children, ranging from eating an extremely sists of 58 items, many of which are pertinent to autism/pervasive restricted choice of foods to having to be fed with a syringe because developmental disorder. Such items include &dquo;injures self on pur- of sensory issues (two children). Motor activity levels ranged from pose&dquo; ; &dquo;seeks isolation from others&dquo;; &dquo;fixed facial expression, lacks almost immobile to constantly running around the room. Four emotional responsiveness&dquo;; &dquo;repetitive speech&dquo;; &dquo;repetitive hand, &dquo; children were hyperlexic, teaching themselves to read before 4 years body, or head movements&dquo;; &dquo;is difficult to reach, get through to.&dquo;

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These 58 items on the Aberrant Behavior Checklist are grouped into effect was evident across all six behavioral measures, it five categorical subscales as follows: Subscale I, Irritability and Self- was modest in amplitude: (1) for the placebo group, the aver- Abusive Behavior (15 items); Subscale II, Lethargy, Social With- age improvement was just 0.87 points, with a range from 0.32 drawal, and Withdrawal (16 items); Subscale III, Stereotypic for Aberrant Behavior Checklist Subscale V to 1.68 for the Behavior (7 items); Subscale IV, Hyperactivity (16 items); and Sub- 36 questions of the Vineland; (2) for the dimethylglycine scale V, Inappropriate Speech (4 items). These question items rate group, the average improvement was 0.71, with a range the severity of the behavioral problem across three levels such that from 0.06 for the Aberrant Behavior Checklist Subscale V a score of 0 indicates no problem and 3 indicates very severe. to 1.94 for the 16 questions of the Aberrant Behavior Check- Each subscale is scored as the sum of all items (eg, the maximum list Subscale II. However, there was no group by time inter- possible Aberrant Behavior Checklist Subscale II score equals 48, action (F(4,32) = 0.067, P < .7967), such that the overall ie, three times 16 questions), such that improvements are indicated improvement across all behavioral measures for the by a reduction in the subscale score. All statistics were performed dimethylglycine group was not different from the improve- on these sum scores for each subscale. ment for the placebo group. Data from the behavioral assessments were analyzed with Sta- To evaluate each of the behavioral measures, we per- tistical Analysis Software. formed one-tailed t-tests on the Vineland Maladaptive Behav- ior Domain and each of the Aberrant Behavior Checklist Neurologic Assessments Subscales I to V, based on the differences of the post- ver- A standardized general and neurologic examination was performed sus pretreatment assessment scores. Statistical analysis on 33 of the children (16 placebo and 17 dimethylglycine) by a pedi- showed no effects of dimethylglycine treatment on any of atric neurologist (V S.M.) at each visit. This examination included the behavioral measures. Although some of the children assessment of alertness, duration of eye contact, ability to follow appeared to improve over the 4 weeks of the study, the verbal and nonverbal commands, gait, strength, muscle tone, and improvements seen in the dimethylglycine group (58%) deep tendon reflexes. Fine motor skills were assessed by asking were not statistically significantly different from the placebo each child to stack building blocks and to draw simple geometric group (53%). Although one child was withdrawn for possi- figures such as a straight line, circle, and square. Running and ble adverse behavioral changes, no negative behavioral walking gaits were assessed. The examinations were performed in effects of dimethylglycine were noted by the examiner dur- as consistent a manner as possible across visits. ing the assessments. In fact, more children in the placebo group (32%) were reported to have negative effects than in Dimethylglycine and Dosage the treatment group (16%). These negative effects will be dis- Foil-wrapped dimethylglycine and placebo (mannitol) tablets, cussed in the section on parental reports. identical in appearance, were supplied by FoodScience Laborato- ries. The pharmacists at Children’s Medical Center of Dallas pack- Neurologic Assessments aged and labeled the tablets and were responsible for randomized The influence of dimethylglycine on neurologic status in chil- group assignments (dimethylglycine or placebo). The dosage used dren with autism/pervasive developmental disorder was 5 in the study was recommended by the Autism Research Institute.5 evaluated by comparing the pre- and post-treatment neu- Both placebo and dimethylglycine tablets were 125 mg each and rologic assessments. A chi-square statistic