Lintas, C. & Persico, A. M. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J. Med. Genet. 46, 1-8

Foundation Santa Lucia, Roma, Latium, Italy
Journal of Medical Genetics (Impact Factor: 6.34). 09/2008; 46(1):1-8. DOI: 10.1136/jmg.2008.060871
Source: PubMed


Autism spectrum disorders represent a group of developmental disorders with strong genetic underpinnings. Several cytogenetic abnormalities or de novo mutations able to cause autism have recently been uncovered. In this study, the literature was reviewed to highlight genotype-phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Based on this information, a set of practical guidelines is proposed to help clinical geneticists pursue targeted genetic testing for patients with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology.

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    • "Една съществена разлика в генетиката на аутизма е, тази между "синдромният"(Авджиева, Д, 2009) и "не-синдромният" аутизъм (Lintas, 2009). Терминът несиндромен се използва за описание на състояние, при което аутизма е първичната диагноза, а не вторична (аутистично поведение), както при състояния, причинени от известни генетични промени, като например, туберозна склероза, синдром на Рет, синдром на чупливата X хромозома, туберозна склероза или други генетични заболявания (Lintas, 2009). Гените, причина за синдромния аутизъм вероятно принадлежат към един континуум от генетични вариации участващи в развитието на нервната система, които се проявяват по различен начин в зависимост от епигенетични и екологични фактори (Agnes, 2013). "
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    ABSTRACT: Abstract: Autism spectrum disorders (ASD) are disorders of the central nervous system characterized by impairments in communication and social reciprocity. Despite thousands of studies on this topic, the etiopathogenesis of these disorders remains unclear, apart from a general belief that they derive from an interaction between several genes and the environment. The aim of this review is to summarize the key findings from genetic research, which show that autism is a complex disorder resulting from the combination of genetic and non genetic factors.
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    • "It is likely that several of these alterations in cellular mechanisms contribute to the ASD/ID phenotype, while others are reactionary changes in response to ELS, SRS, ID and/or ASD and do not contribute to the phenotype. Too little has been discussed and explored regarding gender, especially since ASD primarily affects males (reviewed in Lintas and Persico, 2009). Most studies have focused primarily on males. "
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    ABSTRACT: Recent work in Exp Neurol by Lugo et al. (2014b) demonstrated chronic alterations in sociability, learning and memory following multiple early life seizures (ELSs) in a mouse model. This work adds to the growing body of evidence supporting the detrimental nature of ELSs on the developing brain to contribute to aspects of an autistic phenotype with intellectual disability. Review of the face validity of behavioral testing and the construct validity of the models used informs the predictive ability and thus the utility of these models to translate underlying molecular and cellular mechanisms into future human studies.
    Experimental Neurology 10/2014; 263. DOI:10.1016/j.expneurol.2014.09.018 · 4.70 Impact Factor
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    • "Specifically, samples were dissected from contiguous Brodmann areas 41/42 or 22, depending on tissue availability. Largely overlapping postmortem brain samples have been the object of several previous reports from our group (Campbell et al., 2007; Garbett et al., 2008; Lintas et al., 2009; Palmieri et al., 2010). Patients and controls have comparable sex, age and post-mortem interval (PMI) distributions (Table S3), and were below 40 years of age at the time of death. "
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    ABSTRACT: Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.07.021 · 3.96 Impact Factor
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