Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

BioEssays

Volumn 39, Issue 8, 2017, Pages

  Beaudet, Arthur L ^a  

^a TEXAS CHILDREN S HOSPITAL   (United States)

Author keywords

autism; blood brain barrier; carnitine; diet; epigenetic; gene environment; inborn errors of metabolism; microbiome; sex ratio

Indexed keywords

CARNITINE;

AMINO ACID SYNTHESIS; AUTISM; BRAIN; BREAST FEEDING; CARNITINE DEFICIENCY; DIETARY REFERENCE INTAKE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; FEEDING; GENE; GENETIC RISK; HUMAN; HYPOTHESIS; KNOWLEDGE; MEAT; NONHUMAN; NUTRIENT; NUTRITIONAL STATUS; PREVALENCE; REVIEW; RISK ASSESSMENT; RISK FACTOR; SEX DIFFERENCE; SYMPTOM; BLOOD BRAIN BARRIER; CARDIOMYOPATHY; COMPLICATION; DEFICIENCY; FEMALE; HYPERAMMONEMIA; INBORN ERROR OF METABOLISM; MALE; METABOLISM; MICROFLORA; MUSCLE DISEASE; PATHOLOGY; PHYSIOLOGY; SEX FACTOR;

AUTISTIC DISORDER; BLOOD-BRAIN BARRIER; BRAIN; CARDIOMYOPATHIES; CARNITINE; FEMALE; HUMANS; HYPERAMMONEMIA; MALE; METABOLISM, INBORN ERRORS; MICROBIOTA; MUSCULAR DISEASES; SEX FACTORS;

EID: 85023648121     PISSN: 02659247     EISSN: 15211878     Source Type: Journal    
DOI: 10.1002/bies.201700012     Document Type: Review

References (110)

