The diagnosis for autism is based on behavioral differences, the first signs of which can be observed in infants. Autism is classified as a spectrum disorder. That is, its diagnosis covers a spectrum of abnormal behaviors that differ in severity, ranging from people who repetitively self-injure and may be considered mentally retarded to individuals who score extremely high on intelligence tests and may develop an intense, obsessive passion for a particular subject, but profoundly lack social skills. The Austrian pediatrician Hans Asperger was the first to recognize the latter as a distinct group of patients (Asperger's syndrome), and autism has been classified as a spectrum disorder with repetitive behaviors and difficulty with empathy as common symptoms.
The heritability of autism spectrum disorder (ASD) is high. ASD may run in families. The odds of developing autism are enhanced for a twin whose sibling is diagnosed with the disorder (Hallmayer and others, 2011). Gene sequencing has implicated a plethora of genes modified during late pregnancy. In addition, a recent genome-wide study showed that in sperm new genetic mutations known as single nucleotide polymorphisms (SNPs) increase with male age, increasing the odds of SNPs to effect developmental disorders like autism and schizophrenia in children sired by older fathers (Kong and others, 2012). In particular cases of familial autism, genetic deletions have been identified, the precise role of which needs to be elucidated (Morrow and others, 2008).
Cellular and molecular modifications
People with ASD show no striking differences in gross brain anatomy, except for a modest diminution in the size of the corpus callosum (see review by Booth and others, 2011). The nerve cell connections between the cerebral hemispheres travel through this structure. The precise cellular and molecular mechanisms underlying the disorder remain poorly understood. However, a particular type of nerve cell in cerebral cortex, which Constantin von Economo called spindle cells, has recently been found associated with empathy (see my post with the title "Constantin von Economo's Spindle Cells & The Mind" published on Aug. 21, 2009) and may play an instrumental role in asocial behavior.
On the molecular level, the excitatory neurotransmitter glutamate and its receptors, notably the ionotropic N-methyl-D-aspartate (NMDA) receptor, have been shown to be crucial for the plasticity of nerve cell connections important to learning and memory. The receptors, which are composed of voltage-gated calcium channels, help strengthen connections of nerve cells that are most active together. The American psychologist D.O. Hebb postulated this strengthening based on his observations on animal learning (see my post with the title "Cortical Development & Schizophrenia" published online Aug. 14, 2008).
Nerve cell connections in the developing brain undergo a period of exuberance during which nerve cells grow a multitude of arbors, seeking contact with other nerve cells (see my post with the title "Genes, Brain Plasticity & Memory" published online May 7, 2009). However, idle connections are subsequently pruned, while those that are used strengthen and endure as Hebb suggested. The survival of these connections depends on excitatory sensory input and is experience-dependent.
Developmental mental disorders are thought to result from disruptions of Hebb's mechanism. Fragile X syndrome (FXS), which leads to behavior that can be considered autistic, may serve as example. The gene mutation involved in FXS blocks the synthesis of a regulatory protein, permitting excessive protein biosynthesis that leads to abnormalities in the development of glutamatergic nerve cell connections. Recent clinical trials have shown that some FXS patients improve with drugs affecting the glutamatergic nervous system (Berry-Kravis and others, 2012).
However, despite progress addressing the needs of specific groups of the spectrum, autism remains a disorder with manyfold causes affecting numerous molecular pathways in varied fashion. The effect of each genetic modification may be inconspicuous. Yet, molecular pathways crosstalk and their multiplexed interactions combined may decisively skew the experience-dependent development of cerebral nerve cell connections. In ASD, the synergism of the modified molecular pathways may diminish or defocus brain plasticity during a period in which the shaping of nerve cell connections peaks and the brain seems most susceptible to stimulation.
Because glutamate is the most prevalent neurotransmitter in the brain, the effects of the pathway modifications can be expected to be wide-spread, though the brain's most plastic structures may be particularly vulnerable. The latter include the hippocampus, which plays an instrumental role in memory, and the amygdala involved in fear responses. However, glutamate's ubiquitous role renders the development of a universal drug therapy specifically targeting autistic behavior difficult. Rather, each spectral subgroup's peculiar causes must be identified and therapies need to be developed that target these peculiarities.
ASD may not be based on genetic mutations alone. The famous feral child Kaspar Hauser, who was left in social depravity for years (see my post with the title "Theory of Mind I: Feral Children & Language Development" published online Dec. 31, 2008), might have well been diagnosed with ASD today. Despite his delayed entry into civil life, the adolescent Kaspar was able to learn language, calculus, fine arts and social skills from various caretakers and a professor, in whose hands he seemed to have thrived. In his time, Kaspar was cast as a devious, good-for-nothing 'idiot'. By contrast, with emerging expertise in child psychology and special education, modern-day children on the spectrum may reap benefit from early behavioral interventions that stimulate and strengthen nerve cell connections mediated by our own endogenous neurotransmitters and neuromodulators without the need for genomic sequencing and psychoactive drugs (Dawson and others, 2009).
- Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RF (2012) Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Sci. Transl. Med. 4, 152ra127.
- Booth R, Wallace GL, Happé F (2011) Connectivity and the corpus callosum in autism spectrum conditions: insights from comparison of autism and callosal agenesis. Prog Brain Res 189:303-317.
- Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J (2009) Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics doi:10.1542/peds.2009-0958.
- Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N (2011) Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry doi:10.1001/archgenpsychiatry.2011.76
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- Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218-223.