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JAMA Neurol. 2013 Nov;70(11):1403-10. doi: 10.1001/jamaneurol.2013.3849.

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

Author information

1
INSERM, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Hôpital de la Salpêtrière, F-75013, Paris, France2Université Pierre Marie Curie-Paris 06, UMR_S975, F-75013, Paris, France3Centre national de la recherche scientifique, UMR 7225, F-75013, Paris, France4AP-HP, Hôpital de la Pitié-Salpêtrière, Centre de Référence des Démences Rares, Paris, France5AP-HP, Hôpital de la Pitié-Salpêtrière, Département des maladies du système nerveux, Paris, France.

Abstract

IMPORTANCE:

Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD.

OBJECTIVE:

To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients.

DESIGN:

A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes.

SETTING:

Primary care or referral center.

PARTICIPANTS:

An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS.

MAIN OUTCOMES AND MEASURES:

Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes.

RESULTS:

We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations.

CONCLUSIONS AND RELEVANCE:

Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

PMID:
24042580
PMCID:
PMC4199096
DOI:
10.1001/jamaneurol.2013.3849
[Indexed for MEDLINE]
Free PMC Article

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