1. Celestino-Soper PB, Violante S, Crawford EL, Luo R, et al. 2012. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci USA 109: 7974–81.
2. Maestrini E, Paul A, Monaco AP, Bailey A. 2000. Identifying autism susceptibility genes. Neuron 28: 19–24.
3. Risch N, Spiker D, Lotspeich L, Nouri N, et al. 1999. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 65: 493–507.
4. Sebat J, Lakshmi B, Malhotra D, Troge J, et al. 2007. Strong association of de novo copy number mutations with autism. Science 316: 445–9.
5. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, et al. 2014. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515: 216–21.
6. Ronemus M, Iossifov I, Levy D, Wigler M. 2014. The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet 15: 133–41.
7. Miles JH, Hillman RE. 2000. Value of a clinical morphology examination in autism. Am J Med Genet 91: 245–53.
8. Ziats MN, Comeaux MS, Yang Y, Scaglia F, et al. 2015. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A 167A: 2496.
9. Xie Z, Jones A, Deeney JT, Hur SK, et al. 2016. Inborn errors of long-chain fatty acid beta-oxidation link neural stem cell self-renewal to autism. Cell Rep 14: 991–9.
10. Garber K. 2007. Neuroscience. Autism's cause may reside in abnormalities at the synapse. Science 317: 190–1.
11. Bouitbir J, Haegler P, Singh F, Joerin L, et al. 2016. Impaired exercise performance and skeletal muscle mitochondrial function in rats with secondary carnitine deficiency. Front Physiol 7: 345.
12. Lombard J. 1998. Autism: a mitochondrial disorder? Med Hypotheses 50: 497–500.
13. Filipek PA, Juranek J, Nguyen MT, Cummings C, et al. 2004. Relative carnitine deficiency in autism. J Autism Dev Disord 34: 615–23.
14. Mostafa GA, El-Gamal HA, El-Wakkad ASE, El-Shorbagy OE, et al. 2005. Polyunsaturated fatty acids, carnitine and lactate as biological markers of brain energy in autistic children. Int J Child Neuropsychiatry 2: 179–88.
15. Mostafa GA, Al-Ayadhi LY. 2015. Reduced levels of plasma polyunsaturated fatty acids and serum carnitine in autistic children: relation to gastrointestinal manifestations. Behav Brain Funct 11: 4.
16. Wrottesley SV, Lamper C, Pisa PT. 2016. Review of the importance of nutrition during the first 1000 days: maternal nutritional status and its associations with fetal growth and birth, neonatal and infant outcomes among African women. J Dev Orig Health Dis 7: 144–62.
17. Martins Y, Young RL, Robson DC. 2008. Feeding and eating behaviors in children with autism and typically developing children. J Autism Dev Disord 38: 1878–87.
18. El-Hattab AW, Li FY, Shen J, Powell BR, et al. 2010. Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genet Med 12: 19–24.
19. Lee NC, Tang NL, Chien YH, Chen CA, et al. 2010. Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. Mol Genet Metab 100: 46–50.
20. Fujiwara T, Morisaki N, Honda Y, Sampei M, et al. 2016. Chemicals, nutrition, and autism spectrum disorder: a mini-Review. Front Neurosci 10: 174.
21. Meguid NA, Atta HM, Gouda AS, Khalil RO. 2008. Role of polyunsaturated fatty acids in the management of Egyptian children with autism. Clin Biochem 41: 1044–8.
22. Brigandi SA, Shao H, Qian SY, Shen Y, et al. 2015. Autistic children exhibit decreased levels of essential fatty acids in red blood cells. Int J Mol Sci 16: 10061–76.
23. Jory J. 2016. Abnormal fatty acids in Canadian children with autism. Nutrition 32: 474–7.
24. Tesei A, Crippa A, Ceccarelli SB, Mauri M, et al. 2016. The potential relevance of docosahexaenoic acid and eicosapentaenoic acid to the etiopathogenesis of childhood neuropsychiatric disorders. Eur Child Adolesc Psychiatry in press https://doi.org/10.1007/s00787-016-0932-4
25. Sprecher H. 1996. New advances in fatty-acid biosynthesis. Nutrition 12: S5–7.
26. Werling DM, Geschwind DH. 2013. Sex differences in autism spectrum disorders. Curr Opin Neurol 26: 146–53.
27. Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, et al. 2011. Why are autism spectrum conditions more prevalent in males? PLoS Biol 9: e1001081.
28. Baron-Cohen S, Knickmeyer RC, Belmonte MK. 2005. Sex differences in the brain: implications for explaining autism. Science 310: 819–23.
