Progressive gaa expansions in dorsal root ganglia of Friedreich's ataxia patients

Authors

  • Irene De Biase MD, PhD,

    1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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  • Astrid Rasmussen MD, PhD,

    1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
    2. Department of Neurogenetics and Molecular Biology, Instituto Nacional de Neurologïa y Neurocirugïa Manuel Velasco Suärez, Mexico City, Mexico
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  • Dan Endres PhD,

    1. Department of Mathematics and Statistics, University of Central Oklahoma, Edmond, OK
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  • Sahar Al-Mahdawi PhD,

    1. Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, United Kingdom
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  • Antonella Monticelli MD,

    1. Department of Molecular and Cellular Pathology and IEOS, University of Naples “Federico II,” Naples, Italy
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  • Sergio Cocozza MD,

    1. Department of Molecular and Cellular Pathology and IEOS, University of Naples “Federico II,” Naples, Italy
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  • Mark Pook PhD,

    1. Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, United Kingdom
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  • Sanjay I. Bidichandani MBBS, PhD

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
    2. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK
    • Dr Bidichandani, 975 NE, 10th, BRC458, Oklahoma City, OK 73104
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Abstract

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).

Interpretation

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. Ann Neurol 2007;61:55–60

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