Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner

Nethisinghe, S.; Kesavan, M.; Ging, H.; Labrum, R.; Polke, J.M.; Islam, S.; Garcia-Moreno, H.; Callaghan, M.F.; Cavalcanti, F.; Pook, M.A.; Giunti, P. Int. J. Mol. Sci. 2021, 22, 7507. doi:10.3390/ijms22147507 

The GAA repeat tract in some cases may be impure with sequence variations called interruptions. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5′ and 3′ ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3′ interruptions being most frequent. Based on detection of interruptions by TP PCR assay, the patient cohort (n = 101) was stratified into four groups: 5′ interruption, 3′ interruption, both 5′ and 3′ interruptions or lacking interruption. Those patients with 3′ interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Based on this modelling, a 3′ interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5′ and 3′ interruptions. This highlights the key role of interruptions at the 3′ end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.

Would Francisco Soca have been the first to relate toe phenomenon as pyramidal disorders?

élio A.G. Teive, Carlos Henrique F. Camargo, Nicolás Sommaruga, Héctor Ignacio Amorin-Costábile, Olivier Walusinski; Journal of Clinical Neuroscience, Volume 91, 2021, Pages 172-175, doi:10.1016/j.jocn.2021.07.013. 

 The Uruguayan physician Francisco Soca, who specialized in neurology in Jean-Martin Charcot’s clinic, defended a thesis at the Paris Faculty of Medicine in 1888 on Friedreich's ataxia in eleven patients. In this work he described the presence of toe phenomenon. In the late 1800s Soca completed a specialization in neurology at the service run by Charcot in Paris. He defended an important thesis in 1888 assessing data from 11 Friedreich’s ataxia. In his thesis, Soca also described the toe phenomenon and the presence of structural changes in the feet of these patients that were not described in the Friedreich study published in 1863. The Soca’s thesis contained the description of toe extension associated with pyramidal tract lesions, eight years later described and further immortalized as Babiński's sign. Therefore, Soca had already publicized this sign as being representative of a pyramidal dysfunction before Babiński or any other neurologist.