29. Zhao X, Leotta A, Kustanovich V, Lajonchere C, et al. 2007. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 104: 12831–6.
30. Levy D, Ronemus M, Yamrom B, Lee YH, et al. 2011. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70: 886–97.
31. 0,+) in the blood-brain barrier. Biochem Biophys Res Commun 376: 267–70.
32. 0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. J Biol Chem 286: 31830–8.
33. Kekuda R, Torres-Zamorano V, Fei YJ, Prasad PD, et al. 1997. Molecular and functional characterization of intestinal Na(+)-dependent neutral amino acid transporter B0. Am J Physiol 272: G1463–72.
34. 0,+ from mouse colon expressed in HRPE cells and Xenopus oocytes. J Physiol 532: 297–304.
35. 0,+ in the transport of carnitine through an in vitro model of the blood-brain barrier. J Neurochem 91: 860–72.
36. Okura T, Kato S, Deguchi Y. 2014. Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model. Drug Metab Pharmacokinet 29: 69–74.
37. Szilagyi M. 1998. L-carnitine as essential methylated compound in animal metabolism. An overview. Acta Biol Hung 49: 209–18.
38. Lombard KA, Olson AL, Nelson SE, Rebouche CJ. 1989. Carnitine status of lactoovovegetarians and strict vegetarian adults and children. Am J Clin Nutr 50: 301–6.
39. Strijbis K, van Roermund CW, Hardy GP, van den Burg J, et al. 2009. Identification and characterization of a complete carnitine biosynthesis pathway in Candida albicans. FASEB J 23: 2349–59.
40. Meadows JA, Wargo MJ. 2015. Carnitine in bacterial physiology and metabolism. Microbiology 161: 1161–74.
41. Shinawi M, Gruener N, Lerner A. 1998. CSF levels of carnitine in children with meningitis, neurologic disorders, acute gastroenteritis, and seizure. Neurology 50: 1869–71.
42. Vaz FM, Wanders RJ. 2002. Carnitine biosynthesis in mammals. Biochem J 361: 417–29.
43. Strijbis K, Vaz FM, Distel B. 2010. Enzymology of the carnitine biosynthesis pathway. IUBMB Life 62: 357–62.
44. Michalec K, Mysiorek C, Kuntz M, Berezowski V, et al. 2014. Protein kinase C restricts transport of carnitine by amino acid transporter ATB(0,+) apically localized in the blood-brain barrier. Arch Biochem Biophys 554: 28–35.
45. Nezu J, Tamai I, Oku A, Ohashi R, et al. 1999. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21: 91–4.
46. Rasmussen J, Kober L, Lund AM, Nielsen OW. 2014. Primary Carnitine deficiency in the Faroe Islands: health and cardiac status in 76 adult patients diagnosed by screening. J Inherit Metab Dis 37: 223–30.
47. Koizumi A, Nozaki J, Ohura T, Kayo T, et al. 1999. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet 8: 2247–54.
48. Wang Y, Korman SH, Ye J, Gargus JJ, et al. 2001. Phenotype and genotype variation in primary carnitine deficiency. Genet Med 3: 387–92.
49. Kocovska E, Billstedt E, Ellefsen A, Kampmann H, et al. 2013. Autism in the Faroe Islands: diagnostic stability from childhood to early adult life. ScientificWorldJournal 2013: 592371.
50. Stanley CA. 2004. Carnitine deficiency disorders in children. Ann N Y Acad Sci 1033: 42–51.
51. Ryckman KK, Smith CJ, Jelliffe-Pawlowski LL, Momany AM, et al. 2014. Metabolic heritability at birth: implications for chronic disease research. Hum Genet 133: 1049–57.
52. Gallant NM, Leydiker K, Tang H, Feuchtbaum L, et al. 2012. Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol Genet Metab 106: 55–61.
53. Illig T, Gieger C, Zhai G, Romisch-Margl W, et al. 2010. A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42: 137–41.
54. Shin SY, Fauman EB, Petersen AK, Krumsiek J, et al. 2014. An atlas of genetic influences on human blood metabolites. Nat Genet 46: 543–50.
55. Buie T, Campbell DB, Fuchs GJ, 3rd, Furuta GT, et al. 2010. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125: S1–18.
56. Elsabbagh M, Divan G, Koh YJ, Kim YS, et al. 2012. Global prevalence of autism and other pervasive developmental disorders. Autism Res 5: 160–79.
57. Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators; Centers for Disease Control and Prevention (CDC). 2014. Prevalence of autism spectrum disorder among children aged 8 years − autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 63: 1–21.
