The first autism disease genes

September 02, 2008

The autistic disorder was first described, more than sixty years ago, by Dr. Leo Kanner of the Johns Hopkins Hospital (USA), who created the new label 'early infantile autism'. At the same time an Austrian scientist, Dr. Hans Asperger, described a milder form of the disorder that became known as Asperger Syndrome, characterised by higher cognitive abilities and more normal language function. Today, both disorders are classified in the continuum of 'Pervasive Developmental Disorders' (PDD), more often referred to as Autism Spectrum Disorders (ASD).

The prevalence of (classic) autism in the general population is about 15-20 in 10.000, while all Autism Spectrum Disorders (ASD) affect about 60 in 10.000 children. Males are affected four times more often than females. In approximately 10% of cases, autism is associated with a recognized cause, such as Fragile X Syndrome, Tuberous Sclerosis or diverse chromosomal abnormalities (mean observed rates between 5-10%), but in a vast majority of cases, no known causes are associated with autism (see figure).

All of these neurodevelopmental disorders are characterized by varying deficits in communication skills, social interactions, and restricted, repetitive and stereotyped patterns of interests and activities. Problems that may accompany these disorders are sensory distortion, mental retardation or seizures. Disease onset occurs during the first three years of life. Although early intervention has considerable impact on reducing symptoms and increasing a child's ability to learn new skills, it is estimated that only 50% of children are diagnosed before the age of 3 years.

Most children with ASD respond well to behavioural management and highly structured, specialized programs in educational settings. Other therapeutic interventions comprise medications to treat behavioural problems such as aggression, self-injury, or severe tantrums.

Warning signs for Autism Spectrum Disorders such as social symptoms, communication deficits and repetitive behaviours should be considered sufficient reason to have a child evaluated by specialized professionals. The earlier the disorder is diagnosed, the sooner the child can be helped through treatment interventions.

Advances in autism research: genetic influences

Research into the causes, diagnosis, and the treatment of ASD has advanced interactively. Imaging studies have shown that many major brain structures are implicated in autism. Other research is focusing on the role of neurotransmitters such as serotonin, dopamine, and epinephrine. The past decade has been marked by an increased interest in the genetic basis of autism, and recent developments point to genetic factors playing a prominent role in the causes for ASD.

The role of gene mutations in autism

Twin and family studies have suggested an underlying genetic vulnerability to ASD. The estimated prevalence of autism in siblings is 5-10%. A higher recurrence risk in families with autistic subjects (45-times greater than the prevalence in the general population) and higher concordance for autism among monozygotic (60-90%) than dizygotic (0-10%) twins argue for a genetic predisposition to idiopathic autism. These data are interpreted as showing that liability to autism is in large part due to oligogenic inheritance in which a combination of multiple - possibly interacting - susceptibility alleles results in autism. A series of multiple independent whole genome scans and chromosomal abnormality studies have pointed out several candidate regions on chromosomes 2q, 7q, 6q, 15q and sex chromosomes. These regions possess candidate genes that have been screened for mutations or association with autism. In a European multicentre project called PARIS (Paris Autism Sib-pair International Study; coordinated by C. Gillberg & M. Leboyer) a large number of multiply affected families were identified, and several mutations of genes encoding proteins implicated in the process of synapse formation (synaptogenesis) have been described.

Autism and synapse formation (synaptogenesis)

In 2003 two new highly conserved members of the human neuroligin family - HNL4, located at Xp22.3 - were characterized (Jamain et al, 2003). A crucial factor in synapse formation, neuroligins are cell adhesion molecules that can trigger the formation of presynaptic structures in non-neuronal cells. The rare mutations of the neuroligins (1%) are associated with autism spectrum conditions. Another step forward in this compelling neurobiological story was the identification of a de novo frame-shift mutation in the X-linked HNL4 gene in two brothers, one with autism and the other with Asperger Syndrome. Since autism and Asperger Syndrome are overly represented in males, mutations in these genes may influence the process of synaptogenesis, and consequently may predispose males to Autism Spectrum Disorders.

In 2007, mutations of another gene encoding SHANK3 were reported (Durand et al, 2007). This gene regulates the structural organization of dendritic spines in neurons and is a binding partner of neuroligins, previously found to be mutated in autism and Asperger Syndrome. Surprisingly, a mutation of a single copy of SHANK3 at chromosome 22q13 is sufficient to induce language impairment, learning disabilities and/or social communication disorders associated with Autism Spectrum Disorders. Frequency of SHANK3 variants is very low even among autism patients and nearly absent in the general population. These results have thus shed light on one synaptic pathway sensitive to gene dosage and associated to Autism Spectrum Disorders.

