Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described.
We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient.
Conclusions and Relevance
This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.
Posterior cortical atrophy (PCA)1 is a rare neurodegenerative syndrome affecting the primary visual occipital, occipitotemporal, and biparietal cortices. Patients usually present with progressive high-order visual and visuomotor deficits.2 A classification into dorsal and ventral subtypes has been proposed.2,3 The dorsal stream (biparietal/occipitoparietal cortices) is implicated in object location, visually guided motor movements, and motor planning. The patients present with apraxia, visuospatial problems, agraphia, or Balint syndrome with preserved basic perceptual abilities, object recognition, and reading. The ventral visual stream (occipitotemporal cortices) is implicated in recognition of objects, faces, and written words. The patients with ventral/visual stream lesions have alexia, apperceptive visual agnosia, and prosopagnosia.3 A rarer variant associated with severe occipital involvement (the visual variant) is characterized by primary visual failure and impairment of basic perceptual abilities.3
Posterior cortical atrophy is considered to be an atypical variant of Alzheimer disease (AD) because most cases have AD pathologic characteristics.4,5 In rare cases, pathologic lesions of Lewy body dementia, corticobasal degeneration, prion disease, or subcortical gliosis are identified.4
In most instances, patients have no family history of dementia. Mutations of the PSEN1,6PRNP,7 and IT158 genes have been identified in a few patients, but the genetic basis of PCA remains elusive.2 We identified a mutation in the GRN gene (RefSeq NM_002087.2) in a patient presenting with visual deficits, apperceptive visual agnosia, and occipital cortical atrophy, which fit the criteria of PCA.1- 3 This study extends the phenotypic spectrum of GRN mutations and contributes to better delineation of the nosologic boundaries of genetic dementias.
This study was approved by the Ethics Committee of the Assistance Publique–Hôpitaux de Paris, Paris, France. All participants provided written informed consent.
The proband (individual 005) had a corticobasal syndrome and was referred for genetic counseling because of a family history of dementia (Figure 1A). His sibling (individual 004) had progressive blurred vision at 58 years of age. Individual 004 had difficulty recognizing the shape of objects but no problem with color perception. He had difficulties in face recognition but he could identify the person by recognizing the voice. Reading and watching television were difficult. At that time, he was living alone without other cognitive deficits. He was autonomous in his travels and activities of daily life and served as the caregiver for a parent with dementia. Results of oculomotricity and the ophthalmologic, visual field, and visual acuity examinations were normal.
A, The proband is individual 005. Solid symbol indicates affected individual; white symbol, unaffected individual; gray symbol, affected by unspecified dementia but no DNA available; slash, deceased; and arrow, patient described in the report. Diamonds were used for confidentiality of sex. AA indicates actual age; AAD, age at death; AAO, age at onset; asterisk, DNA available; CBS, corticobasal syndrome; LBD, Lewy body dementia; PCA, posterior cortical atrophy; and UD, unspecified dementia. B, Chromatogram of the c.328C>T (p.Arg110*) mutation is in the upper half (arrow), with the normal sequence below. mt Indicates mutated; wt, wild-type.
The neuropsychological examination of individual 004 at 60 years of age (Table) revealed basic impairment of visuoperceptual skills and apperceptive visual agnosia. The identification of objects was possible by tactile, auditory, and olfactory modalities. The Balint and Gerstmann syndromes were absent. The perception of visually guided motor movements and spatial localization were normal without optic apraxia. Praxis and language were normal. The patient had alexia caused by the perceptive deficit. Word spelling was preserved. He had moderate conceptualization, strategy, and working memory deficits. Verbal and semantic memories were normal. Magnetic resonance imaging at 60 years of age revealed bilateral occipital atrophy mainly affecting the inferior occipital gyrus with extension to the superior lingual and the fusiform gyri (Figure 2A) and mild frontal and occipitoparietal junction atrophy. He had no parkinsonism or motor symptoms. He received a diagnosis of PCA. Four years later, the visuoperceptual deficit still predominated but memory problems had appeared (encoding and storage deficits). At 63 years of age, he developed apathy and perseverative behaviors. Magnetic resonance imaging showed marked diffuse atrophy (Figure 2B). The patient progressively became mute and bedridden.
We used fluid-attenuated inversion recovery and T1-weighted sequences for MRI. A, Axial and coronal sections 2 years after disease onset (at 60 years of age). The MRIs reveal greater atrophy in the bilateral inferior occipital, superior lingual, and fusiform gyri and mild atrophy in the frontal areas and occipitoparietal junction. The hippocampus appears to be spared. B, Axial, coronal, and sagittal sections 6 years after disease onset (at 64 years of age). The MRIs show marked and diffuse brain atrophy, particularly involving the insular and medial frontal regions. R indicates right.
The proband (individual 005) had corticobasal syndrome at 60 years of age (Figure 1A). The parent (individual 001) had a clinical diagnosis of Lewy body dementia at 87 years of age; the parent’s sibling (individual 003) had unspecified dementia at 73 years of age.
Initially, a GRN mutation was searched for in the proband because of the corticobasal syndrome and the family history. Individuals 001, 002 (the spouse of individual 001), and 004 underwent analyses secondarily.
We collected blood and plasma samples from these individuals. The progranulin plasma level was measured with a human enzyme-linked immunosorbent assay kit (ELISA kit Proepithelin; Adipogen). The 13 exons of GRN were sequenced using Sanger methods. The apolipoprotein E (APOE) genotype was determined using a commercially available assay (TaqMan; Applied Biosystems).
The plasmatic progranulin level was reduced in the proband (39 μg/L) and individuals 001 (47 μg/L) and 004 (29 μg/L) (reference range, 100-300 μg/L). A heterozygous c.328C>T (p.Arg110*) GRN mutation was found in individuals 001 and 004 and the proband (Figure 1B) but not in individual 002. This mutation has been identified previously.10 The APOE genotype of all the mutation carriers was ε3/ε3.
We identified a GRN mutation in a patient with PCA characterized by prominent visual deficits, apperceptive visual agnosia, alexia, and prosopoagnosia with preservation of other cognitive functions. Greater impairment of basic visuoperceptual skills was compatible with a main involvement of visual cortices. Apperceptive visual agnosia, with the preservation of object recognition by other sensorial modalities, indicated the extension of damage along the ventral visual stream.2,3 Predominant atrophy of the primary visual cortex—and to a lesser degree of the parieto-occipital region—was in agreement with the clinical criteria of a visual/ventral variant of PCA.2,3
Mutations of the GRN gene are associated with a large spectrum of phenotypes of frontotemporal lobar degeneration (FTLD).10 Most mutation carriers present with a behavioral variant of FTLD, progressive nonfluent aphasia, corticobasal syndrome, or a phenotype mimicking Lewy body dementia. The presentation of individual 004 was very unusual because isolated visual agnosia at onset has not been reported in GRN carriers. The topography of the lesions was also different from that of GRN carriers, in whom atrophy predominantly involves the frontal, temporal, and parietal cortices but preserves the occipital regions at onset.11 This study extends the clinical spectrum of GRN mutations and demonstrates that, in rare cases, the pathologic changes can be confined to the posterior cortex at onset. The phenotypic variability characterizing GRN carriers is not explained by the type of mutations, all leading to progranulin haploinsufficiency and thus supporting the strong influence of additional disease modifiers.
Mutations of GRN are associated with TDP-43 neuronal inclusions.12 To our knowledge, no pathologic cases of PCA with TDP-43 inclusions have been described. We cannot exclude coincidental association of AD pathologic features in individual 004 owing to the absence of brain pathologic examination, cerebrospinal fluid analyses, and amyloid positron emission tomographic study. The association of TDP-43 and AD pathologic features has been described previously in 2 GRN carriers presenting with the typical phenotypes of AD or logopenic progressive aphasia.13 In that study, both patients were heterozygous for the APOE ε4 allele, suggesting that AD pathologic features could be explained, at least in part, by the APOE status. A highly significant association exists between the APOE ε4 allele and the risk for PCA and posterior AD.14 The absence of the APOE ε4 allele in our patient suggests a distinct pathologic process and that PCA could be an extreme phenotype of the GRN disease spectrum. This conclusion is supported by the rapid progression of atrophy to the anterior cortical regions (Figure 2), which is rather different from PCA with AD pathologic features. In the latter process, the damage remains relatively centered on the posterior lobes, even in the late stage.1,15
This study enlarges the mutational spectrum of PCA to GRN mutations and provides evidence that GRN analyses could be indicated in PCA, particularly when the damage progresses to the anterior cerebral regions and a family history of dementia is present. The link between PCA and genetic forms of FTLD is supported by the recent identification of a MAPT mutation in 1 case of PCA.16 Analyses of genes in FTLD in patient cohorts will be necessary to better evaluate their genetic contribution to PCA. Finally, this study underlines a possible continuum in degenerative dementias and highlights the limits of actual nosologic boundaries. Clarifying these boundaries by identifying factors driving phenotypic heterogeneity will have important implications for the definition of new diagnosis criteria of degenerative dementias and recruitment for clinical trials in the future.
Accepted for Publication: September 5, 2014.
Corresponding Author: Paola Caroppo, MD, PhD, Institut du Cerveau et de la Moelle Épinière, Hôpital de la Salpêtrière, 47 Boulevard de l’hôpital, 75013 Paris, France (firstname.lastname@example.org).
Published Online: December 29, 2014. doi:10.1001/jamaneurol.2014.3308.
Author Contributions: Dr Le Ber had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Caroppo, Brice, Le Ber.
Acquisition, analysis, or interpretation of data: Caroppo, Belin, Grabli, Maillet, De Septenville, Migliaccio, Clot, Lamari, Camuzat, Dubois, Le Ber.
Drafting of the manuscript: Caroppo, Clot, Camuzat, Le Ber.
Critical revision of the manuscript for important intellectual content: Belin, Grabli, Maillet, De Septenville, Migliaccio, Lamari, Brice, Dubois.
Obtained funding: Caroppo, Brice, Le Ber.
Administrative, technical, or material support: De Septenville, Clot, Lamari, Camuzat.
Study supervision: Le Ber.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by contract ANR-10-IAIHU-06 from Investissements d’avenir (Dr De Septenville); by a doctoral fellowship from Carlo Besta Institute (Dr Caroppo); and by contract R12091DD from the France Alzheimer Association (Dr Brice).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Lydia Guennec, BS, Isabelle Lagroua, RN, Sylvie Forlani, PhD, and Christelle Dussert, BS, of the DNA and cell bank of Centre de Recherche de la ICM, Hôpital de la Salpêtrière, Paris, France, provided excellent technical assistance. None of these contributors received financial compensation for their roles.
Caroppo P, Belin C, Grabli D, Maillet D, De Septenville A, Migliaccio R, Clot F, Lamari F, Camuzat A, Brice A, Dubois B, Le Ber I. Posterior Cortical Atrophy as an Extreme Phenotype of GRN Mutations. JAMA Neurol. 2015;72(2):224-228. doi:10.1001/jamaneurol.2014.3308