was computed were taken by mouth once every morning for 4 weeks. The dosage on the proportion of children in each group who improved. was as follows: one tablet for children weighing less than 40 lbs, We found that dimethylglycine treatment did not affect the two tablets for 41 to 70 lbs, three tablets for 71 to 100 lbs, four tablets neurologic status of these children (XI [1, N = 33] = 0.31, for 101 to 130 lbs, and five tablets for > 131 lbs. P < .57). However, three children in the dimethylglycine group did show improvement in gross motor function, one RESULTS with improved muscle tone, one with improved coordination, and one with less posturing and toe walking. This improve- Behavioral Assessments ment was not noted in any of the children in the placebo group. All five measures of the Aberrant Behavior Checklist were None of the children showed any adverse neurologic effects analyzed together as a three-factor analysis of variance: (1) due to either the placebo or the dimethylglycine treatment. post-treatment versus pretreatment assessment scores, (2) behavioral assessment measure (ie, Vineland Maladaptive Parental Reports Behavior Domain and Aberrant Behavior Checklist Sub- Of the 19 children who participated in the dimethylglycine scales I-V), and (3) dimethylglycine group versus placebo group, parents reported that 11 children (58%) responded group. Two of these factors were treated as repeated mea- positively to dimethylglycine, 3 children (16%) responded sures : (1) post- versus preassessments and (2) behavioral negatively (including the 1 child who discontinued due to measures. We found a main effect for post- versus pre- negative behavioral effects), and 5 children (26%) showed assessment scores (F(4,32) = 15.00, P < .0005). This indicates no response. Of the 19 children in the placebo group, par- that across all subjects (ie, placebo and treatment groups) ents reported that 10 children (53%) responded positively, and all behavioral measures, there was a significant improve- 6 children (32%) responded negatively, and 3 children (16%) ment over the duration of the experiment. Although this showed no response.

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Positive effects reported in the placebo and dimethyl- Table 1. Comparison of Dimethylglycine versus Placebo Pretreatment Scores on Each of the Behavioral Measures glycine groups were similar, such as (1) talking more; (2) more interested in others; (3) improved bowel and bladder control; (4) more &dquo;cuddly&dquo;; (5) less sensory defensiveness; (6) less resistant to change; (7) improved sleeping; (8) increase in vocabulary, use of sentences, and use of personal pronouns; (9) more interest in their immediate surroundings; (10) more responsive to their name; (11) more interactive; (12) increased ability to tolerate therapy; (13) decrease in Positive ivalues indicate dimethylglycine score exceeded placebo. MBD = Maladaptive Behavior Domain, ABC = Aberrant Behavior Checklist. or cessation in and frequency complete self-injury; (14) **Statistically significant. improved eating. Of these responses, an increased interest in others was the most predominant in the treatment group. Negative effects were reported by some parents of chil- mental disorder reveals abnormalities beyond the neuro- dren in the study and were similar in both the placebo and logic system. Nonspecific and variable abnormalities have treatment groups. These parental reports of negative effects been found in the immunologic system, digestive system, and included (1) increased activity (hyperactivity); (2) difficulty certain metabolic pathways. The variety and extent of abnor- sleeping; and/or (3) increased aggressiveness. In the dimethyl- mal biologic findings in autism/pervasive developmental glycine group, parents reported difficulty sleeping in one disorder combined with the variability of features and symp- child, increased aggressiveness in one child, and increased tomatology support the hypothesis that autism/pervasive activity (hyperactivity) in two children. In the placebo group, developmental disorder is not a single disorder, and descrip- parents reported increased aggressiveness in two children tive studies indicate that there are subtypes in autism that and increased activity (hyperactivity) in four children, two differ according to etiology. Heterogeneity regarding pathol- of whom also experienced sleeping problems. ogy makes finding effective treatments more difficult. Researchers have used various methods to subtype autism Group Differences and the broader pervasive developmental disorder class of Although the children who participated in this study were conditions,4 but, at present, no clear delineation has been a heterogeneous