Rethinking Autism (ePub)

"Rethinking Autism is a book that needed to be written, and Waterhouse has written it extremely well. The central claim of the book that researchers must move beyond the construct of the ICD or DSM diagnosis of autism is very well supported, and, in my view, nearly irrefutable. The book makes clear that understanding the varied risk factors for autism symptoms and the variable pathogenesis of autism symptoms is crucial with respect to treatment implications and outcome.

Some researchers have reported that a minority of boys with the fragile X premutation have autism spectrum disorder (as is illustrated by a clinical description of twins in the book). However, it is important to note that studies making a premutation-autism link have been affected by sampling bias, and the actual risk for intellectual or behavioral disability in this population, though yet to be definitively established, is probably quite low. Further, though the book correctly notes that the vast majority of individuals with the fragile X premutation have normal intellectual abilities and no autism symptoms, the book's statements on p. 53 and 193 errantly identify excess FMR1 messenger RNA found in association with the fragile X permutation as a cause for autism symptoms. While there is significant evidence that the lack of FMR1 protein is linked to autism symptoms and intellectual disability in the fragile X syndrome, there is little evidence that excess FMR1 messenger RNA in fragile X premutation causes autism symptoms or intellectual disability. What may be possible in some humans with the premutation, as Qin et al. (2011) reported for mice with the premutation, is that lower levels of FMRP protein may contribute to increased risk for autism symptoms."

Allan L. Reiss, M.D., Robbins Professor and Director, Center for Interdisciplinary Brain Sciences Research Vice Chair, Department of Psychiatry and Behavioral Sciences Professor of Radiology and of Pediatrics Stanford University School of Medicine

Dr. Waterhouse's note on Fragile X permutation brain effects:

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in the world. As is discussed in the book, a small but significant subset of individuals diagnosed with autism are found to have Fragile X syndrome. Moreover, as is outlined in the beginning of Chapter 2, in rare cases individuals with autism symptoms have been found to have a related genetic disorder, the Fragile X premutation. Fragile X premutation and Fragile X syndrome both result from too many repeats of three linked amino acids in a neighboring region of the Fragile X mental retardation 1 (FMR1) gene. In Fragile X syndrome, there are 200 or more repeats. By contrast, in the Fragile X premutation syndrome there are only 55-200 repeats. There is also a gray area of 41-54 repeats that has been associated with physical and mental problems.

Intellectual disability and social impairment in Fragile X syndrome and Fragile X premutation have been tied to lower levels of the Fragile X mental retardation protein (FMRP) in the brain. However, not all those with Fragile X premutation have severely reduced FMR1 protein in their brains, and many have abnormally high levels of the FMR1 RNA. RNA is required for genes to produce proteins, but abnormally high levels of RNA have been found to have toxic brain effects in those with repeat mutations in a variety of genetic diseases.

The toxicity of excessive FMR1 RNA in the brain has been linked to tremors, problems in walking, and cognitive decline in individuals with Fragile X premutation who develop Fragile X-associated tremor/ataxia syndrome (FXTAS) in adulthood. However, Tassone and Hagerman (2012) have noted that evidence of RNA toxicity can be found in early brain development, and they concluded that excessive FMR1 RNA is a likely cause of brain disruption in children who have Fragile X premutation.