Top

Journal of Autism and Developmental Disorders

Gepubliceerd in:

05-05-2021 | Original Paper

A Meta-analysis of Gut Microbiota in Children with Autism

Auteurs: Pedro Andreo-Martínez, María Rubio-Aparicio, Julio Sánchez-Meca, Alejandro Veas, Agustín Ernesto Martínez-González

Gepubliceerd in: Journal of Autism and Developmental Disorders | Uitgave 3/2022

Abstract

Previous studies have reported dysbiosis in the gut microbiota (GM) of children with autism spectrum disorders (ASD), which may be a determining factor on child development through the microbiota-gut-brain axis. However, it is not clear if there is a specific group of dysbiotic bacteria in ASD. The aim of this study was to carry out a meta-analysis on the studies that analyze GM in children with ASD. 18 studies fulfilled our selection criteria. Our results showed a lower relative abundance of Streptococcus (SMD₊ = − 0.999; 95% CI − 1.549, − 0.449) and Bifidobacterium genera (SMD₊ = − 0.513; 95% CI − 0.953, − 0.073) in children with ASD. Overall, the Bifidobacterium genera is involved. However, differences found between studies are attributed to factors such as reporting bias.

vorige artikel Characterizing Social Functioning in School-Age Children with Sensory Processing Abnormalities

volgende artikel Brief Report: Examining Test-Retest Reliability of the Autism Diagnostic Observation Schedule (ADOS-2) Calibrated Severity Scores (CSS)

Alleen toegankelijk voor geautoriseerde gebruikers

Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism—Comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11(22), 1–13. https://doi.org/10.1186/1471-230x-11-22.CrossRef

Andreo-Martínez, P., García-Martínez, N., Sánchez-Samper, E. P., & Martínez-González, A. E. (2019). An approach to gut microbiota profile in children with autism spectrum disorder. Environmental Microbiology Reports, 12(2), 115–135. https://doi.org/10.1111/1758-2229.12810.CrossRefPubMed

APA. (2013). American Psychiatric Association. Autism spectrum disorder. In Diagnostic and statistical manual of mental disorders, 5 Eds (DSM-5). American Psychiatric Publishing.

Baj, J., Sitarz, E., Forma, A., Wróblewska, K., & Karakuła-Juchnowicz, H. (2020). Alterations in the nervous system and gut microbiota after β-hemolytic Streptococcus group A infection—Characteristics and diagnostic criteria of PANDAS recognition. International Journal of Molecular Sciences, 21(4), 1476. https://doi.org/10.3390/ijms21041476.CrossRefPubMedCentral

Bonnet-Brilhault, F., Rajerison, T. A., Paillet, C., Guimard-Brunault, M., Saby, A., Ponson, L., Tripi, G., Malvy, J., & Roux, S. (2018). Autism is a prenatal disorder: Evidence from late gestation brain overgrowth. Autism Research, 11(12), 1635–1642. https://doi.org/10.1002/aur.2036.CrossRefPubMed

Borenstein, M. (2019). Common mistakes in meta-analysis and how to avoid them. Englewood, NJ: Biostat Inc.

Borenstein, M., Hedges, L. V., Higgins, J. P. T., & Rothstein, H. R. (2009). Introduction to meta-analysis. Wiley.CrossRef

Bridgemohan, C., Cochran, D. M., Howe, Y. J., Pawlowski, K., Zimmerman, A. W., Anderson, G. M., Choueiri, R., Sices, L., Miller, K. J., Ultmann, M., & Helt, J. (2019). Investigating potential biomarkers in autism spectrum disorder. Frontiers in Integrative Neuroscience, 13, 31. https://doi.org/10.3389/fnint.2019.00031.CrossRefPubMedPubMedCentral

Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). 12 Lawrence Erlbaum Associates Inc.

Cooper, H., Hedges, L. V., & Valentine, J. C. (2019). The handbook of research synthesis and meta-analysis. Russell Sage Foundation.CrossRef

Coretti, L., Paparo, L., Riccio, M. P., Amato, F., Cuomo, M., Natale, A., Borrelli, L., Corrado, G., De Caro, C., Comegna, M., & Buommino, E. (2018). Gut microbiota features in young children with autism spectrum disorders. Frontiers in Microbiology, 9, 3146. https://doi.org/10.3389/fmicb.2018.03146.CrossRefPubMedPubMedCentral

Da Silva, H. D., & Winkelströter, L. K. (2019). Universal gestational screening for Streptococcus agalactiae colonization and neonatal infection—A systematic review and meta-analysis. Journal of Infection and Public Health, 12(4), 479–481. https://doi.org/10.1016/j.jiph.2019.03.004.CrossRefPubMed

