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Very late-onset Friedreich’s ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type
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  • Published on:
    Ref: bcr-2021-242073.R2 - Very Late Onset Friedreich’s Ataxia with rapid course mimicking as Possible Multiple System Atrophy Cerebellar Type. Rapid Response from Dr. Stefan M. Pulst, Professor & Chair, Neurology, University of Utah
    • Tushar Vidhale, Assistant Professor Grant Government Medical College and JJ Group of Hospitals, Mumbai

    Response from Tushar Vidhale, MD (Dated: July 8th, 2022)

    Respected Editor and Dr. Pulst,
    Thank you for your interest in our case. We agree with your comment that Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene, but our patient had eight GAA repeats on allele-1 and 37 repeats (pre-mutated allele) on allele-2. The pre-mutated allele can be responsible for the disease, in
    rare cases, by causing somatic expansion or pre-mutation in cell populations. But this occurs only when in the setting of the second allele in the clear pathogenic range of expansion. This intronic GAA expansion further silences the FXN gene, resulting in pathologically suppressed levels of the frataxin protein. As per the respected reader, even though the patient had the probability of compound
    heterozygous mutation with a pathogenic point mutation in one allele, the second allele would not be pathogenic at 37 GAA repeats.

    Usually, individuals with ataxia who are heterozygous for an expanded GAA repeat (> 66) may contain a separate loss-of-function mutation in the FXN gene copy over the allele with normal GAA repeat length. In the relevant clinical context, these patients should be considered to have Friedreich ataxia. [1] However, in populations where the prevalence of Friedreich ataxia carriers is high, such an individual may have a different disorder respon...

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    Conflict of Interest:
    None declared.
  • Published on:
    Friedreich ataxia diagnosis

    Dear Madam/Sir,
    We read with great interest the article by Vidhale and colleagues.1 They provide a detailed description of a man presenting with a relatively rapidly progressing neurodegenerative disease including his neuroimaging findings.

    After testing for a few DNA repeat expansion diseases, the authors arrived at the conclusion that their patient’s diagnosis was Friedreich ataxia (FRDA). FRDA is a recessive neurodegenerative disease caused by bi-allelic expansion of an intronic GAA repeat in the frataxin (FXN) gene. Their patient had 5 and 37 GAA repeats. The lower limit for full penetrance alleles is > 66 GAA repeats.2 Thus, it is not apparent how their patient meets diagnostic criteria for FRDA.

    The 37 GAA repeat allele falls at the lower end of premutation alleles (range 34-65), so named as these alleles do not cause disease, but can rarely expand to the disease range during meiosis. In rare cases, somatic expansion of pre-mutations in cell populations has been postulated to cause disease, but this occurs only in the setting of the 2nd allele in the clear pathogenic range of expansion.

    The authors alternatively postulate that the patient could represent a compound heterozygous state based on his clinical presentation. Comparison with cases of very late-onset FRDA (vLOFA), however, clearly shows that the patient’s course is too rapid and severe for vLOFA. Even if the patient were to carry a pathogenic point mutation in one of the allel...

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    Conflict of Interest:
    None declared.