FIGURE 4-1 Comparison of brain-stem neuroanatomy of a control and a patient with autism. In the brain on the right, the number of neurons in the facial nucleus is greatly reduced, and a region caudal to it appears to be missing. The more caudal nuclei are shifted rostrally. The missing area is similar to the embryonic fifth rhombomere, from which most of the facial nucleus arises. Source: Adapted from Rodier et al. (1996).

able to describe alterations of the human brain stem related to autism and to create an animal model of the initial insult using exposure to valproic acid (Rodier et al. 1996). In addition, in cases of autism of unknown cause, they documented the existence of minor physical anomalies that were similar to those reported in the thalidomide-exposed cases (Rodier et al. 1997). The craniofacial symptoms had been reported before in the autism literature, but ignored because they seemed trivial in comparison to the disabling behavioral symptoms. However, the craniofacial defects speak directly to the embryological origin of the disorder. The anatomical studies described effects almost identical to those seen in mice with null mutations of the gene HoxA1 (Chisaka et al. 1992; Carpenter et al. 1993), which is essential to brain-stem and ear development and expressed only during the period of neural tube closure. No variants of HoxA1 had ever been detected in any mammalian species, but the teratological findings suggested the hypothesis that defective versions of the gene must exist and must contribute to the genetic etiology of autism.

Remarkably, an alternate allele of HoxA1 was discovered in a substantial number of people diagnosed with ASD (Rodier 1998). The variant allele not only appeared significantly more frequently in familial cases than in historical controls or parent controls, but the number of homozygotes was significantly reduced from the expected value in all groups, suggesting that homozygosity for the variant reduces viability. (The mouse knockout of the same gene is lethal soon after birth.) A second variant of HoxA1 has since been detected in cases of autism and is under investigation (Stodgell et al. 1999). Further, it has now been



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