Syndromic autism: causes and pathogenetic pathways.
BACKGROUND
Autism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype.


METHODS
The PubMed database was searched with the keywords "autism" and "chromosomal abnormalities", "metabolic diseases", "susceptibility loci".


RESULTS
Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems.


CONCLUSIONS
A wide variety of cytogenetic abnormalities have been recently described, particularly in the low functioning individuals with dysmorphic features. Routine metabolic screening studies should be performed in the presence of autistic regression or suggestive clinical findings. As etiologies of autism are progressively discovered, the number of individuals with idiopathic autism will progressively shrink. Studies of genetic and environmentally modulated epigenetic factors are beginning to provide some clues to clarify the complexities of autism pathogenesis. The role of the neuropediatrician will be to understand the neurological basis of autism, and to identify more homogenous subgroups with specific biologic markers.
Benvenuto
Arianna
A
Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University, via Montpellier 1, 00133, Rome, RM, Italy.
Moavero
Romina
R
Alessandrelli
Riccardo
R
Manzi
Barbara
B
Curatolo
Paolo
P
D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15; D002885:Chromosomes, Human, Pair 16; D002889:Chromosomes, Human, Pair 2; D002897:Chromosomes, Human, Pair 7; D015897:Comorbidity; D005600:Fragile X Syndrome / Q000453:epidemiology; D006801:Humans; D009154:Mutation; D014402:Tuberous Sclerosis / Q000453:epidemiology
Brain Pathol. 2007 Oct;17(4):434-47
17919129
J Autism Dev Disord. 2003 Apr;33(2):201-4
12757360
Int J Dev Neurosci. 2005 Apr-May;23(2-3):201-19
15749246
Mol Psychiatry. 2009 Jul;14(7):705-18
18317465
J Child Neurol. 2007 Sep;22(9):1121-3
17890412
Science. 2007 Apr 20;316(5823):445-9
17363630
Am J Med Genet B Neuropsychiatr Genet. 2005 Jul 5;136B(1):36-44
15892143
Pediatrics. 2009 Mar;123(3):1018-24
19255034
Curr Opin Psychiatry. 2005 Sep;18(5):490-6
16639106
Am J Med Genet C Semin Med Genet. 2006 Feb 15;142C(1):8-12
16419095
Brain Dev. 2009 Feb;31(2):104-13
19028034
Epilepsia. 2007;48 Suppl 8:19-20
18329989
Am J Med Genet. 1989 Mar;32(3):350-2
2729355
J Child Neurol. 2008 Jul;23(7):802-6
18658079
Am J Hum Genet. 2004 Mar;74(3):552-7
14963808
Nat Genet. 2009 Feb;41(2):160-2
19136953
Eur J Med Genet. 2007 Jan-Feb;50(1):33-42
17090394
Lancet Neurol. 2002 Oct;1(6):352-8
12849396
Lancet. 2008 Aug 23;372(9639):657-68
18722871
Mol Psychiatry. 2010 Jan;15(1):38-52
18607376
Am J Hum Genet. 2007 Dec;81(6):1289-97
17999366
Eur J Med Genet. 2009 Jan-Feb;52(1):67-70
18992374
J Med Genet. 2004 Jul;41(7):e90
15235033
Mol Psychiatry. 2005 Oct;10(10):950-60
16027742
Nat Rev Neurosci. 2006 May;7(5):380-93
16760918
Mol Psychiatry. 2005 Apr;10(4):329-32
15622415
Int J Dev Neurosci. 2005 Apr-May;23(2-3):183-7
15749244
Am J Med Genet A. 2007 Mar 15;143A(6):589-93
17286265
J Autism Dev Disord. 2005 Feb;35(1):103-16
15796126
Biol Psychiatry. 2008 May 15;63(10):911-6
18207134
Neuropharmacology. 1999 May;38(5):707-15
10340308
Nat Genet. 2000 Sep;26(1):93-6
10973257
Biol Psychiatry. 2005 Apr 1;57(7):777-87
15820235
J Med Genet. 2007 Feb;44(2):136-43
16971481
J Child Neurol. 2001 May;16(5):301-8
11392513