58. Rossignol DA, Frye RE. 2012. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17: 290–314.
59. Frye RE, James SJ. 2014. Metabolic pathology of autism in relation to redox metabolism. Biomark Med 8: 321–30.
60. Frye RE, Melnyk S, Macfabe DF. 2013. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry 3: e220.
61. Frye RE, Rose S, Slattery J, MacFabe DF. 2015. Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome. Microb Ecol Health Dis 26: 27458.
62. MacFabe DF. 2015. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis 26: 28177.
63. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, et al. 2015. Role of the normal gut microbiota. World J Gastroenterol 21: 8787–803.
64. Slattery J, MacFabe DF, Kahler SG, Frye RE. 2016. Enteric ecosystem disruption in autism spectrum disorder: can the microbiota and macrobiota be restored? Curr Pharm Des 22: 6107–21.
65. Ding HT, Taur Y, Walkup JT. 2017. Gut microbiota and autism: key concepts and findings. Autism Dev Disord 47: 480–9.
66. Vuong HE, Hsiao EY. 2017. Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry 81: 411–23.
67. Berding K, Donovan SM. 2016. Microbiome and nutrition in autism spectrum disorder: current knowledge and research needs. Nutr Rev 74: 723–36.
68. Li Q, Zhou JM. 2016. The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience 324: 131–9.
69. Frye RE, Slattery J, MacFabe DF, Allen-Vercoe E, et al. 2015. Approaches to studying and manipulating the enteric microbiome to improve autism symptoms. Microb Ecol Health Dis 26: 26878.
70. Koeth RA, Wang Z, Levison BS, Buffa JA, et al. 2013. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576–85.
71. Ussher JR, Lopaschuk GD, Arduini A. 2013. Gut microbiota metabolism of L-carnitine and cardiovascular risk. Atherosclerosis 231: 456–61.
72. Bergeron N, Williams PT, Lamendella R, Faghihnia N, et al. 2016. Diets high in resistant starch increase plasma levels of trimethylamine-N-oxide, a gut microbiome metabolite associated with CVD risk. Br J Nutr 116: 2020–9.
73. Senthong V, Wang Z, Li XS, Fan Y, et al. 2016. Intestinal microbiota-generated metabolite trimethylamine-n-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a courage-like patient cohort. J Am Heart Assoc 5: e002816.
74. Finegold SM, Downes J, Summanen PH. 2012. Microbiology of regressive autism. Anaerobe 18: 260–2.
75. Pochini L, Galluccio M, Scumaci D, Giangregorio N, et al. 2008. Interaction of beta-lactam antibiotics with the mitochondrial carnitine/acylcarnitine transporter. Chem Biol Interact 173: 187–94.
76. Rasmussen J, Nielsen OW, Lund AM, Kober L, et al. 2013. Primary carnitine deficiency and pivalic acid exposure causing encephalopathy and fatal cardiac events. J Inherit Metab Dis 36: 35–41.
77. Takahashi Y, Sano R, Kominato Y, Kubo R, et al. 2016. A case of sudden unexpected infant death involving a homozygotic twin with the thermolabile CPT2 variant, accompanied by rotavirus infection and treatment with an antibiotic containing pivalic acid. Leg Med (Tokyo) 22: 13–7.
78. Kobayashi H, Fukuda S, Yamada K, Hasegawa Y, et al. 2016. Clinical features of carnitine deficiency secondary to pivalate-conjugated antibiotic therapy. J Pediatr 173: 183–7.
79. Boemer F, Schoos R, de Halleux V, Kalenga M, et al. 2014. Surprising causes of C5-carnitine false positive results in newborn screening. Mol Genet Metab 111: 52–4.
80. Raskind JY, El-Chaar GM. 2000. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 34: 630–8.
81. Qi Q, Wang R, Liu L, Zhao F, et al. 2015. Comparative effectiveness and tolerability of esomeprazole and omeprazole in gastro-esophageal reflux disease: a systematic review and meta-analysis. Int J Clin Pharmacol Ther 53: 803–10.
82. Pochini L, Scalise M, Indiveri C. 2009. Inactivation by omeprazole of the carnitine transporter (OCTN2) reconstituted in liposomes. Chem Biol Interact 179: 394–401.
83. Kondapalli KC, Prasad H, Rao R. 2014. An inside job: how endosomal Na(+)/H(+) exchangers link to autism and neurological disease. Front Cell Neurosci 8: 172.
