**5. Associated syndromes and comorbidity in autism**

Similar to intellectual disabilities or delay in motor developmental, the autistic behavioral phenotype can occur alone or as part of the spectrum of phenotypic manifestations in a par‐ ticular condition of environmental, genetic or multifactorial etiology. In some situations, the autistic behavioral phenotype is observed in individuals with only one other clinical mani‐ festation, such as epilepsy. This simultaneous occurrence (co-occurrence) has been discussed much and is referred to in the literature either as an association or as comorbidity. Probably the truth is, that in most cases, the different manifestations result from the same causal fac‐ tor, which suggests the term "association" is more appropriate than "comorbidity".

guidance in genetic counseling, these investigations can assist in the elucidation of the recur‐

Following a promising approach in the investigation of complex disease etiologies, studies on endophenotypes ("intermediate phenotypes") may be used to direct the search for the etiology of ASD (Weinberger et al., 2001). Manifestations related to autistic behavior are of‐ ten observed in varying degrees of severity in unaffected individuals of previous genera‐ tions in the same family, thereby characterizing the phenomenon of genetic anticipation in

A Swedish study reported that the existence of individuals with schizophrenia and bipolar dis‐ order in the family is a risk factor for the occurrence of autism. The authors found an association between schizophrenic parents or siblings with increased risk of ASD. Bipolar disorder also

Studies of autistic families have also shown a significant increase in the recurrence of ASD in first-degree relatives of carriers. For example, siblings of individuals with ASD have a 22- to 25 fold higher risk of having the disorder (Lauritsen et al., 2005; Abrahams & Geschwind, 2008). There are significantly higher risks of ASD in offspring of parents with ASD and those with fam‐ ilial history of psychiatric problems. Depression and personality disorders have been reported to be more common in mothers of children diagnosed with ASD than in mothers of children with normal development (Daniels et al., 2008; Constantino et al., 2010). Even some non-affect‐ ed individuals of different generations in the same family may show subtle impairment in cog‐ nitive development, language changes or in social interaction; this is termed the *broad autism phenotype*. This phenotypic diversity of autistic behavior and psychiatric manifestations in fam‐ ilies of the patients indicate that the genetic factors that influence ASD may be composed of dis‐ tinct elements that manifest differently between affected and non-affected family members

In the molecular field, studies on genealogies with multiple affected family members and studies on twins suggest that allelic variations are associated with increased susceptibility to ASD and that there are etiological factors common to both ASD and milder autistic pheno‐ types (Lundstrom et al., 2010; Arking et al., 2008; Wang et al., 2009). Hence, epidemiological studies have been developed with families in an attempt to clarify the relative proportions of cases of autism and *broad autism phenotypes* in the population that might explain these

Similar to intellectual disabilities or delay in motor developmental, the autistic behavioral phenotype can occur alone or as part of the spectrum of phenotypic manifestations in a par‐ ticular condition of environmental, genetic or multifactorial etiology. In some situations, the autistic behavioral phenotype is observed in individuals with only one other clinical mani‐ festation, such as epilepsy. This simultaneous occurrence (co-occurrence) has been discussed

proved to be a risk factor, but not as strong as schizophrenia (Sullivan et al., 2012).

rence risks in future generations (Constantino et al., 2010).

218 Recent Advances in Autism Spectrum Disorders - Volume I

*(*Pickles et al., 2000; Szatmari et al., 2000; Goldberg et al., 2005).

**5. Associated syndromes and comorbidity in autism**

complex mechanisms of genetic transmission.

ASD (Losh et al., 2008).

Monozygotic and dizygotic twin studies indicate a variety of neuropsychiatric diagnoses as‐ sociated with ASD, including attention deficit and hyperactivity disorder (ADHD) and anxi‐ ety disorder (Lichtenstein et al., 2010). High frequencies of these diseases have been reported in children with autism, as has bipolar disorder in adolescents and young adults (Munesue et al., 2008; Simonoff et al., 2008). The wide range of clinical behavioral symptoms among carriers may be justified and be a good argument to consider the diagnosis of ASD alone, with all the possible manifestations expected in the spectrum, as no individual is ex‐ actly like another. In this way, families would be less anxious and confused on receiving three or four diagnoses for the same child.