group, the dimethylglycine and placebo established, behavioral or biomedical. The varied apparent groups were not statistically significantly different on any response seen in this study may have been due to the het- of the pretreatment behavioral measures except for Subscale erogeneity of the group in regard to pathology. In this case, II of the Aberrant Behavior Checklist (Table 1). On this the results of the study may corroborate the hypothesis that measure of lethargy, the children who were randomly autism is not a single disorder in regard to pathology. assigned to the dimethylglycine group were more severely A number of studies in autism indicate abnormal affected than the children in the placebo group. Although immune function.27&dquo;1 Dimethylglycine has demonstrated there was an a priori difference by chance between the two significant immunologic effects in cell cultures, animals, and groups on this one of the six behavioral measures, there was humans. For example, Reap and Lawsonzl found that room for improvement among the children in the placebo dimethylglycine may have significant benefits to individu- group (the mean Aberrant Behavior Checklist Subscale II als with impaired immune systems. Further studies would pretreatment score was 6.2 in the placebo group and 14.8 be needed to determine if dimethylglycine has any effect on in the dimethylglycine group). The difference in the amount modulating immune parameters in persons with autism of improvement in this Aberrant Behavior Checklist Subscale with abnormal immune function. II between the dimethylglycine and placebo groups was not statistically significant (see Table 1; 0.95 points = 13.6% CONCLUSION improvement in the placebo group compared to 1.94 points = 15.3% improvement in the dimethylglycine group; t = 1.21, Dimethylglycine is promoted in health food stores as a [df = 35] P < .12). In addition, the dimethylglycine versus dietary supplement for athletes and persons with autism/per- placebo difference decreased as the dimethylglycine subjects vasive developmental disorder. Anecdotal reports indicate with the highest Aberrant Behavior Checklist Subscale II pre- that many parents of children with autism supplement their treatment scores were eliminated from this t-test analysis child’s diet with dimethylglycine in the hope of improving to equalize the pretreatment group means. the child’s condition. The children in this study were a het- erogeneous group, and their apparent responses to the DISCUSSION dimethylglycine varied. Some of the children were reported by their parents to respond positively to dimethylglycine; oth- Autism/pervasive developmental disorder is a neurologic ers were reported to show no response or were reported to disorder of unknown etiology. Whether the neurologic sys- respond negatively. As mentioned earlier, more children tem is the system of origin or whether the neurologic prob- were reported to have negative side effects from the placebo lems are a result of a malfunction in another system is than the dimethylglycine. Neither examiner noted any neg- unclear. Biologic research in autism/pervasive develop- ative effects from the dimethylglycine or the placebo.

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We conclude that in a heterogeneous group of children betaines as liposome cryoprotectants. J Pharm Pharmacol 1992;44:507-511. with a diagnosis of autism/pervasive developmental disor- 21. Lawson J: Stimulation of the immune by dimethyl- der, the effect of dimethylglycine was not statistically sig- Reap E, system glycine, a nontoxic metabolite. J Lab Clin Med 1990;115:481-486. nificantly different from the placebo. It is unclear the extent 22. Graber CD, Goust JM, Glassman AD, et al: Immunomodulating to which the of the children lessened the heterogeneity properties of dimethylglycine in humans. J Infect Dis power in statistical analyses. 1981;143:101-105. 23. Gascon G, Patterson B, Yearwood K, Slotnick H: N,N-dimethyl- References glycine and . Epilepsia 1989;30:90-93. 1. Bryson SE, Clark BS, Smith IM: First report of a Canadian epi- 24. Sparrow S, Balla D, Cicchetti D: Vineland Adaptive Behavior demiological study of autistic syndromes. J Child Psychol Psy- Scales. Circle Pines, MN, American Guidance Service, 1994. chiatry 1988;29:433-446. 25. Aman M, Singh N: Aberrant Behavior Checklist. New York, Slos- 2. Sugiyama T, Abe T: The prevalence of autism in Nagoya, Japan: son Educational Publications, 1986. A total population study. J Autism Dev Disord 1989;19:87-96. 26. Horvath K, Stefanatos G, Sokolski KN, et al: Improved social and 3. American Psychiatric Association: Diagnostic and statistical language skills after secretin administration in patients with autis- manual of mental disorders, 2nd ed. Washington, DC, APA, 1994. tic spectrum disorders. J Assoc Acad Minor Phys 1998;9:9-15. 