"Frontotemporoparietal" dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation.
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.
Moreno
F
F
Department of Neurology, Hospital Donostia, Paseo Dr. Begiristain sn, CP 20014, San Sebastian, Gipuzkoa, Spain. fermin.morenoizco@osakidetza.net
Indakoetxea
B
B
Barandiaran
M
M
Alzualde
A
A
Gabilondo
A
A
Estanga
A
A
Ruiz
J
J
Ruibal
M
M
Bergareche
A
A
Martí-Massó
J F
JF
López de Munain
A
A
D000328:Adult; D017668:Age of Onset; D000368:Aged; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics; D003863:Depression / Q000175:diagnosis / Q000235:genetics; D018450:Disease Progression; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D010296:Parietal Lobe; D010641:Phenotype; D000077153:Progranulins; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D013030:Spain; D013577:Syndrome
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins