Alzheimer and Parkinson Diagnoses in Progranulin Null Mutation Carriers in an Extended Founder Family

Brouwers, Nathalie; Nuytemans, Karen; Zee, Julie van der; Gijselinck, Ilse; Engelborghs, Sebastiaan; Theuns, Jessie; Kumar‐Singh, Samir; Pickut, Barbara A.; Pals, Philippe; Dermaut, Bart; Bogaerts, Veerle; Pooter, Tim De; Serneels, Sally; Broeck, Marleen Van den; Cuijt, Ivy; Mattheijssens, Maria; Peeters, Karin; Sciot, Raf; Martin, Jean‐Jacques; Cras, Patrick; Santens, Patrick; Vandenberghe, Rik; Deyn, Peter Paul De; Cruts, Marc; Broeckhoven, Christine Van; Sleegers, Kristel

doi:10.1001/archneur.64.10.1436

Cited by 132 publications

(118 citation statements)

References 25 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…So far, a few patients clinically diagnosed with aMCI or AD and carrying a GRN mutation have been described [6,10,11]. The patient described here is the first one carrying this mutation and diagnosed first as aMCI and then as AD.…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

Carecchio

Fenoglio

Riz

et al. 2009

Journal of the Neurological Sciences

View full text Add to dashboard Cite

Progranulin (GRN) mutations are associated with different clinical phenotypes, including FrontotemporalLobar Degeneration (FTLD), Corticobasal Degeneration and Alzheimer's disease (AD). In addition, the range of age at onset is very wide and patients presenting initial symptoms around eighty years have been described. Previous studies demonstrated that progranulin plasma levels determination may be a reliable method to identify GRN deletion carriers. We thus evaluated progranulin plasma levels in all patients followed at our Alzheimer's Centre whose plasma was available (n = 176) and found four patients displaying low values. Three of them carried the CACT deletion in exon 7 and their clinical diagnosis was behavioral variant Frontotemporal Dementia. We also identified a patient carrying a previously reported CAGT deletion in exon 5. Here, we report on this case. The onset of symptoms was at 77 years and the initial diagnosis was of amnestic Mild Cognitive Impairment (aMCI), which converted to AD six months later. In the following years, the patient also developed behavioral disturbances, gait apraxia and parkinsonian symptoms. At present, she is 84 years old and is still followed-up periodically. This case confirms progranulin plasma levels as a reliable biomarker to identify GRN deletion carriers and discriminate between FTLD and other dementias which may mimic it. We thus encourage the inclusion of this non-invasive and easy test in clinical practice.

show abstract

Section: Discussionmentioning

confidence: 81%

“…Extrapyramidal features have been described in association with FTD, and they can present both at the onset of the disease and in the late stages, making the clinical phenotype of GRN mutation carriers even more complex and variable, including CBD, Lewy body dementia and PD [10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

Carecchio

Fenoglio

Riz

et al. 2009

Journal of the Neurological Sciences

View full text Add to dashboard Cite

show abstract

“…One nonsense mutation, p.R535X, was exclusively found in an AD patient [Brouwers et al, 2007]. This mutation was experimentally shown to escape the NMD mechanism and hence did not result in a null allele [Brouwers et al, 2007].…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…The loss of functional protein is mainly the result of loss of GRN transcript caused by NMD of transcripts containing PTCs (n 5 52) or by nuclear degradation of transcripts retaining the first intron due to splice-site mutations in intron 1 (n 5 2) Le Ber et al, 2007]. PTCs can be the result from nonsense mutations (n 5 12), splice-site mutations (n 5 10), and small insertions/deletions (n 5 30) Baker et al, 2006;Huey et al, 2006;Pickering-Brown et al, 2006Boeve et al, 2006;Masellis et al, 2006;Gass et al, 2006;Benussi et al, 2008;Bronner et al, 2007;Mesulam et al, 2007;Behrens et al, 2007;Leverenz et al, 2007;Bruni et al, 2007;Van Deerlin et al, 2007;Brouwers et al, 2007;Rademakers et al, 2007;Llado et al, 2007;Le Ber et al, 2007;Davion et al, 2007;Kelley et al, in press;Spina et al, 2007a;Mukherjee et al, 2008;Beck et al, 2008;Le Ber et al, 2008]. Second, loss of translation as a result of mutations affecting the Kozak sequence (n 5 4) Baker et al, 2006;Pickering-Brown et al, 2006;Boeve et al, 2006;Gass et al, 2006;Le Ber et al, 2008] and reduction of secreted protein due to missense mutations affecting the signal sequence (n 5 2) [Mukherjee et al, 2006;Gass et al, 2006;Kelley et al, in press;Mukherjee et al, 2008;Le Ber et al, 2008], results in reduced GRN.…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

“…This mutation was experimentally shown to escape the NMD mechanism and hence did not result in a null allele [Brouwers et al, 2007]. Because the termination codon is located only 42 nucleotides upstream of the last exon-exon boundary, it is probably not recognized as premature by the NMD apparatus, according to the ''50-54 nt boundary rule'' [Zhang et al, 1998;Thermann et al, 1998].…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

View full text Add to dashboard Cite

Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

show abstract

C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

et al. 2013

View full text Add to dashboard Cite

Alzheimer and Parkinson Diagnoses in Progranulin Null Mutation Carriers in an Extended Founder Family

Cited by 132 publications

References 25 publications

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

Contact Info

Product

Resources

About