An algorithm for genetic testing of frontotemporal lobar degeneration

Goldman, Jill; Rademakers, Rosa; Huey, Edward D.; Boxer, Adam L.; Mayeux, Richard; Miller, Bruce L.; Boeve, Bradley F.

doi:10.1212/wnl.0b013e31820a0d13

Cited by 68 publications

(61 citation statements)

References 57 publications

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“…With respect to genetic findings, it should be underlined that while familial FTD accounts for 10% of cases, familial PPA is usually considered infrequent [43]. Three of our nfvPPA patients had a first-degree relative with early-onset dementia and were shown upon testing to be carriers of a dementia-causing mutation, supporting the idea that genetic alterations are more frequent in nfvPPA than in lvPPA or svPPA.…”

Section: Discussionsupporting

confidence: 59%

Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

Gil-Navarro

Lladó

Rami

et al. 2013

Dement Geriatr Cogn Disord

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Background/Aim: To investigate in variants of primary progressive aphasia (PPA) the association between current clinical and neuroimaging criteria and biochemical/genetic markers at the individual level. Methods: Thirty-two PPA patients were classified as non-fluent/agrammatic (nfvPPA), semantic (svPPA), or logopenic variant (lvPPA) or as unclassifiable (uPPA). In all patients, we evaluated the neuroimaging criteria (magnetic resonance imaging and/or single photon emission computed tomography/positron emission tomography) of each variant and studied serum progranulin levels, APOE genotype and Alzheimer’s disease (AD)-cerebrospinal fluid (CSF) biomarkers. Cases with a first-degree family history of early-onset dementia were genetically tested. Results: Ten of 15 (66%) nfvPPA, 5/5 (100%) svPPA and 7/7 (100%) lvPPA patients showed at least one positive neuroimaging-supported diagnostic criterion. All lvPPA and 3/5 (60%) uPPA patients presented AD-CSF biomarkers, which were absent in nfvPPA and svPPA cases. Four (27%) nfvPPA patients had dementia-causing mutations: 2 carried a GRN mutation and 2 the C9ORF72 hexanucleotide expansion. Conclusions: There was an excellent association between clinical criteria and neuroimaging-supported biomarkers in svPPA and lvPPA, as well as with AD-CSF biochemical markers in the lvPPA. Neuroimaging, biochemical and genetic findings in nfvPPA were heterogeneous. Incorporating biochemical/genetic markers into the PPA clinical diagnosis would allow clinicians to improve their predictions of PPA neuropathology, especially in nfvPPA and uPPA cases.

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Section: Discussionsupporting

confidence: 59%

Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

Gil-Navarro

Lladó

Rami

et al. 2013

Dement Geriatr Cogn Disord

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“…Thus, the peripheral dosage of progranulin could be incorporated into the recently developed algorithm of genetic testing for neurodegenerative diseases [27] . Before it is systematically translated into clinical practice and, more importantly, included in diagnostic criteria for dementias, further refinement and standardization of the test is required and preanalytical (e.g.…”

Section: Discussionmentioning

confidence: 99%

Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

et al. 2011

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Background: Recently, attention was drawn to a role for progranulin in the central nervous system with the identification of mutations in the progranulin gene (GRN) as an important cause of frontotemporal lobar degeneration. GRN mutations are associated with a strong reduction of circulating progranulin and widely variable clinical phenotypes: thus, the dosage of plasma progranulin is a useful tool for a quick and inexpensive large-scale screening of carriers of GRN mutations. Objective: To establish the best cutoff threshold for normal versus abnormal levels of plasma progranulin. Methods: 309 cognitively healthy controls (25–87 years of age), 72 affected and unaffected GRN+ null mutation carriers (24–86 years of age), 3 affected GRN missense mutation carriers, 342 patients with neurodegenerative diseases and 293 subjects with mild cognitive impairment were enrolled at the Memory Clinic, IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy, and at the Alzheimer Unit, Ospedale Maggiore Policlinico and IRCCS Istituto Neurologico C. Besta, Milan, Italy. Plasma progranulin levels were measured using an ELISA kit (AdipoGen Inc., Seoul, Korea). Results: Plasma progranulin did not correlate with age, gender or body mass index. We established a new plasma progranulin protein cutoff level of 61.55 ng/ml that identifies, with a specificity of 99.6% and a sensitivity of 95.8%, null mutation carriers among subjects attending to a memory clinic. Affected and unaffected GRN null mutation carriers did not differ in terms of circulating progranulin protein (p = 0.686). A significant disease anticipation was observed in GRN+ subjects with the lowest progranulin levels. Conclusion: We propose a new plasma progranulin protein cutoff level useful for clinical practice.

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“…In 1998, mutations in the microtubule-associated protein tau gene ( MAPT ) in chromosome 17 were described in some of these families [2]. To date, nearly 50 pathogenic MAPT mutations have been reported [3], accounting for 10-23% of familial cases of frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) [4]. Clinically, FTLD related to MAPT mutations may affect behavior, language, memory, and executive functions.…”

Section: Introductionmentioning

confidence: 99%

Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain

Borrego‐Écija

Morgado

Palencia-Madrid

et al. 2017

Dement Geriatr Cogn Disord

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Background/Aims: We identified and studied 13 patients carrying the P301L mutation in the MAPT gene from the same area (Baix Llobregat County) in Barcelona, Spain. Methods: The demographic and clinical features were reviewed retrospectively. Detailed neuropathological characterization was obtained in 9 subjects. To investigate the origin of the P301L mutation in these families, 20 single nucleotide polymorphisms (SNPs) in the MAPT gene were analyzed. Results: The mean age at disease onset was 51 years and the mean disease duration was 7 years. The most common initial symptoms were behavioral changes (54%), followed by language disturbances (31%) and memory loss (15%). 46% developed parkinsonism. Neuropathology showed an extensive neuronal and glial 4-repeat (4R) tauopathy with “mini-Pick”-like bodies in the dentate gyrus as the characteristic underlying pathology in all cases. In 1 subject, additional 4R globular glial inclusions were observed. All the mutation carriers showed the same haplotype for the SNPs analyzed, suggesting a common ancestor. Conclusion: These findings suggest a relative homogeneous clinicopathological phenotype in P301L MAPT mutation carriers in our series. This phenotype might help in the differential diagnosis from other tauopathies and be a morphological hint for genetic testing. The haplotype analysis results suggest a founder effect of the P301L mutation in this area.

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An algorithm for genetic testing of frontotemporal lobar degeneration

Abstract: Recent findings in genetics, pathology, and imaging allow clinicians to use the clinical presentation of the patient with FTLD to inform genetic testing decisions.

Cited by 68 publications

References 57 publications

Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

Optimal Plasma Progranulin Cutoff Value for Predicting Null Progranulin Mutations in Neurodegenerative Diseases: A Multicenter Italian Study

Frontotemporal Dementia Caused by the P301L Mutation in<b> </b>the<b><i> MAPT</i></b> Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain

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