The need for unbiased cognitive assessment in Rett syndrome: is eye tracking the answer?

Although Rett syndrome was initially described in 1966, it was virtually unknown in the broader medical community until 1983. Since then, major advances have taken place, including the implication of the MECP2 gene in the majority of cases of Rett syndrome, as well as the development of mouse models recapitulating the core characteristics of the disorder. Progress also has been made in understanding many aspects of the genotype-phenotype associations observed in Rett syndrome. Significant effort is being made towards developing targeted therapeutics to reverse or rescue the phenotype. Despite this impressive progress towards a complete understanding of the genetic underpinnings of the disorder, research aimed at developing a full observationally-based description of the Rett syndrome behavioral phenotype has been relatively stagnant over the last three decades (the RTT natural history study notwithstanding). As progress continues at the bench, there is a renewed need to refine (and possibly redefine) the range of therapeutic outcomes and clinical endpoints relevant to Rett syndrome. There remain relatively large knowledge gaps specific to the Rett syndrome behavioral phenotype. It is not clear what directly observable features of the syndrome may be most relevant for understanding health and behavior needs of individuals living with Rett syndrome, and how that information could be used to improve intervention/support service options. Novel and valid assessment approaches to understanding the Rett syndrome behavioral phenotype are needed. Initial clinical descriptions of Rett syndrome in the 1980s and 1990s included scores from standardized IQ and adaptive behavior assessments that indicated that affected individuals were functioning at levels consistent with severe to profound intellectual impairment. In reporting these results, however, the researchers rarely acknowledged the bias inherent in assessing individuals with severe apraxia and ataxia using standardized assessments founded on an assumption of verbal and motoric competencies consistent with cognitive functioning. As a result, conventional wisdom has held that Rett syndrome results in severe to profound intellectual impairment. More recently, some researchers have begun to recognize the need for the development of appropriate, accessible methods of assessment for use in this population. Because of the widespread belief among parents and practitioners that individuals with Rett syndrome communicate with their eyes, eye-tracking technology has quickly become the method of choice for such assessments. Three previous studies used eye tracking as a means of assessing cognition and comprehension among young females with Rett syndrome. Among these, however, only one included a control group, making interpretation of the results nearly impossible. The results of the one study in which a control group was included suggested that cognitive skills may be much more variable among individuals with Rett syndrome than had been previously thought, as some affected individuals performed at or near the level of age-matched, typically developing peers. Despite this provocative finding, over a decade passed without another study attempting to replicate or extend these results. The research by Rose et al. represents an important step towards the development of accessible, unbiased assessments for use with individuals with Rett syn-