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"Frontotemporoparietal" dementia

Clinical phenotype associated with the c.709-1G>A PGRN mutation

From the Department of Neurology (F.M., B.I., M.B., A.G., J.R., J.F.M.-M., A.L.d.M.), Hospital Donostia; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) (F.M., B.I., M.B., A.A., A.G., J.R., J.F.M.M., A.L.d.M.); Neurogenetics Research Unit (A.A., A.E.), Ilundain Fundazioa-Instituto Biodonostia; Department of Medicine (M.R.), Division of Neurology, Hospital Zumarraga; and Department of Medicine (A.B.), Division of Neurology, Hospital Bidasoa, Gipuzkoa, Spain.

Address correspondence and reprint requests to Dr. Fermin Moreno Izco, Department of Neurology, Hospital Donostia, Paseo Dr. Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain fermin.morenoizco{at}osakidetza.net

Background: Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration with tau-negative and ubiquitin-positive neuronal inclusions. Most previous studies aimed at characterizing the clinical and neuropsychological phenotype of PGRN mutation carriers included patients with different PGRN mutations, assuming that the common proposed pathogenetic mechanism of haploinsufficiency will lead to a comparable phenotype.

Methods: We studied 21 patients with a single pathogenic splicing mutation in the PGRN gene (c.709-1G>A) in the same tertiary referral center using homogenous diagnostic criteria and protocols. All patients were of Basque descent.

Results: Patients exhibited a variable phenotype both in age at onset and initial symptoms. Behavioral variant frontotemporal dementia (52.4%) and progressive nonfluent aphasia (23.8%) were the most common presenting syndromes. Apathy was the most common behavioral symptom. Patients developed a relatively rapidly progressive dementia with features that led to a secondary diagnosis in 61.9% of cases 2 years after primary diagnosis. Notably, this secondary or tertiary diagnosis was corticobasal syndrome in 47.6% of cases, which confirmed the neuropsychological features of parietal lobe dysfunction seen at the initial assessment in 81.8% of patients.

Conclusions: Patients carrying the c.709-1G>A mutation in the PGRN gene showed heterogeneous clinical and neuropsychological features and commonly developed corticobasal syndrome as the disease progressed.

Abbreviations: bvFTD = behavioral variant of frontotemporal dementia; CBS = corticobasal syndrome; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; FTLD = frontotemporal lobar degeneration; MMSE = Mini-Mental State Examination; PNFA = progressive nonfluent aphasia.

*These authors contributed equally.

Supported by Diputación Foral de Gipuzkoa (dossier 76/08) and the Basque Government (SAIOTEK program).

Disclosure: Author disclosures are provided at the end of the article.

Received May 10, 2009. Accepted in final form July 29, 2009.