Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred

Document Type

Article

Abstract

The Asp22fs(g.63_64insC) mutation in progranulin gene (GRN) has been so far reported in one patient who developed frontotemporal dementia (FTD) at the age of 65. Here, we describe the clinical heterogeneity associated with the GRN Asp22fs mutation in a large Italian family. Clinical and instrumental workup of two symptomatic carriers in two generations has been carried out, together with genetic analysis of probands and of nine asymptomatic family members. The first proband was a 47-year old male clinically diagnosed with FTD. Family history was positive and suggestive of an autosomal dominant pattern of inheritance. Evaluation of plasma GRN levels was consistent with the presence of a mutation in its encoding gene, that was demonstrated by sequencing [Asp22fs(g.63_64insC)]. Brain MRI showed multiple T2 and FLAIR hyperintense areas in the frontal lobe white matter and right hemisphere cortical atrophy. The second proband was his 79 year old uncle, presenting with mild cognitive impairment. Brain MRI showed small T2 hyperintense lesions and widespread cortical atrophy. Cerebrospinal fluid amyloid-β, tau, and phosphotau protein levels were in both cases in the range of normality. Additional nine asymptomatic family members were studied. This family's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by GRN mutations, suggesting that the diagnosis could be missed in some individuals with an atypical presentation, and points up the importance of GRN plasma level evaluation.

Medical Subject Headings

Age of Onset; Aged; Aspartic Acid (genetics); Atrophy (pathology); Cognition Disorders (etiology, genetics); Female; Frontotemporal Dementia (complications, genetics); Humans; Intercellular Signaling Peptides and Proteins (genetics); Italy; Magnetic Resonance Imaging (methods); Male; Middle Aged; Motor Skills Disorders (etiology, genetics); Mutation (genetics); Neuropsychological Tests; Phenotype; Progranulins; Temporal Lobe (pathology)

Publication Date

1-1-2011

Publication Title

Journal of Alzheimer's disease : JAD

E-ISSN

1875-8908

Volume

24

Issue

2

First Page

253

Last Page

9

PubMed ID

21258152

Digital Object Identifier (DOI)

10.3233/JAD-2011-101704

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