Elsevier

Research in Autism Spectrum Disorders

Volume 6, Issue 4, October–December 2012, Pages 1311-1320
Research in Autism Spectrum Disorders

Targeted treatments in autism and fragile X syndrome

https://doi.org/10.1016/j.rasd.2012.05.007Get rights and content

Abstract

Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted as highly heritable, there is no genetic cure at this time. Autism is shown to be linked to several genes and is a feature of some complex genetic disorders, including fragile X syndrome (FXS), fragile X premutation involvement, tuberous sclerosis and Rett syndrome. The term autism spectrum disorders (ASDs) covers autism, Asperger syndrome and pervasive developmental disorders (PDD-NOS) and the etiologies are heterogeneous. In recent years, targeted treatments have been developed for several disorders that have a known specific genetic cause leading to autism. Since there are significant molecular and neurobiological overlaps among disorders, targeted treatments developed for a specific disorder may be helpful in ASD of unknown etiology. Examples of this are two drug classes developed to treat FXS, Arbaclofen, a GABAB agonist, and mGluR5 antagonists, and both may be helpful in autism without FXS. The mGluR5 antagonists are also likely to have a benefit in the aging problems of fragile X premutation carriers, the fragile X-associated tremor ataxia syndrome (FXTAS) and the Parkinsonism that can occur in aging patients with fragile X syndrome. Targeted treatments in FXS which has a well known genetic etiology may lead to new targeted treatments in autism.

Highlights

► There is a need for efficient treatments in ASDs which has a heterogeneous etiology. ► Autism is caused by single-gene disorders in some cases including fragile X syndrome. ► Targeted treatments in FXS may be a good starting point for targeted treatments in ASDs.

Introduction

Autism spectrum disorders (ASDs) are common and occur in about 1% of the general population (Baron-Cohen et al., 2009). Although behavioral interventions at a young age are significantly helpful in children with ASD (Dawson et al., 2010), there are no pharmacological cures for these very impairing conditions that affect social interaction, communication, and behavioral domains. The etiology of autism is heterogeneous and may include genetic, environmental, and autoimmune etiologies (Levy, Mandell, & Schultz, 2009).

Section snippets

Neurobiology of autism

Autism is a highly genetic disorder and heritability is reported to be moderate to high (Hallmayer et al., 2011, Ronald and Hoekstra, 2011) and shared environmental factor are also important (Hallmayer et al., 2011). Research tells us that the genetics of autism is complex and caused by many different genetic mechanisms (Lo-Castro, Benvenuto, Galasso, Porfirio, & Curatolo, 2010). Some of the linkage and association studies have found candidate genes that contribute small effects on the autism

Aging with autism

Although it was reported that general symptomatic improvements occur as individuals with autism get older, social interaction and communication problems continue into adolescence and adulthood (Levy & Perry, 2011). There is evidence that adults with ASDs are at high risk for psychopathology (Hofvander et al., 2009). In a prospective study assessing the autism symptoms and maladaptive behaviors in adolescents and adults with ASDs, it was reported that many of the individuals’ symptoms remained

Fragile X syndrome

FXS is the most common single-gene cause of the autism and approximately 30% have full autism but when PDD NOS, which occurs in an additional 30%, is also included the total percentage with an ASD is 60% (Harris et al., 2008). FXS is caused by a full mutation (>200 CGG repeats) in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1) which is near the distal arm of the long end of the X chromosome. This mutation causes hypermethylation at the FMR1 promoter region and

Targeted treatment studies in autism

Although there are many studies on treating secondary behavioral problems in autism, treatments targeting the core symptoms of autism are relatively few. In a recent review, McPheeters et al. (2011) reported that risperidone and aripiprazole are effective in aggressive, self injurious, hyperactive and repetitive behavior in children with ASDs, although they have some adverse effects. Perhaps the most significant side effect is weight gain that can lead to metabolic problems including type II

Conclusion

There is still continuing need for more effective treatments in autism for both core and behavioral symptoms. The lack of molecular information for many types of autism has slowed down the development of targeted treatments for this heterogeneous group of disorders. FXS has been helpful for leading the way for targeted treatment in autism because of the molecular similarities between FXS and some types of autism (Wang, Berry-Kravis, & Hagerman, 2010). As targeted treatments are developed for

Conflict of interest statement

Randi Hagerman has received grant support from Novartis, Roche, Seaside Therapeutics, Curemark, Forest and HRSA for treatment studies in fragile X syndrome and autism treatment.

Acknowledgements

This work was supported by National Institute of Health grants HD036071, and HD02274; Neurotherapeutic Research Institute (NTRI) grants DE019583, and DA024854; National Institute on Aging grants AG032119 and AG032115; National Institute of Mental Health grant MH77554; National Center for Resources UL1 RR024146; and support from the Health and Human Services Administration of Developmental Disabilities grant 90DD05969.

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