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Author Notes:

Email Address: David R. Lynch : lynchd@gmail.med.upenn.edu

Mr. Lazaropoulos, Dr. Dong, Mr. Greeley, Dr. Deutsch, Mr. Christie, Ms. Clark were involved in Performance of basic experiments.

Ms. Seyer, Ms. Brigatti, Mr. Christie, Mr. Greeley, Dr. Perlman, Dr. Lynch, Dr. Mathews, Dr. Zesiewicz, Dr. Subramony, Dr. Wilmot, Dr. Gomez, Dr. Yoon, and Dr. Hoyle contributed to collection of clinical data.

Ms. Seyer, Ms. Brigatti, Ms. Clark, Dr. Deutsch, Dr. Perlman, Dr. Lynch, Dr. Mathews, Dr. Zesiewicz, Dr. Subramony, Dr. Wilmot, Dr. Gomez, Dr. Yoon, Dr. Wilson, and Dr. Hoyle were involved in conceptualization of experiments.

Mr. Lazaropoulos, Dr. Lynch, Dr. Deutsch, Ms. Brigatti contributed to writing of first Draft. All authors performed critical revision and editing.

We acknowledge the support of Marek Napierela (University of Alabama) for aid in fibroblast culture, and the coordinators of the Friedreich Ataxia Clinical Outcome Measure Study for data entry.

We also thank the subjects and families for donating their time and samples in participating.

Mr. Christie, Ms. Brigatti, Mr. Greeley, Dr. Dong, Ms. Clark, Dr. Deutsch, Ms. Seyer, Dr. Wilson, and Mr. Lazaropoulos have nothing to disclose.

Dr. Lynch reports grants from Friedreich Ataxia Research Alliance for the present work, and grants from Edison Pharmaceutical, Viropharma, and Reata outside the submitted work.

Dr. Subramony reports grants from Friedreich Ataxia Research Alliance FARA, during the conduct of the study; personal fees from Athena Diagnostics, outside the submitted work.

Drs. Perlman, Yoon, Gomez, Zesiewicz, Hoyle, and Brocht report grants from the Friedreich’s Ataxia Research Alliance during the conduct of the study.

Dr. Mathews reports grants from Friedreich’s Ataxia Research Alliance during the conduct of the study, and grants from Viropharma, Serepta, Prosensa, and Eli Lilly outside the submitted work.

Dr. Wilmot reports grants from the Friedreich Ataxia Research Alliance during the study, and personal income from Santhera pharmaceuticals outside the study.

Ms. Farmer is an employee of the Friedreich At axia Research Alliance.


Research Funding:

This work was supported by a grant from the Friedreich Ataxia Research Alliance.

Frataxin levels in peripheral tissue in Friedreich ataxia.

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Journal Title:

Annals of Clinical and Translational Neurology


Volume 2, Number 8


, Pages 831-842

Type of Work:

Article | Final Publisher PDF


OBJECTIVE: Friedreich ataxia (FRDA) is an autosomal recessive ataxia resulting from mutations in the frataxin gene (FXN). Such mutations, usually expanded guanine-adenine-adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues. The goal was to understand the relationship of frataxin levels in peripheral tissues to disease status. METHODS: Frataxin levels were measured in buccal cells and blood, and analyzed in relation to disease features. Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations. RESULTS: There was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood. INTERPRETATION: The present data show that peripheral frataxin levels reflect disease features in FRDA, but emphasize the need for interpretation of such levels in the context of specific mutations.

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© 2015 The Authors.

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