Br J Psychiatry. 2000 Jan;176:20-5
10789321
Eur Child Adolesc Psychiatry. 2007 Feb;16(1):61-6
16932856
J Clin Neurophysiol. 2003 Nov-Dec;20(6):462-72
14734935
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16834-9
17053076
Curr Opin Neurobiol. 2007 Feb;17(1):112-9
17275285
N Engl J Med. 2006 Mar 30;354(13):1370-7
16571880
Am J Hum Genet. 2005 Sep;77(3):377-88
16080114
BMC Neurosci. 2007 Apr 12;8:25
17428348
Philos Trans R Soc Lond B Biol Sci. 1996 Oct 29;351(1346):1483-93; discussion 1494
8941960
J Neuropathol Exp Neurol. 2005 Nov;64(11):925-35
16254487
Genet Med. 2008 Jan;10(1):4-12
18197051
J Autism Dev Disord. 2007 Apr;37(4):738-47
17031449
Am J Hum Genet. 2008 Feb;82(2):477-88
18252227
J Child Neurol. 2007 Sep;22(9):1102-7
17890408
Curr Opin Neurol. 2008 Apr;21(2):143-9
18317271
J Lipid Res. 2000 Aug;41(8):1339-46
10946022
J Child Neurol. 2008 Mar;23(3):307-14
18079313
Eur J Paediatr Neurol. 2004;8(6):327-32
15542389
Ment Retard Dev Disabil Res Rev. 2004;10(4):284-91
15666333
Comp Funct Genomics. 2008;:609684
18509488
Mol Psychiatry. 2008 Apr;13(4):385-97
18180767
Am J Med Genet A. 2004 Sep 1;129A(3):225-34
15326621
World J Biol Psychiatry. 2007;8(2):127-30
17455106
J Neurophysiol. 2008 Nov;100(5):2615-26
18784272
Biol Psychiatry. 2008 Jun 15;63(12):1111-7
18374305
Mol Psychiatry. 2006 Jan;11(1):1, 18-28
16205736
Eur J Hum Genet. 2009 Jan;17(1):37-43
18716609
J Neural Transm (Vienna). 2009 Mar;116(3):381-8
19139806
Brain Dev. 2009 Feb;31(2):95-103
19006654
Pediatrics. 1999 Sep;104(3 Pt 1):405-18
10469763
Eur J Hum Genet. 2008 May;16(5):614-8
18231125
Hum Mol Genet. 2008 Dec 15;17(24):3887-96
18782849
Am J Med Genet A. 2004 Nov 1;130A(4):331-9
15386475
Nat Rev Genet. 2008 May;9(5):341-55
18414403
JAMA. 1980 Jan 11;243(2):126-8
7350353
Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):484-91
17427195
N Engl J Med. 2008 Feb 14;358(7):667-75
18184952
J Neurosci. 2008 May 14;28(20):5178-88
18480274
Am J Med Genet A. 2006 Jul 15;140(14):1511-8
16761297
Cell. 2004 Oct 1;119(1):19-31
15454078
Semin Pediatr Neurol. 2008 Sep;15(3):127-31
18708003
Pediatrics. 2004 Aug;114(2):451-7
15286229
Brain Behav Immun. 2009 Jan;23(1):64-74
18706993
J Med Genet. 2009 Jan;46(1):1-8
18728070
J Dev Behav Pediatr. 2001 Dec;22(6):409-17
11773805
Eur J Pediatr. 2000 Oct;159 Suppl 2:S102-6
11043154
Genet Couns. 2004;15(3):293-301
15517821
Rev Neurol. 2006 Sep 1-15;43(5):302-8
16941429
J Biol Chem. 2002 Jan 4;277(1):303-9
11689558
Nat Genet. 2007 Sep;39(9):1071-3
17704777
Genet Med. 2007 May;9(5):268-74
17505203
Trends Neurosci. 2004 Jul;27(7):400-6
15219739
Hum Mol Genet. 2001 Apr 15;10(9):973-82
11392322
Am J Hum Genet. 2003 Mar;72(3):539-48
12567325
Neurosci Lett. 2007 Feb 2;412(3):227-32
17197085
Epilepsia. 2008 Nov;49(11):1865-70
18557779
Am J Hum Genet. 2008 Jan;82(1):150-9
18179893
Trends Neurosci. 2006 Jul;29(7):349-358
16808981
Trends Neurosci. 2008 Mar;31(3):137-45
18258309
Brain Dev. 2007 Jul;29(6):336-45
17113261
Nat Genet. 2007 Mar;39(3):319-28
17322880
Hum Mol Genet. 2008 Feb 15;17(4):628-38
18156158
Am J Psychiatry. 2005 Nov;162(11):2182-4
16263864
Int J Dev Neurosci. 2007 Apr;25(2):69-85
17236739
Nat Genet. 2007 Jan;39(1):25-7
17173049
Brain. 2004 Dec;127(Pt 12):2572-83
15329353
Neuropediatrics. 2007 Dec;38(6):310-2
18461508
Biochem Biophys Res Commun. 2008 Dec 19;377(3):926-9
18957284