There are a number of diseases associated with autism, whose genetic etiology is well estab‐ lished, i.e. autistic behavior is one of the possible manifestations. The most common is Frag‐ ile X syndrome (FRAXA). This is the most frequent form of inherited mental retardation and is considered a monogenic cause of ASD. Symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior, which are accompanied by macroorchid‐ ism and distinct facial morphology. It is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (*FMR1*) gene result‐ ing in loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads of affected men. FMRP has multiple functions in the RNA metabolism, including mRNA decay, dendritic targeting of mRNAs and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired (De Rubeis et al., 2012). Frequen‐ cies of between 2% and 3% of FRAXA have been observed in studies on boys with ASD, while in boys with FRAXA, the frequencies of ASD range from 20% to 40% (Kaufmann et al., 2004; Shibayama et al., 2004). Tuberous Sclerosis, another monogenic disease that results from mutations in the *TSC1* and *TSC2* genes, is observed in about 1% of individuals with ASD and is regarded as the second most common genetic cause of the autistic phenotype (Smalley, 1998).

The list of medical conditions associated with the autistic phenotype, including genetic syn‐ dromes, is growing. Examples of genetic conditions associated with autism and the gene re‐ gions involved are: Angelman Syndrome (*UBE3A*), Rett syndrome (*MECP2*), neurofibromatosis (*NF1*), Timothy syndrome (*CACNA1C*), Smith-Lemli-Opitz syndrome (*DHCR7*), CHARGE (*CHD7*), Cohen syndrome (*VPS13B*), Noonan syndrome (*PTPN11*), 2q37 deletion syndrome, Cornelia de Lange syndrome (*NIPBL, SMC1A* and *SMC3*), DiGeorge/ Velocardiofacial syndrome (22q11), Smith-Magenis (*RAI1*), Williams-Beuren syndrome (7q11.23) and Phelan-McDermid syndrome (22q13.3) (Berg et al.,2007; Phelan, 2008; Dela‐ haye et al., 2009; Van der Aa et al., 2009; Laje et al., 2010; Betancour, 2011).

Many inborn errors of metabolism also seem to contribute to at least 5% of ASD cases as the de‐ ficiency of certain enzymes in metabolic diseases can result in the accumulation of substances that may have toxic effects on brain development. An example is phenylketonuria, an autoso‐ mal recessive disorder that, if untreated, leads to excessively high levels of phenylalanine and toxic metabolites, resulting in intellectual disabilities and ASD (Manzi et al., 2008).

Due to the high number of cases that have been described and the type of genes located in them, the association of eight chromosomal regions is well established in autism including: 1q21, 7q11.23, 15q13, 15q11-13, 16p11.2, 17p11.2, 22q13.3 and 22q11.21. Rearrangements in‐ volving these regions are detected by classic cytogenetic techniques but it is recommended that more sophisticated techniques, such as array comparative genomic hybridization (ar‐

Genetic Etiology of Autism http://dx.doi.org/10.5772/53106 221

As expected, unbalanced changes are more frequently found in dysmorphic individuals and with delays in neuropsychomotor development due to the "extent of damage" because they result in significant gains and losses of gene content. Balanced rearrangements, however, are less frequent and can be related to mutations in DNA breakpoints. Some are so rare that it is difficult and risky to consider them a cause of autism. However, some occur at high enough frequencies to be considered risk factors for the disease. Identifying balanced changes is im‐ portant for genetic counseling, not only due to the etiologic implications, but also because these changes may predispose descendants to unbalanced rearrangements (Carter, 2011;

