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Case report and literature review of Huntington disease with intermediate CAG expansion
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  • Published on:
    Author Response
    • Stefan D Jevtic, Internal Medicine Resident McMaster University
    • Other Contributors:
      • John Provias, Neuropathologist

    We would like to begin by thanking Dr. Ratna for his interest and thoughtful comments surrounding our paper. As we previously highlighted, there are several case reports in the literature of individuals with fewer than 36 CAG repeats and clinical signs of Huntington Disease (HD). These cases are not definitive and often do not feature autopsy confirmation of diagnosis; however, they present an interesting clinical dilemma for physicians. In our case, there was both convincing evidence for clinical and neuropathological diagnosis that would suggest HD. Alternative diagnoses, including neuroacanthosis, were not consistent with the patient’s history and initial presentation. Specifically, orofacial movements were not prominent in her initial assessment and reflexes were present. Furthermore, there was no significant history of infectious symptoms or likelihood of toxic ingestion to suggest these alternative diagnoses. Family history was limited, and additional genetic testing was not pursued after consulting several expert neurologists, who ultimately supported a clinical diagnosis of HD.

    Unfortunately, due to technical limitations we were unable to obtain staining for huntingtin protein on our tissue samples. Similarly, DNA extraction and additional molecular techniques were unavailable, but we agree that these would have been ideal to further investigate underlying
    mechanisms of disease. The interesting pathology findings of amyloid-beta staining involved the c...

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    Conflict of Interest:
    None declared.
  • Published on:
    Reply to Case report and literature review of Huntington disease with intermediate CAG expansion
    • Nikhil Ratna, PhD scholar National Institute of Mental Health and Neurosciences

    This case report by Jevtic et al addresses one of the interesting and critical issue sdefining the genetic mutation causing Huntington's disease. Threshold of repeat number causing HD was defined and redefined since 1993 due to the emerging data and the development of novel, precise methods for determining CAG repeats such as those exclude CGG expansions at the C terminal end of CAG tract.

    Despite all these efforts, there are sporadic case reports of HD phenotypes with repeats < 36 (widely accepted threshold for causing HD). Most of these case reports do not exclude HD like syndromes (HDL1/2/3/4, Neuro-acanthocytosis) caused by other mutations. Besides these mutations there could be toxins, infections which could have contributed to the HD phenotype and the occurrence of Intermediate alleles (IAs) in these patients is a chance event. This possibility could be duly considered for the fact that many IAs carried by parent generation of de-novo HD cases do not cause any symptoms. However IAs cannot be given a clean chit in HD pathogenesis until proven by studying CAG distribution in normal population along with HD population with enough statistical power.

    In this case report, firstly authors could have brought more evidence to their proposition by ruling out alternative diagnoses such as Neuro-acanthocytosis which can be clinically distinguished (absence of deep tendon reflexes, more prominent oro-facial movements) even in the absence of genetic mutatio...

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    Conflict of Interest:
    None declared.