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Novel prion protein insert mutation associated with prolonged neurodegenerative illness

From the Department of Pathology (V. Lewis and A. Boyd, and Drs. Collins, Hill, McLean, Smith, and Masters) and The Australian National Creutzfeldt-Jakob Disease Registry (V. Lewis and A. Boyd, and Drs. Collins and Masters), The University of Melbourne; and Molecular Biology Laboratory (Dr. Smith), Melbourne Health Shared Pathology Services, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Address correspondence and reprint requests to Dr. S. Collins, Australian National CJD Registry, Department of Pathology, The University of Melbourne, Victoria, Australia 3010; e-mail: stevenjc{at}unimelb.edu.au

Background: Mutations in the prion protein gene (PRNP) are found in approximately 13 to 15% of persons classified as dying from a transmissible spongiform encephalopathy. Point and octapeptide repeat insert and deletion mutations are described in the open reading frame (ORF) of PRNP. The authors present a clinicopathologic study of a patient with a family history of a lengthy and progressive neurodegenerative disorder associated with a novel large octapeptide repeat insert mutation.

Methods: Neuropathologic examination, including immunohistochemistry for the prion protein, was undertaken. The ORF of PRNP was amplified by PCR, cloned, and sequenced. Homogenate of cerebral tissue underwent Western blot analysis for the prion protein before and after proteinase K treatment.

Results: The proband died after a 16-year illness commencing at age 29 years. Confident premortem clinical diagnosis was not achieved despite a brain biopsy. Autopsy examination of the brain confirmed a spongiform encephalopathy. Prion protein immunohistochemistry revealed occasional granular deposits in the cerebellar granular layer. The proband was found to harbor a novel PRNP 168 base pair (bp) insert mutation.

Conclusion: The authors have identified a novel 168 bp octapeptide repeat insert mutation. Prion protein immunohistochemistry differs from previous cases harboring seven octapeptide repeat and other long insert mutations. Optimization of PRNP analysis, especially PCR conditions, is essential to avoid overlooking this type of mutation and delay the correct molecular genetic diagnosis.

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