Dall’Aglio, L., Muka, T., Cecil, C. A. M., Bramer, W. M., Verbiest, M., Nano, J., Hidalgo, A. C., Franco, O. H., & Tiemeier, H. (2018). The role of epigenetic modifications in neurodevelopmental disorders: A systematic review. Neuroscience & Biobehavioral Reviews, 94, 17–30. https://doi.org/10.1016/j.neubiorev.2018.07.011.CrossRef

De Angelis, M., Piccolo, M., Vannini, L., Siragusa, S., De Giacomo, A., Serrazzanetti, D. I., Cristofori, F., Guerzoni, M. E., Gobbetti, M., & Francavilla, R. (2013). Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PloS One, 8(10), e76993. https://doi.org/10.1371/journal.pone.0076993.CrossRefPubMedPubMedCentral

Diaz Heijtz, R. (2016). Fetal, neonatal, and infant microbiome: Perturbations and subsequent effects on brain development and behavior. Seminars in Fetal and Neonatal Medicine, 21(6), 410–417. https://doi.org/10.1016/j.siny.2016.04.012.CrossRefPubMed

Ding, H. T., Taur, Y., & Walkup, J. T. (2017). Gut microbiota and autism: Key concepts and findings. Journal of Autism and Developmental Disorders, 47(2), 480–489. https://doi.org/10.1007/s10803-016-2960-9.CrossRefPubMed

Duval, S., & Tweedie, R. (2000). Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics, 56(2), 455–463. https://doi.org/10.1111/j.0006-341x.2000.00455.x.CrossRef

Finegold, S. M., Dowd, S. E., Gontcharova, V., Liu, C., Henley, K. E., Wolcott, R. D., Youn, E., Summanen, P. H., Granpeesheh, D., Dixon, D., & Liu, M. (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16(4), 444–453. https://doi.org/10.1016/j.anaerobe.2010.06.008.CrossRefPubMed

Finegold, S. M., Summanen, P. H., Downes, J., Corbett, K., & Komoriya, T. (2017). Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children. Anaerobe, 45, 133–137. https://doi.org/10.1016/j.anaerobe.2017.02.008.CrossRefPubMed

Haas, K. N., & Blanchard, J. L. (2017). Kineothrix alysoides, gen. nov., sp. nov., a saccharolytic butyrate-producer within the family Lachnospiraceae. International Journal of Systematic and Evolutionary Microbiology, 67(2), 402–410. https://doi.org/10.1099/ijsem.0.001643.CrossRefPubMed

Hartung, J. (1999). An Alternative method for meta-analysis. Biometrical Journal, 41(8), 901–916. https://doi.org/10.1002/(sici)1521-4036(199912)41:8%3c901::aid-bimj901%3e3.0.co;2-w.CrossRef

Hedges, L., & Olkin, I. (1985). Statistical methods for meta-analysis. Academic Press.

Herd, P., Palloni, A., Rey, F., & Dowd, J. B. (2018). Social and population health science approaches to understand the human microbiome. Nature Human Behaviour, 2(11), 808–815. https://doi.org/10.1038/s41562-018-0452-y.CrossRefPubMedPubMedCentral

Heuer, L. S., Croen, L. A., Jones, K. L., Yoshida, C. K., Hansen, R. L., Yolken, R., Zerbo, O., DeLorenze, G., Kharrazi, M., Ashwood, P., & Van de Water, J. (2019). An exploratory examination of neonatal cytokines and chemokines as predictors of autism risk: The early markers for autism study. Biological Psychiatry, 86(4), 255–264. https://doi.org/10.1016/j.biopsych.2019.04.037.CrossRefPubMedPubMedCentral

Huedo-Medina, T. B., Sanchez-Meca, J., Marin-Martinez, F., & Botella, J. (2006). Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychological Methods, 11(2), 193–206. https://doi.org/10.1037/1082-989x.11.2.193.CrossRefPubMed

Iglesias-Vázquez, L., van Ginkel Riba, G., Arija, V., & Canals, J. (2020). Composition of gut microbiota in children with autism spectrum disorder: A systematic review and meta-analysis. Nutrients, 12, 792. https://doi.org/10.3390/nu12030792.CrossRefPubMedCentral

Inoue, R., Sakaue, Y., Sawai, C., Sawai, T., Ozeki, M., Romero-Perez, G. A., & Tsukahara, T. (2016). A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism spectrum disorders. Bioscience, Biotechnology, and Biochemistry, 80(12), 2450–2458. https://doi.org/10.1080/09168451.2016.1222267.CrossRefPubMed