In a large international study with a sample of 1.168 multiplex families, another exciting discovery led to the detection of sub-microscopic chromosomal abnormalities (Autism Genome Project, 2007): Copy Number Variant analysis (CNV) highlighted the role of a gene encoding neurexin, which is a tightly linked protein to neuroligin, implicated in synapse formation for glutamate neurons. This revealed a hemizygous deletion of coding exon for neurexin gene for a pair of affected siblings. Accumulating evidence thus points out that neurexin/neuroligin/Shank3 (NLGN3/4, SHANK3, NRXN1) genes are related to autism risk, establishing a direct proof of the association of autism with synaptic abnormalities. Neurexin induces glutamate postsynaptic differentiation in contacting dendrites, while neuroligins induce presynaptic differentiation in glutamate axons. The neurexin-neuroligin link thus appears to be fundamental for glutamatergic synapse formation. Furthermore, aberrant glutamate function is often cited as a cause for autism.

By influencing the process of synapse formation for glutamate neurons, gene mutations predispose individuals to Autism Spectrum Disorders.

Autism and circadian rhythms

Another approach in research of the genetics of autism implies the melatonin pathway. Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level was reported in individuals with Autism Spectrum Disorders, but the underlying cause of this deficit was unknown. In several individuals with Autism Spectrum Disorders, deletions of the ASMT-gene were found. This gene, located on the pseudo-autosomal region 1 of the sex chromosomes, encodes the last enzyme of melatonin synthesis. Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in AMST activity and melatonin level in individuals with Autism Spectrum Disorders (Melke et al., 2008).

Recent research indicates that a low melatonin level, caused by a primary deficit in gene activity (AMST), is a risk factor for Autism Spectrum Disorders, and highlights the crucial role of melatonin in human cognition and behaviour.

Clinical implications

* These findings stress the importance of further research into genetic abnormalities in autism to obtain a better understanding of the underlying disease mechanisms. However, several questions such as correlations between genotypes and phenotypes including cognition and brain imaging studies still remain to be investigated.

* Research to unravel autism requires multidisciplinary approaches involving psychiatrists, psychologists, geneticists and brain imaging specialists.

* Autistic patients require a broad workout taking into account psychiatric, somatic, cognitive, social and professional issues; furthermore they should be invited to participate in various research projects, ranging from fundamental research to more applied projects on the development of new therapeutic strategies. In view of these requirements the French Ministry of Research has established in 2007 the foundation Fondation FondaMental with the aim to intensify research in this field and to offer high-functioning autistic subjects optimal treatment and care in specialized expert centers.

###

References

1. Jamain S, Quach H, Betancur C, et al. on behalf of the PARIS study investigators. A de novo frameshift mutation of HNL4, an X-linked neuroligin, is associated with autism. Nature Genetics 2003;34:27-29
2. Durand C, Betancur C, Boeckers T, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 2007;39:25-27
3. The Autism Genome Project. Mapping autism risk loci using genetic linkage and chromosomal rearrangement, Nature Genetics 2007;39:319-328
4. Melke J, Botros H-G, Chaste P, et al. Abnormal Melatonin Synthesis in Autism Spectrum Disorders. Molecular Psychiatry 2008;13:90-98

