Autism, ID linked to levels of fragile X syndrome

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27 Oct 2020, 3:00 am

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People with particularly low levels of FMRP, the protein lacking in those with fragile X syndrome, are more likely to also have autism and severe intellectual disability, according to a new study1. The lower the level of FMRP, the more severe a person’s traits.

Fragile X syndrome occurs when a section of the FMR1 gene, which codes for FMRP, contains more DNA ‘letter’ repeats than usual. The repeats silence the gene by driving DNA methylation: Molecules called methyl groups attach to a region of the gene where it can be switched on, blocking production of FMRP, a protein necessary for communication among neurons. Most people with the syndrome have intellectual disability (ID), and many also have autism.

The extent to which the methyl groups attach to the gene can vary among people with fragile X and from cell to cell, leading to different levels of FMRP in people with the same underlying genetics2. The new work confirms the relationship between the number of repeats and an individual’s traits with greater precision than before: More repeats lead to more methylation, causing lower protein levels and more severe traits.

The researchers analyzed blood samples and cheek swabs from 42 people with FMR1 mutations, nine of them female. Two male and three female participants have 55 to 200 DNA letter repeats, something known as a premutation.

They were able to analyze FMRP levels in 31 individuals who have full mutations — more than 200 repeats. The boys and men have lower FMRP levels than the girls and women. Because FMR1 is located on the X chromosome, girls and women — who have two X chromosomes — are less likely to be severely affected.

Among the 26 boys and men with full mutations, those who show mosaicism, or different levels of methylation or gene expression in different cells, have twice as much FMRP overall as those without mosaicism. (There were too few girls and women in the study for this analysis.) Individuals with full mutations have higher methylation levels and lower FMRP levels than do those with premutations.

The researchers evaluated the participants with full mutations for autism, anxiety, practical life skills, difficult behaviors and ID, as measured by intelligence quotient (IQ). Nearly all have some level of ID, and almost half also have autism.

Those with fragile X and autism have half as much FMRP as those without autism, the team found. Among boys and men with fragile X, those with severe ID have even lower levels of the protein than boys and men with mild or moderate disability, regardless of whether they are autistic.

The findings were published in Brain Science in September.


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DSM 5: Autism Spectrum Disorder, DSM IV: Aspergers Moderate Severity

My autism is not a superpower. It also isn’t some kind of god-forsaken, endless fountain of suffering inflicted on my family. It’s just part of who I am as a person. - Sara Luterman