Iovene, M. R., Bombace, F., Maresca, R., Sapone, A., Iardino, P., Picardi, A., Marotta, R., Schiraldi, C., Siniscalco, D., Serra, N., & de Magistris, L. (2017). Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia, 182(3–4), 349–363. https://doi.org/10.1007/s11046-016-0068-6.CrossRefPubMed

Jiang, H. Y., Zhang, X., Yu, Z. H., Zhang, Z., Deng, M., Zhao, J. H., & Ruan, B. (2018). Altered gut microbiota profile in patients with generalized anxiety disorder. Journal of Psychiatric Research, 104, 130–136. https://doi.org/10.1016/j.jpsychires.2018.07.007.CrossRefPubMed

Kang, D. W., Park, J. G., Ilhan, Z. E., Wallstrom, G., Labaer, J., Adams, J. B., & Krajmalnik-Brown, R. (2013). Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PloS One, 8(7), e68322. https://doi.org/10.1371/journal.pone.0068322.CrossRefPubMedPubMedCentral

Kang, D.-W., Ilhan, Z. E., Isern, N. G., Hoyt, D. W., Howsmon, D. P., Shaffer, M., Lozupone, C. A., Hahn, J., Adams, J. B., & Krajmalnik-Brown, R. (2018). Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe, 49, 121–131. https://doi.org/10.1016/j.anaerobe.2017.12.007.CrossRefPubMed

Knapp, G., & Hartung, J. (2003). Improved tests for a random effects meta-regression with a single covariate. Statistics in Medicine, 22, 2693–2710. https://doi.org/10.1002/sim.1482.CrossRefPubMed

Krajmalnik-Brown, R., Lozupone, C., Kang, D.-W., & Adams, J. B. (2015). Gut bacteria in children with autism spectrum disorders: Challenges and promise of studying how a complex community influences a complex disease. Microbial Ecology in Health and Disease, 26, 26914. https://doi.org/10.3402/mehd.v26.26914.CrossRefPubMed

Kumar, H., Lund, R., Laiho, A., Lundelin, K., Ley, R. E., Isolauri, E., & Salminen, S. (2014). Gut microbiota as an epigenetic regulator: Pilot study based on whole-genome methylation analysis. MBio, 5(6), e02113–e02114. https://doi.org/10.1128/mBio.02113-14.CrossRefPubMedPubMedCentral

Lopez-Lopez, J. A., Marin-Martinez, F., Sanchez-Meca, J., Van den Noortgate, W., & Viechtbauer, W. (2014). Estimation of the predictive power of the model in mixed-effects meta-regression: A simulation study. The British Journal of Mathematical and Statistical Psychology, 67(1), 30–48. https://doi.org/10.1111/bmsp.12002.CrossRefPubMed

Ma, B., Liang, J., Dai, M., Wang, J., Luo, J., Zhang, Z., & Jing, J. (2019). Altered gut microbiota in Chinese children with autism spectrum disorders. Frontiers in Cellular and Infection Microbiology, 9, 40–40. https://doi.org/10.3389/fcimb.2019.00040.CrossRefPubMedPubMedCentral

Martínez-González, A. E., & Andreo-Martínez, P. (2019). The role of gut microbiota in gastrointestinal symptoms of children with ASD. Medicina, 55(8), 408. https://doi.org/10.3390/medicina55080408.CrossRefPubMedCentral

Martínez-González, A. E., & Andreo-Martínez, P. (2020a). Prebiotics, probiotics and fecal microbiota transplantation in autism: A systematic review. Revista de Psiquiatría y Salud Mental, 13(3), 150–164. https://doi.org/10.1016/j.rpsm.2020.06.002.CrossRefPubMed

Martínez-González, A. E., & Andreo-Martínez, P. (2020b). Una propuesta de probiótico basada en el bifidobacterium para el autismo. Revista Archivos Latinoamericanos de Nutrición, 70(4).

