This feasibility study was to determine the potential of measuring FMRpolyG, a polyglycine protein in FXTAS that triggers inclusion formation within patient derived skin cells.

Patients meeting diagnostic criteria for FXTAS were recruited from the Rush program. Neurological examination and FXTAS rating scale were performed and skin collected from three areas using a 3 mm punch biopsy:  distal leg, distal thigh and posterior cervical region. A meso-scale delivery (MSD) assay system was used to measure FMRpolyG quantitatively in model systems and patient derived samples.

Three patients with FXTAS were recruited (2 men, 1 woman), with an age range of 61-85 years and CGG repeat size of 83-129.  Duration of disease was 7-11 years and FXTAS rating scale score was 17-20, indicating moderate disease. Case 3 also had dementia and an initial diagnosis of neuronal inclusion disease with aggregates seen on EM on skin sample. The custom MSD assay using FMRpolyG antibodies exhibited linear quantification into the femtomolar range. All three participants had FMRPolyG identified in the samples in the sweat glands and/or outermost skin layer. In case #3, with the most severe phenotype and highest repeat size, FMRPolyG was seen only in the leg sample.

This first-of-its-kind feasibility study shows that FMRPolyG can be identified in skin biopsy samples, albeit in only a proportion of the biopsies, in both men and a woman with FXTAS. Studies are currently being conducted utilizing this assay in a larger sample size to determine if the FMRPolyG is seen only in FXTAS compared to premutation carriers without FXTAS or non-FMR1 disease controls.