Progressive GAA expansions in dorsal root ganglia of Friedreich's ataxia patients.
OBJECTIVE
Friedreich's ataxia patients are homozygous for expanded alleles of a GAA triplet-repeat sequence in the FXN gene. Patients develop progressive ataxia due to primary neurodegeneration involving the dorsal root ganglia (DRGs). The selective neurodegeneration is due to the sensitivity of DRGs to frataxin deficiency; however, the progressive nature of the disease remains unexplained. Our objective was to test whether the expanded GAA triplet-repeat sequence undergoes further expansion in DRGs as a possible mechanism underlying the progressive pathology seen in patients.


METHODS
Small-pool polymerase chain reaction analysis, a sensitive technique that allows the measurement of repeat length in individual FXN genes, was used to analyze somatic instability of the expanded GAA triplet-repeat sequence in multiple tissues obtained from six autopsies of Friedreich's ataxia patients.


RESULTS
DRGs showed a significantly greater frequency of large expansions (p < 0.001) and a relative paucity of large contractions compared with all other tissues. There was a significant age-dependent increase in the frequency of large expansions in DRGs, which ranged from 0.5% at 17 years to 13.9% at 47 years (r = 0.78; p = 0.028).


CONCLUSIONS
Progressive pathology involving the DRGs is likely due to age-dependent accumulation of large expansions of the GAA triplet-repeat sequence. Thus, somatic instability of the expanded GAA triplet-repeat sequence may contribute directly to disease pathogenesis and progression. Progressive repeat expansion in specific tissues is a common theme in the pathogenesis of triplet-repeat diseases.
De Biase
Irene
I
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Rasmussen
Astrid
A
Endres
Dan
D
Al-Mahdawi
Sahar
S
Monticelli
Antonella
A
Cocozza
Sergio
S
Pook
Mark
M
Bidichandani
Sanjay I
SI
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics* / Q000473:pathology*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000096923:Frataxin
D033862:Iron-Binding Proteins; D000096923:Frataxin