Clinical Manifestations

Area of Science:

• Neurology
• Genetics
• Linguistics

Background:

• Progranulin (GRN) mutations are a known cause of frontotemporal lobar degeneration (FTLD), often presenting as behavioral variant FTD (bvFTD) or primary progressive aphasia (PPA).
• GRN mutations are increasingly recognized in non-familial cases and atypical PPA phenotypes, including semantic (sPPA), logopenic (lvPPA), and mixed (mPPA) variants.

Purpose of the Study:

• To report the clinical, genetic, and imaging features of a rare case of sporadic primary progressive aphasia with a mixed phenotype and a GRN mutation.
• To underscore the importance of considering GRN mutations in patients with atypical or mixed PPA presentations, irrespective of family history.

Main Methods:

• Detailed clinical assessment, including neurological examination and neuropsychological evaluation.
• Brain MRI to identify patterns of atrophy.
• Genetic testing to confirm the presence of a GRN gene mutation.

Main Results:

• A 68-year-old woman presented with a 9-year history of progressive language impairment, including difficulties with naming, comprehension, and spontaneous speech, consistent with a mixed nfvPPA and sPPA phenotype.
• Neuropsychological testing revealed anomia, impaired single-word comprehension, apraxia of speech, and agrammatism. Brain MRI showed marked left-hemisphere atrophy, particularly in the temporal and fronto-insular regions.
• Genetic testing confirmed a GRN gene mutation.

Conclusions:

• Mixed PPA associated with GRN mutations can manifest with simultaneous impairments across grammatical, verbal fluency, and semantic language domains, affecting diverse neural pathways.
• The findings suggest that genetic testing for GRN mutations should extend beyond familial cases to include sporadic and atypical PPA presentations.
• GRN mutations should be strongly considered in patients presenting with mixed or atypical PPA phenotypes due to their potential to cause overlapping syndromes with heterogeneous clinical features.