Mayer, E. A., Labus, J., Aziz, Q., Tracey, I., Kilpatrick, L., Elsenbruch, S., Schweinhardt, P., Van Oudenhove, L., & Borsook, D. (2019). Role of brain imaging in disorders of brain–gut interaction: A Rome Working Team Report. Gut, 68(9), 1701–1715. https://doi.org/10.1136/gutjnl-2019-318308%JGut.CrossRefPubMed

McElhanon, B. O., McCracken, C., Karpen, S., & Sharp, W. G. (2014). Gastrointestinal symptoms in autism spectrum disorder: A meta-analysis. Pediatrics, 133(5), 872–883. https://doi.org/10.1542/peds.2013-3995.CrossRefPubMed

Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & Group, a. t. P. (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Annals of Internal Medicine, 151(4), 264–269. https://doi.org/10.7326/0003-4819-151-4-200908180-00135.CrossRefPubMed

Moya-Pérez, A., Perez-Villalba, A., Benítez-Páez, A., Campillo, I., & Sanz, Y. (2017). Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice. Brain, Behavior, and Immunity, 65, 43–56. https://doi.org/10.1016/j.bbi.2017.05.011.CrossRefPubMed

Niu, M., Li, Q., Zhang, J., Wen, F., Dang, W., Duan, G., Li, H., Ruan, W., Yang, P., Guan, C., & Tian, H. (2019). Characterization of intestinal microbiota and probiotics treatment in children with autism spectrum disorders in China. Frontiers in Neurology, 10, 1084–1084. https://doi.org/10.3389/fneur.2019.01084.CrossRefPubMedPubMedCentral

Oh, M., Kim, S. A., & Yoo, H. J. (2020). Higher lactate level and lactate-to-pyruvate ratio in autism spectrum disorder. Experimental Neurobiology, 29(4), 314. https://doi.org/10.5607/en20030.CrossRefPubMedPubMedCentral

Ooi, Y. P., Weng, S. J., Kossowsky, J., Gerger, H., & Sung, M. (2017). Oxytocin and autism spectrum disorders: A systematic review and meta-analysis of randomized controlled trials. Pharmacopsychiatry, 50(1), 5–13. https://doi.org/10.1055/s-0042-109400.CrossRefPubMed

Parracho, H. M., Bingham, M. O., Gibson, G. R., & McCartney, A. L. (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology, 54(Pt 10), 987–991. https://doi.org/10.1099/jmm.0.46101-0.CrossRefPubMed

Plaza-Díaz, J., Gómez-Fernández, A., Chueca, N., Torre-Aguilar, M. J. D. L., Gil, Á., Perez-Navero, J. L., Flores-Rojas, K., Martín-Borreguero, P., Solis-Urra, P., Ruiz-Ojeda, F. J., & Garcia, F. (2019). Autism spectrum disorder (ASD) with and without mental regression is associated with changes in the fecal microbiota. Nutrients, 11(2), 337. https://doi.org/10.3390/nu11020337.CrossRefPubMedCentral

Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Molecular Psychiatry, 17, 290. https://doi.org/10.1038/mp.2010.136.CrossRefPubMed

Rothstein, H. R., Sutton, A. J., & Borenstein, M. (2005). Publication bias in meta-analysis: Prevention, assessment and adjustments. Willey.CrossRef

Rubio-Aparicio, M., López-López, J., Viechtbauer, W., Marín-Martínez, F., Botella, J., & Sanchez-Meca, J. (2019). Testing categorical moderators in mixed-effects meta-analysis in the presence of heteroscedasticity. The Journal of Experimental Education, 88, 288–310. https://doi.org/10.1080/00220973.2018.1561404.CrossRef

Rücker, G., & Schumacher, M. (2008). Simpson’s paradox visualized: The example of the rosiglitazone meta-analysis. BMC Medical Research Methodology, 8(1), 1–8.CrossRef

Sánchez-Meca, J., & Marín-Martínez, F. (2008). Confidence intervals for the overall effect size in random-effects meta-analysis. Psychological Methods, 13(1), 31–48. https://doi.org/10.1037/1082-989X.13.1.31.CrossRefPubMed

Sanchez-Meca, J., Marin-Martinez, F., & Chacon-Moscoso, S. (2003). Effect-size indices for dichotomized outcomes in meta-analysis. Psychological Methods, 8(4), 448–467. https://doi.org/10.1037/1082-989x.8.4.448.CrossRefPubMed

Shaaban, S. Y., El Gendy, Y. G., Mehanna, N. S., El-Senousy, W. M., El-Feki, H. S. A., Saad, K., & El-Asheer, O. M. (2017). The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutritional Neuroscience, 21(9), 1–6. https://doi.org/10.1080/1028415x.2017.1347746.CrossRef

Sharp, W. G., Berry, R. C., McCracken, C., Nuhu, N. N., Marvel, E., Saulnier, C. A., Klin, A., Jones, W., & Jaquess, D. L. (2013). Feeding problems and nutrient intake in children with autism spectrum disorders: A meta-analysis and comprehensive review of the literature. Journal of Autism and Developmental Disorders, 43(9), 2159–2173. https://doi.org/10.1007/s10803-013-1771-5.CrossRefPubMed

