A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

Proceedings of the National Academy of Sciences of the United States of America

Volumn 109, Issue 21, 2012, Pages 7974-7981

  Celestino Soper, Patrícia B S ^a   Violante, Sara ^b,c   Crawford, Emily L ^d   Luo, Rui ^e   Lionel, Anath C ^f   Delaby, Elsa ^g   Cai, Guiqing ^h   Sadikovic, Bekim ^a   Lee, Kwanghyuk ^a   Lo, Charlene ^a   Gao, Kun ^e   Person, Richard E ^a   Moss, Timothy J ^a   German, Jennifer R ^a   Huang, Ni ⁱ   Shinawi, Marwan ^a,j,r   Treadwell Deering, Diane ^a,j   Szatmari, Peter ^k,l   Roberts, Wendy ^m   Fernandez, Bridget ⁿ   Schroer, Richard J ^o   Stevenson, Roger E ^o   Buxbaum, Joseph D ^h   Betancur, Catalina ^g   Scherer, Stephen W ^f,m   Sanders, Stephan J ^p   Geschwind, Daniel H ^e   Sutcliffe, James S ^d   Hurles, Matthew E ⁱ   Wanders, Ronald J A ^b   Shaw, Chad A ^a   Leal, Suzanne M ^a   Cook, Edwin H ^q   Goin Kochel, Robin P ^a,j   Vaz, Frédéric M ^b   Beaudet, Arthur L ^a,j   more..

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF AMSTERDAM   (Netherlands)

^c UNIVERSITY OF LISBON   (Portugal)

^d VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f HOSPITAL FOR SICK CHILDREN   (Canada)

^g INSERM   (France)

^h MOUNT SINAI SCHOOL OF MEDICINE   (United States)

ⁱ WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^j TEXAS CHILDREN S HOSPITAL   (United States)

^k MCMASTER CHILDREN S HOSPITAL   (Canada)

^l MCMASTER UNIVERSITY   (Canada)

^m HOSPITAL FOR SICK CHILDREN   (Canada)

ⁿ MEMORIAL UNIVERSITY OF NEWFOUNDLAND   (Canada)

^o GREENWOOD GENETIC CENTER   (United States)

^p YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^q UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^r WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXY 6 N TRIMETHYLLYSINE; GAMMA BUTYROBETAINE; LYSINE; OXYGENASE; TRIMETHYLLYSINE; TRIMETHYLLYSINE HYDROXYLASE EPSILON; UNCLASSIFIED DRUG;

AMINO ACID BLOOD LEVEL; AMINO ACID URINE LEVEL; ARTICLE; AUTISM; CONTROLLED STUDY; ENZYME ACTIVITY; EXON; FEMALE; GENE DELETION; GENE SEQUENCE; GENETIC RISK; GENOME ANALYSIS; HUMAN; INBORN ERROR OF METABOLISM; INHERITANCE; MAJOR CLINICAL STUDY; MALE; PRIORITY JOURNAL; RISK ASSESSMENT; SEQUENCE ANALYSIS; SEX RATIO; SIBLING; TRIMETHYLLYSINE HYDROXYLASE EPSILON DEFICIENCY;

EID: 84861443524     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1120210109     Document Type: Article

References (47)