European College of Neuropsychopharmacology

---

---

	Social Skills for Teenagers with Developmental and Autism Spectrum Disorders: The Peers Treatment Manual by T & F Books US This book is essential reading for any clinician or researcher working with teens with autism spectrum disorders. This parent-assisted intervention for teens is based on a comprehensive, evidence-based, 14-week program at UCLA‘s Semel Institute for Neuroscience and Human Behavior, the manualization of the popular UCLA PEERS Program, and the success of the Children‘s Friendship Training (Routledge, 2002) manual for children.After reviewing techniques designed to help parents and therapists tailor the manual to the needs of the teens with whom they are working, the text moves on to the individual treatment sessions and strategies for tackling issues such as developing conversational skills, choosing friends, using humor, get-togethers, teasing, bullying, gossiping, and handling...
	Autism Spectrum Disorders: Foundations, Characteristics, and Effective Strategies by E. Amanda Boutot (Author), Brenda Smith Myles (Author) Responding to the increasing numbers of students diagnosed with autism spectrum disorders (ASD) in schools, and the need for all teachers to be prepared with research-based strategies to instruct these students, this new book provides a comprehensive overview of what autism spectrum disorders are, their identification, and treatment approaches; specific information on diagnosis, learning behavioral, cognitive, and sensory characteristics, and etiology; and evidence-based practices for instruction, including social skills, communication, and academics. Other featured concepts include: a model for determining appropriate, individualized practices; assessment and planning including environmental planning; information to support teachers as they develop programs and learning environments;...
	Incredible 5-Point Scale Assisting Students with Autism Spectrum Disorders in Understanding Social Interactions and Controlling Their Emotional Responses by Kari Dunn Buron (Author), Mitzi Curtis (Author) This must-have resource shows how the use of a simple 5-point scale can help students understand and control their emotional reactions to everyday events. This book shows how to break down a given behavior and, with the student s active participation, develop a scale that identifies the problem and suggests alternative, positive behaviors at each level of the scale.
	Autism Spectrum Disorders: The Complete Guide to Understanding Autism, Asperger's Syndrome, Pervasive Developmental Disorder, and Other ASDs by Chantal Sicile-Kira (Author), Temple Grandin (Foreword) Based on nearly two decades of Chantal Sicile-Kira's personal and professional experiences with individuals and families affected by this growing epidemic, Autism Spectrum Disorders explains all aspects of the condition, including: - The causes of autism spectrum disorders - How to properly diagnose ASDs - Treatments based on behavioral, psychological and biomedical interventions - Coping strategies for families - Educational needs and programs - Living and working conditions for adults with ASD - Community interaction - Teaching strategies and resources for educators and other professionals
	The Survival Guide for Kids with Autism Spectrum Disorders (And Their Parents) by Elizabeth Verdick (Author), Elizabeth Reeve M.D. (Author) This positive, straightforward book offers kids with autism spectrum disorders (ASDs) their own comprehensive resource for both understanding their condition and finding tools to cope with the challenges they face every day. Some children with ASDs are gifted; others struggle academically. Some are more introverted, while others try to be social. Some get "stuck" on things, have limited interests, or experience repeated motor movements like flapping or pacing ("stims"). The Survival Guide for Kids with Autism Spectrum Disorders covers all of these areas, with an emphasis on helping children gain new self-understanding and self-acceptance. Meant to be read with a parent, the book addresses questions ("What’s an ASD?" "Why me?") and provides strategies for communicating, making and...
	Assessment of Autism Spectrum Disorders by Sam Goldstein PhD (Editor), Jack A. Naglieri PhD (Editor), Sally Ozonoff PhD (Editor) Significant progress has been made in assessing children with autism spectrum disorders, but the field has lacked a single, comprehensive resource that assembles current best practices within a unified assessment framework. This authoritative book demonstrates how to craft a complete, scientifically grounded, and clinically useful portrait of a child's strengths and difficulties in social behavior, language and communication, intellectual functioning, motor skills, and other key areas of impairment and comorbidity. Leading experts illustrate ways in which school and clinical practitioners can integrate data from a variety of sources to improve the accuracy of diagnosis and inform the development of individualized interventions. (20100105)
	Adolescents on the Autism Spectrum: A Parent's Guide to the Cognitive, Social, Physical, and Transition Needs ofTeenagers with Autism Spectrum Disorders by Chantal Sicile-Kira (Author), Temple Grandin (Foreword) From the award-winning author of Autism Spectrum Disorders, comes Adolescents on the Autism Spectrum, a complete guide to the cognitive, emotional, social, and physical needs of preteens and teenagers with autistic disorders, ranging from the relatively mild Asperger's Syndrome to more severe ability impairment. Using clear examples, practical advice, and supportive insights, this book covers: - Health risks such as seizures and depression - Treatments, therapies, and teaching strategies - Teaching skills to cope with puberty, self-care, and social skills - Teenage emotions, sexuality, appropriate relationships, and dating - Middle school, high school, and developing an Individual Educational Program - Preparing for life after high school
	Students with Autism Spectrum Disorders : Effective Instructional Practices by L. Juane Heflin (Author), Donna Florino Alaimo (Author) Broadened public awareness of autism and other associated spectrum disorders, combined with continuing research, means that more students than ever before are being identified with these disabilities. This book is an excellent resource for any teacher working with students who have ASD because it discusses how to identify and describe individuals with autism spectrum disorder, develop effective programs, create contexts for instruction, accommodate sensory issues, use applied behavior analytic instructional strategies and program for challenging behavior. Separate chapters are devoted to communication, socialization, academic skill acquisition and non-academic environments.  Information on the use of technology is infused throughout the book and makes this an invaluable reference for...
	Autism Spectrum Disorders: Identification, Education, and Treatment by Dianne Zager (Editor) The field of autism has been growing at an unprecedented rate in recent years. In addition to an actual rise in the number of classic DSM-IV cases, broadened diagnostic criteria have uncovered a wider range of autistic behaviors and ability levels. The third edition of this well-known text continues the mission of its predecessors--to present a comprehensive, readable, up-to-date overview of the field of autism, one that links research, theory, and practice in ways that are accessible to both practitioners and parents. Key features include: *Expanded Coverage--To accommodate the recent explosion of research, the book has been expanded from 11 to 14 chapters that examine the impact of autism on the individual and the family from infancy through...
	Autism Spectrum Disorders and AAC (Augmentative and Alternative Communication) (Aac Series) by Pat Mirenda (Author), Pat Mirenda (Editor) As a volume in the AAC series, this book addresses the use of AAC for children and adolescents with autism to enhance their language, communication, and literacy development.