84. Schobersberger W, Dunnwald T, Gmeiner G, Blank C. 2017. Story behind meldonium-from pharmacology to performance enhancement: a narrative review. Br J Sports Med 51: 22–5.
85. Spaniol M, Brooks H, Auer L, Zimmermann A, et al. 2001. Development and characterization of an animal model of carnitine deficiency. Eur J Biochem 268: 1876–87.
86. Slonim AE, Borum PR, Tanaka K, Stanley CA, et al. 1981. Dietary-dependent carnitine deficiency as a cause of nonketotic hypoglycemia in an infant. J Pediatr 99: 551–5.
87. Novak M. 1990. Carnitine supplementation in soy-based formula-fed infants. Biol Neonate 58: 89–92.
88. Borum PR, Bennett SG. 1986. Carnitine as an essential nutrient. J Am Coll Nutr 5: 177–82.
89. Rebouche CJ. 1986. Is carnitine an essential nutrient for humans? J Nutr 116: 704–6.
90. Hulett JL, Weiss RE, Bwibo NO, Galal OM, et al. 2014. Animal source foods have a positive impact on the primary school test scores of Kenyan schoolchildren in a cluster-randomised, controlled feeding intervention trial. Br J Nutr 111: 875–86.
91. Tang M, Sheng XY, Krebs NF, Hambidge KM. 2014. Meat as complementary food for older breastfed infants and toddlers: a randomized, controlled trial in rural China. Food Nutr Bull 35: S188–92.
92. Tang M, Krebs NF. 2014. High protein intake from meat as complementary food increases growth but not adiposity in breastfed infants: a randomized trial. Am J Clin Nutr 100: 1322–8.
93. Tanoue Y, Oda S. 1989. Weaning time of children with infantile autism. J Autism Dev Disord 19: 425–34.
94. Al-Farsi YM, Al-Sharbati MM, Waly MI, Al-Farsi OA, et al. 2012. Effect of suboptimal breast-feeding on occurrence of autism: a case-control study. Nutrition 28: e27–32.
95. Husk JS, Keim SA. 2015. Breastfeeding and autism spectrum disorder in the national survey of children's health. Epidemiology 26: 451–7.
96. Babu E, Bhutia YD, Ramachandran S, Gnana-Prakasam JP, et al. 2015. Deletion of the amino acid transporter Slc6a14 suppresses tumor growth in spontaneous mouse models of breast cancer. Biochem J 469: 17–23.
97. Ozonoff S, Young GS, Carter A, Messinger D, et al. 2011. Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics 128: e488–e95.
98. Folstein SE, Rosen-Sheidley B. 2001. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2: 943–55.
99. Muhle R, Trentacoste SV, Rapin I. 2004. The genetics of autism. Pediatrics 113: e472–e86.
100. Wood CL, Warnell F, Johnson M, Hames A, et al. 2015. Evidence for ASD recurrence rates and reproductive stoppage from large UK ASD research family databases. Autism Res 8: 73–81.
101. Werling DM, Geschwind DH. 2015. Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins. Mol Autism 6: 27.
102. Hazlett HC, Gu H, Munsell BC, Kim SH, et al. 2017. Early brain development in infants at high risk for autism spectrum disorder. Nature 542: 348–51.
103. Williams E, Thomas K, Sidebotham H, Emond A. 2008. Prevalence and characteristics of autistic spectrum disorders in the ALSPAC cohort. Dev Med Child Neurol 50: 672–7.
104. Baird G, Charman T, Baron-Cohen S, Cox A, et al. 2000. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry 39: 694–702.
105. Whiteley P, Todd L, Carr K, Shattock P. 2010. Gender ratios in autism, Asperger syndrome and autism spectrum disorder. Autism Insights 2: 17–24.
106. Wing L. 1988. The autistic continuum. In: Schopler E, Mesibov GB, ed; Aspects of Autism: Biological Research. New York: Springer.
107. Scott FJ, Baron-Cohen S, Bolton P, Brayne C. 2002. Brief report: prevalence of autism spectrum conditions in children aged 5–11 years in Cambridgeshire, UK. Autism 6: 231–7.
108. Lai DC, Tseng YC, Hou YM, Guo HR. 2012. Gender and geographic differences in the prevalence of autism spectrum disorders in children: analysis of data from the national disability registry of Taiwan. Res Dev Disabil 33: 909–15.
109. Skuse DH, James RS, Bishop DV, Coppin B, et al. 1997. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387: 705–8.
110. D'Esposito M, Ciccodicola A, Gianfrancesco F, Esposito T, et al. 1996. A synaptobrevin-like gene in the Xq28 pseudoautosomal region undergoes X inactivation. Nat Genet 13: 227–9.