There is growing interest in associations between neurodevelopmental and neuropsychiatric disorders across the lifespan. Case in point is the association drawn between fragile X syndrome (FXS) and fragile X–associated tremor/ataxia syndrome (FXTAS) found in subsets of older adults harboring fragile X mental retardation 1 gene (FMR1
FXS is the most common inherited form of intellectual disability.2,3
FXTAS is a condition of progressive tremor and ataxia in individuals who show no premorbid cognitive deficits, developing over the age of 50. Dementia occurs in a subset of those with FXTAS. Macrocephaly is seen in children with FXS,4
as discussed below, and brain atrophy in the cerebrum, brainstem, and cerebellum is seen in FXTAS.2
Mutation of the 5′-untranslated region (UTR) of FMR1
(chromosome Xq27.3), consisting of expanded trinucleotide CGG repeats, causes both FXS and FXTAS. FXS is caused by the full mutation of FMR1
(>200 repeats). FMR1
premutation (between 55 and 200 repeats) leads to FXTAS in a subset of carriers, with greater preponderance in male carriers than in female carriers. The full mutation present in FXS promotes hypermethylation of the gene promoter and 5′ UTR leading to inhibition of gene transcription. The resulting lack of FMR1
protein (FMRP) leads to the disease phenotype. Conversely, patients with FXTAS carrying the FMR1
premutation have elevated FMR1
mRNA levels resulting from upregulation of transcription due to presumed feedback from translational deficits generated by the expanded CGG. Toxicity results from the high levels of expanded CGG repeat-containing mRNA.2
In summary, it is believed that FXS is caused by FMRP loss of function, and FXTAS is caused by a ribo-CGG mRNA gain of function toxicity.
The association of the above-mentioned clinically divergent disorders, occurring via dissimilar mechanisms involving the same gene, sets the stage for our discussion of the amyloid-β precursor protein (APP) in relation to Alzheimer disease (AD) and to the neurodevelopmental disorders of autism and FXS. APP is the parental molecule of neurotoxic amyloid-β peptide (Aβ), produced by amyloidogenic processing of APP and secreted in excess in AD.e1 When APP is processed alternatively via the nonamyloidogenic (α-secretase) pathway, the secreted alpha form of APP (sAPPα) is produced.
Based on data from our laboratory and a review of the current literature, we speculate that overproduction of sAPPα may contribute to autism and FXS phenotypes. We specifically hypothesize that the neurotrophic properties of sAPPαe1
may contribute to the state of brain overgrowth found in FXS and autism. We further review key features of FXS, autism, and AD, and discuss the recently formulated metabotropic glutamate receptor (mGluR) theory of FXS and autism,3
highlighting putative involvement of APP (unpublished data, 2011).5,6
We also discuss the involvement of APP in neurogenesis, cell proliferation, and migration as putative mechanisms underlying macrocephaly in FXS and autism. Finally, the roles of epigenetics and gene–environment interaction are discussed.