1. Conference Proceedings (2004) Carnitine. The science behind a conditionally essential nutrient. Proceedings of a conference. March 25-26, 2004. Bethesda, MD. Ann N Y Acad Sci 1033:1-197.
2. Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q (2010) Role of carnitine in disease. Nutr Metab (Lond) 7:30.
3. Vaz FM, Wanders RJ (2002) Carnitine biosynthesis in mammals. Biochem J 361: 417-429. (Pubitemid 34177810)
4. Slonim AE, et al. (1981) Dietary-dependent carnitine deficiency as a cause of non-ketotic hypoglycemia in an infant. J Pediatr 99:551-555. (Pubitemid 12232086)
5. Schmidt-Sommerfeld E, Penn D (1990) Carnitine and total parenteral nutrition of the neonate. Biol Neonate 58(Suppl 1):81-88. (Pubitemid 20320976)
6. Longo N, Amat di San Filippo C, Pasquali M (2006) Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 142C(2):77-85.
7. Strijbis K, Vaz FM, Distel B (2010) Enzymology of the carnitine biosynthesis pathway. IUBMB Life 62:357-362.
8. Evans JD, Jacobs TF, Evans EW (2008) Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacother 42:1686-1691.
9. Sarma S, Gheorghiade M (2010) Nutritional assessment and support of the patient with acute heart failure. Curr Opin Crit Care 16:413-418.
10. Celestino-Soper PBS, et al. (2011) Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet 20:4360-4370.
11. Vaz FM, et al. (2002) Analysis of carnitine biosynthesis metabolites in urine by HPLC-electrospray tandem mass spectrometry. Clin Chem 48:826-834. (Pubitemid 34587581)
12. Miles JH, et al. (2008) Development and validation of a measure of dysmorphology: Useful for autism subgroup classification. Am J Med Genet A 146A:1101-1116. (Pubitemid 351628596)
13. Jacquemont M-L, et al. (2006) Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 43:843-849. (Pubitemid 44787109)
14. O'Roak BJ, et al. (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43:585-589.
15. Sebat J, et al. (2007) Strong association of de novo copy number mutations with autism. Science 316:445-449. (Pubitemid 46651493)
16. Marshall CR, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82:477-488.
17. van Bon BW, et al. (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: A clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46:511-523.
18. Sebat J, Levy DL, McCarthy SE (2009) Rare structural variants in schizophrenia: One disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 25: 528-535.
19. Shinawi M, et al. (2009) A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat Genet 41:1269-1271.
20. Girirajan S, et al. (2010) A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 42:203-209.
21. 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: 231-237. (Pubitemid 34918775)
22. Kalra V, Seth R, Sapra S (2005) Autism - Experiences in a tertiary care hospital. Indian J Pediatr 72:227-230. (Pubitemid 40529525)
23. Boone PM, et al. (2011) Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. Genet Med 13:582-592.
24. Monfregola J, et al. (2007) Functional characterization of the TMLH gene: Promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants. Gene 395(1-2):86-97. (Pubitemid 46670638)
25. Rossignol DA, Frye RE (2012) Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol Psychiatry 17:290-314.
26. Gargus JJ, Imtiaz F (2008) Mitochondrial energy-deficient endophenotype in autism. American Journal of Biochemistry and Biotechnology 4(2):198-207. (Pubitemid 351573653)
27. Mostafa GA, El-Gamal HA, El-Wakkad ASE, El-Shorbagy OE, Hamza MM (2005) Polyunsaturated fatty acids, carnitine and lactate as biological markers of brain energy in autistic children. International Journal of Child Neuropsychiatry 2(2):179-188.
28. Lombard J (1998) Autism: A mitochondrial disorder? Med Hypotheses 50:497-500.
29. Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ (2004) Relative carnitine deficiency in autism. J Autism Dev Disord 34:615-623. (Pubitemid 40044667)
30. Rubio JC, et al. (1998) Cerebrospinal fluid carnitine levels in patients with Alzheimer's disease. J Neurol Sci 155(2):192-195.
31. Shinawi M, Gruener N, Lerner A (1998) CSF levels of carnitine in children with meningitis, neurologic disorders, acute gastroenteritis, and seizure. Neurology 50: 1869-1871. (Pubitemid 28283270)
32. Fujita M, et al. (2009) Hepatic uptake of gamma-butyrobetaine, a precursor of carnitine biosynthesis, in rats. Am J Physiol Gastrointest Liver Physiol 297:G681-G686.
33. Wong VC, Hui SL (2008) Epidemiological study of autism spectrum disorder in China. J Child Neurol 23(1):67-72.
34. Kim YS, et al. (2011) Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry 168:904-912.
35. Geier DA, et al. (2011) A prospective double-blind, randomized clinical trial of levo-carnitine to treat autism spectrum disorders. Med Sci Monit 17:PI15-PI23.
36. Sanders SJ, et al. (2011) Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism. Neuron 70:863-885.
37. Ou Z, et al. (2008) Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses. Genet Med 10:278-289. (Pubitemid 351544130)
38. McCarroll SA, et al.; International HapMap Consortium (2006) Common deletion polymorphisms in the human genome. Nat Genet 38:86-92. (Pubitemid 43011887)
39. Swiegers JH, Vaz FM, Pretorius IS, Wanders RJ, Bauer FF (2002) Carnitine biosynthesis in Neurospora crassa: Identification of a cDNA coding for epsilon-N-trimethyllysine hydroxylase and its functional expression in Saccharomyces cerevisiae. FEMS Microbiol Lett 210(1):19-23. (Pubitemid 34521944)
40. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254.
41. Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ (2001) Molecular and Biochemical Characterization of Rat epsilon-N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis. J Biol Chem 276:33512-33517.
42. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506-516. (Pubitemid 23311321)
43. Ewens WJ, Spielman RS (1995) The transmission/disequilibrium test: History, subdivision, and admixture. Am J Hum Genet 57:455-464.
44. McGinnis RE, Ewens WJ, Spielman RS (1995) The TDT reveals linkage and linkage disequilibrium in a rare disease. Genet Epidemiol 12:637-640. (Pubitemid 26012034)
45. Spielman RS, Ewens WJ (1996) The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 59:983-989. (Pubitemid 26346336)
46. McNemar Q (1947) Note on the sampling error of the difference between correlated proportions or percentages. Psychometrika 12(2):153-157.
47. Stouffer SA, Suchman EA, DeVinney LC, Star SA, Williams RM, Jr. (1949) Adjustment During Army Life (Princeton Univ Press, Princeton).