Vallée, A., & Vallée, J.-N. (2018). Warburg effect hypothesis in autism Spectrum disorders. Molecular Brain, 11(1), 1. https://doi.org/10.1186/s13041-017-0343-6.CrossRefPubMedPubMedCentral

Viechtbauer, W. (2010). Conducting meta-analyses in R with the metafor package. Journal of Statistical Software, 36, 1–48. https://doi.org/10.18637/jss.v036.i03.CrossRef

Vuong, H. E., & Hsiao, E. Y. (2017). Emerging roles for the gut microbiome in autism spectrum disorder. Biological Psychiatry, 81(5), 411–423. https://doi.org/10.1016/j.biopsych.2016.08.024.CrossRefPubMed

Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2011). Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Applied and Environmental Microbiology, 77(18), 6718–6721. https://doi.org/10.1128/aem.05212-11.CrossRefPubMedPubMedCentral

Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2013). Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Molecular Autism, 4, 42. https://doi.org/10.1186/2040-2392-4-42.CrossRefPubMedPubMedCentral

Wang, S., Harvey, L., Martin, R., van der Beek, E. M., Knol, J., Cryan, J. F., & Renes, I. B. (2018). Targeting the gut microbiota to influence brain development and function in early life. Neuroscience & Biobehavioral Reviews, 95, 191–201. https://doi.org/10.1016/j.neubiorev.2018.09.002.CrossRef

Wells, G. A., Shea, B., O’Connell, D. A., Peterson, J., Welch, V., Losos, M., & Tugwell, P. (2000). The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute. http://www3.med.unipmn.it/dispense_ebm/2009-2010/Corso%20Perfezionamento%20EBM_Faggiano/NOS_oxford.pdf

Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I., Bennett, A., Jabado, O., Hirschberg, D. L., & Lipkin, W. I. (2011). Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PloS One, 6(9), e24585. https://doi.org/10.1371/journal.pone.0024585.CrossRefPubMedPubMedCentral

Williams, B. L., Hornig, M., Parekh, T., & Lipkin, W. I. (2012). Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. MBio, 3(1), e00261–00211. https://doi.org/10.1128/mBio.00261-11.CrossRef

Wu, W., Kong, Q., Tian, P., Zhai, Q., Wang, G., Liu, X., Zhao, J., Zhang, H., Lee, Y. K., & Chen, W. (2020). Targeting gut microbiota dysbiosis: Potential intervention strategies for neurological disorders. Engineering. https://doi.org/10.1016/j.eng.2019.07.026.CrossRefPubMed

Xu, M., Xu, X., Li, J., & Li, F. (2019). Association between gut microbiota and autism spectrum disorder: A systematic review and meta-analysis. Frontiers in Psychiatry, 10, 473. https://doi.org/10.3389/fpsyt.2019.00473.CrossRefPubMedPubMedCentral

Zhang, M., Ma, W., Zhang, J., He, Y., & Wang, J. (2018). Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China. Scientific Reports, 8(1), 13981–13981. https://doi.org/10.1038/s41598-018-32219-2.CrossRefPubMedPubMedCentral

Titel: A Meta-analysis of Gut Microbiota in Children with Autism
Auteurs: Pedro Andreo-Martínez
María Rubio-Aparicio
Julio Sánchez-Meca
Alejandro Veas
Agustín Ernesto Martínez-González
Publicatiedatum: 05-05-2021
Uitgeverij: Springer US
Gepubliceerd in: Journal of Autism and Developmental Disorders / Uitgave 3/2022
Print ISSN: 0162-3257
Elektronisch ISSN: 1573-3432
DOI: https://doi.org/10.1007/s10803-021-05002-y

Bohn Stafleu van Loghum

Deel dit onderdeel of sectie (kopieer de link)

Abstract

Log in om toegang te krijgen

Andere artikelen Uitgave 3/2022

Alcohol and Tobacco use While Breastfeeding and Risk of Autism Spectrum Disorder or Attention Deficit/Hyperactivity Disorder

Brief Report: Examining Test-Retest Reliability of the Autism Diagnostic Observation Schedule (ADOS-2) Calibrated Severity Scores (CSS)

The Effect of Physical Activity Interventions on Executive Function Among People with Neurodevelopmental Disorders: A Meta-Analysis

The Feasibility of Magnetic Resonance Imaging in a Non-Selective Comprehensive Clinical Trial in Pediatric Autism Spectrum Disorder

Brief Report: Prevalence and Severity of Auditory Sensory Over-Responsivity in Autism as Reported by Parents and Caregivers

Health-Related Quality of Life in Pediatric Patients with Syndromic Autism and their Caregivers