However, chromosomic analysis detects only 3-5 megabase abnormalities. New technolo‐ gies using DNA or chromosomal microarrays can identify submicroscopic abnormalities. Microdeletions and duplications, e.g., may be identified with microarrays in individuals with ASD who previously had normal kariotype. Therefore, if cytogenetic analysis is nega‐

According to recent findings, some common mutations, epigenetic mechanisms, chromo‐ some alterations, rare single gene mutations, copy number variations (CNVs) and single nu‐ cleotide polymorphisms (SNPs) result in the autistic phenotype. Because of national and international consortia, many linkage and genome-wide association studies have evolved which elucidated candidate genes and susceptibility of genomic regions relevant to ASD. In contrast to polygenic or complex genetic models for autism, suggested in the majority of cas‐ es, a few forms of ASD are known to be caused by single gene defects, such as in FRAXA

According to a review by Betancour (2011) more than 100 candidate genes for autistic be‐ havior are also related to syndromic or nonsyndromic intellectual disabilities. Many are also associated with epilepsy, with or without intellectual disabilities; this suggests that these

Mutations in a single gene may be autosomal dominant, recessive or X-linked. Some, not al‐ ways related to syndromic cases, are highly penetrating and appear at sufficiently high fre‐ quencies to be considered monogenic causes of autism. Of the growing list, the most important candidate genes are: *NLGN3*, *NLGN4*, *SHANK2*, *SHANK3*, *NRXN1*, *NRXN3*, *PTCHD1/PTCHD1AS*, *SHANK1*, *DPYD*, *ASTN2*, *DPP6*, *MBD5*, *CDH8* and *CNTNAP2*. It is

ray-CGH), are used for their evaluation (Gillberg, 1998; Griswold et al., 2012).

Sherer & Dawson, 2011; Nowakowska et al., 2012).

(Chiocchetti & Klauck, 2011; Dhillon et al., 2011).

**7. Candidate genes**

tive in clinically diagnosed ASD, molecular techniques are necessary.

neurodevelopment disorders have risk factors in common with ASD.

Mitochondria are intracellular organelles that have the function of producing energy. In the mitochondria ATP production, free oxygen radicals and reactive oxygen species (ROS) are produced and then normally removed from the cells by anti-oxidant enzymes. When the production of ROS and free radicals exceeds the limit, oxidative stress occurs, that is, ROS combine with lipids, nucleic acids and proteins in the cells leading to cell death by apoptosis or necrosis. Since brain cells have limited antioxidant activity, a high lipid content and high requirement for energy, it is more prone to the effects of oxidative stress. Some patients with ASD and mutations in mitochondrial DNA have already been reported (Fillano et al., 2002; Dhillon et al., 2011). The first study involving bioenergetic metabolism disorders in ASD was directed by Coleman & Blass (1995), who reported lactic acidosis in four children with autism. Later Lombard (1998) proposed that mitochondrial oxidative phosphorylation can cause abnormal brain metabolism in children with autism resulting in acidosis. A study by Pons et al. (2004) described five children with ASD who had abnormal respiratory chain en‐ zyme activity, characterized by the *A3243G* mutation. Graf et al. (2000) described two broth‐ ers with autism associated with a mitochondrial DNA *G8363A* RNA(Lys) mutation.

All these diseases, in addition to peculiar and specific clinical signs and symptoms, have au‐ tism as a common manifestation. However, with so different genetic etiologies and proba‐ bly, the involvement of different interaction mechanisms, what do they have in common that explains the autistic behavior? The autistic behavior is attributed to changes in neurode‐ velopment and all these diseases cause changes in the brain structure and/or functioning, probably damaging cerebral areas that are linked to autistic symptoms.

In the clinical practice, the recognition of these conditions is fundamental, as it allows the targeting of laboratory tests and assists in the initial breakdown of etiological heterogeneity which categorizes specific cases of autism as syndromic or nonsyndromic. This definition is important because of possible implications in the prognosis and recurrence risk (Miles, 2011; Gurrieri, 2012).
