They took a family where many members stutter, isolated the responsable gene and studied their brains, created a mouse with the same gene issue, studied the brain of these mice and compared them to the brains of the stuttering family members and the other research findings.
They detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members and also significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering.
I am not an expert and didnt delve deep into their research, but this seems to me the strongest concrete evidence for a neurological basis for stuttering. It is fascinating to see how one tiny little gene leads to a different or missing protein in the brain impacting the brain development leading to abnormal neurobiology causing a low capacity speech system leading to an increased frequency and delay of being able to articulate what you know you want to say, which then leads to all kinds of secondary behaviours such as emmms, blocks, tension, word substitution and avoidance of situations leading to social reactions which then back feed onto your brain which under stress and pre-conditioned will have more and longer stuttering events even when the brain would have been able to say it fluently.
Beautiful... in a certain way... terrible for us who are afflicted with the disorder!
Happy Xmas!
Abstract
Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.
