Syndromic autism: causes and pathogenetic pathways
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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.
The PubMed database was searched with the keywords “autism” and “chromosomal abnormalities”, “metabolic diseases”, “susceptibility loci”.
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.
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.
Key wordsautism candidate genes etiologies pathogenetic pathways
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- 1.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington DC: American Psychiatric Association, 1994.Google Scholar
- 2.Tuchman R, Rapin I. Autism: a neurological disorder of early brain development. London: Mac Keith Press for the ICNA, 2006.Google Scholar
- 36.Vorstman JA, Staal WG, van Daalen E, van Engeland H, Hochstenbach PF, Franke L. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 2006;11:1,18–28.Google Scholar
- 49.Kirchhoff M, Bisgaard AM, Bryndorf T, Gerdes T. MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions. Eur J Med Genet 2007;50:33–42.PubMedCrossRefGoogle Scholar
- 54.Lintas C, Sacco R, Garbett K, Mirnics K, Militerni R, Bravaccio C, et al. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry 2008. doi:10.1038/mp.2008.21Google Scholar
- 83.Bayou N, M’Rad R, Belhaj A, Daoud H, Zemni R, Briault S, et al. The creatine transporter gene paralogous at 16p11.2 is expressed in human brain. Comp Funct Genomics 2008:609684.Google Scholar
- 90.Palmieri L, Papaleo V, Porcelli V, Scarcia P, Gaita L, Sacco R, et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry 2008. doi: 10.1038/mp.2008.63Google Scholar