4. Cohen D, Volkmar F: Autism and Pervasive Developmental Dis- 27. Daniels WW, Warren RP, Odell JD, et al: Increased frequency of orders, 2nd ed. New York, John Wiley & Sons, 1997. the extended or ancestral haplotype B44-SC30-DR4 in autism. 5. Rimland B: Dimethylglycine (DMG), a nontoxic metabolite, and Neuropsychobiology 1995;32:120-123. autism. Autism Res Rev Int 1996;4(2):3. 28. Plioplys AV, Greaves A, Kazem K, Silverman E: Lymphocyte func- 6. Balch JF, Balch PA: Nutritional Healing. Garden City Park, NY: tion in autism and . Neuropsychobiology Avery, 1997. 1994;7:49-55. 7. Zubay G: Biochemistry. Reading, MA, Addison-Wesley, 1983. 29. Singh VK, Fudenberg HH, Emerson D, Coleman M: Immunodi- agnosis and immunotherapy in autistic children. Ann N YAcad 8. Meduski J, Hyman S, Kitz R, Kim S: Decrease of lactic acid con- Sci 1988;540:602-604. centration of animals given N,N-dimethylglycine, in Pacific Slope 30. Warren Odell et al: Antibodies to basic Conference Abstracts. Los Angeles, Department of Biological Singh VK, RP, JD, myelin in children with autistic behavior. Brain Behav Immun Sciences and School of Medicine, University of Southern California, protein July 1980. 1993;7:97-103. 31. Singh VK, Warren RP, Odell JD, Cole P: Changes of soluble inter- 9. Livine S, Myhre G, Smith G, Bums J: Effect of nutritional sup- leukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in plement containing N,N-dimethylglycine (DMG) on the racing the serum of autistic children. Clin Immunol standard bred. Equine Pract 1982;4:16-18. Immunopathol 1991;61:448-455. 10. Roach E, Carlin L: N,N-dimethylglycine for epilepsy. N Engl JMed 32. Warren Odell et al: Decreased concen- 1982;307:1081-1082. RP, Burger RA, D, plasma trations of the C4B complement protein in autism. Arch Pediatr 11. Kendall R: Gluconic N,N-dimethylglycine (DMG). Essex Junc- Adolesc Med 1994;148:180-183. tion, VT, DaVinci Laboratories, 1982. 33. Warren RP, Margaretten NC, Pace NC, Foster A: Immune abnor- 12. Freed WJ: N,N-dimethylglycine, betaine, and seizures. Arch Neu- malities in patients with autism. J Autism Dev Disord rol 1984;41:1129-1130. 1986;16:189-197. 13. Freed WJ, Gillin JC, Wyatt RJ: Anticonvulsant properties of 34. Warren RP, Foster A, Margaretten NC: Reduced natural killer cell betaine. Epilepsia 1979;20:209-213. activity in autism. J Am Acad Child Adolesc Psychiatry 14. Ward TN, Smith EB, Reeves AG: Dimethylglycine and reduction 1987;26:333-335. of mortality in penicillin induced seizures. Ann Neurol 1985;17:213. 35. Warren RP, Singh VK, Cole P, et al: Possible association of the 15. Otto A, Stotz M, Sailer HP, Brandsch R: Biogenesis of the cova- extended MHC haplotype B44-SC30-DR4 with autism. Immuno- lently flavinated mitochondrial enzyme dimethylglycine dehy- genetics 1992;36:203-207. drogenase. J Biol Chem 1996;271:9823-9829. 36. Warren RP, Yonk LJ, Burger RA, et al: Deficiency of suppressor- 16. Laryea MD, Zass R, Ritgen J, et al: Simultaneous determination inducer (CD4+CD45RA+) T cells in autism. Immunol Invest of betaine and N,N-dimethylglycine in urine. Clin Chim Acta 1990;19:245-251. 1994;230:169-175. 37. Warren RP, Yonk J, Burger RW, et al: DR-positive T cells in autism: 17. Lang H, Minaian K, Freudenberg N, et al: Tissue specificity of rat Association with decreased plasma levels of the complement mitochondrial dimethylglycine dehydrogenase expression. C4B protein. Neuropsychobiology 1995;31:53-57. Biochem J 1994;299(pt 2):393-398. 38. Weizman A, Weizman R, Szekely GA, et al: Abnormal immune 18. Allen RH, Stabler SP, Lindenbaum J: Serum betaine, N,N-dimethyl- response to brain tissue antigen in the syndrome of autism. Am glycine and N-methylglycine levels in patients with cobalamin and J Psychiatry 1982;139:1462-1465. folate deficiency and related inborn errors of metabolism. Metab 39. Westheimer G, Blair SM: Functional organization of primate ocu- Clin Exp 1993;42:1448-1460. lomotor system revealed by cerebellectomy. Exp Brain Res 19. Dudman NP, Wilcken DE, Wang J, et al: Disordered methion- 1974;21:463-472. ine/homocysteine metabolism in premature vascular disease. Its 40. Warren RP, Yonk LJ, Burger RA, et al: Deficiency of suppressor- occurrence, cofactor therapy, and enzymology. Arterioscler inducer (CD4+CD45RA+) T cells in autism. Immunol Invest Thromb 1993;13:1253-1260. 1990; 19:245-251. 20. Lloyd AW, Baker JA, Smith G, et al: A comparison of glycine, sar- 41. Yonk LJ, Warren RP, Burger RA, et al: CD4+ helper T cell depres- cosine, N,N-dimethylglycine, glycinebetaine and N-modified sion in autism. Immunol Lett 1990;25:341-346.

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