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Original Investigation |

DCTN1 Mutation Analysis in Families With Progressive Supranuclear Palsy–Like Phenotypes

Paola Caroppo, MD, PhD1,2,3; Isabelle Le Ber, MD, PhD1,2,3,4,5; Fabienne Clot, PhD4,6; Sophie Rivaud-Péchoux, PhD1,2,3; Agnès Camuzat, MSc1,2,3; Anne De Septenville, PhD1,2,3; Claire Boutoleau-Bretonnière, MD7; Vanessa Mourlon, PhD4; Mathilde Sauvée, MD8; Thibaud Lebouvier, MD7; Anne-Marie Bonnet, MD2,5; Richard Levy, MD, PhD1,2,3,9; Martine Vercelletto, MD7; Alexis Brice, MD1,2,3,5,10 ; for the French Clinical and Genetic Research Network on Frontotemporal Dementia/Frontotemporal Dementia–Amyotrophic Lateral Sclerosis
[+] Author Affiliations
1Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche (UMR)_S975, Paris, France
2Institut National de la Santé et de la Récherche Médicale, UMR_S975, Centre de Recherche Institut du Cerveau et de la Moelle, Paris, France
3Centre National de la Recherche Scientifique UMR 7225, Paris, France
4Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital de la Pitié-Salpêtrière, Centre de Référence des Démences Rares, Paris, France
5AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Paris, France
6AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique et Cytogénétique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Paris, France
7Service de Neurologie, Centre Hospitalier Universitaire (CHU) Guillaume et René Laënnec, Nantes, France
8Service de Neurologie, CHU, Nancy, France
9AP-HP, Hôpital Saint Antoine, Département de Neurologie, Paris, France
10AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Clinique, Paris, France
JAMA Neurol. 2014;71(2):208-215. doi:10.1001/jamaneurol.2013.5100.
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Importance  Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified.

Objective  To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype).

Design, Setting, and Participants  Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated.

Main Outcomes and Measures  Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers.

Results  We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia.

Conclusions and Relevance  Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.

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Figure 1.
Family Pedigree and DCTN1 Mutation

A, Solid symbols indicate affected members; open symbols, unaffected individuals. Individuals are represented by diamonds for confidentiality. An asterisk indicates DNA availability; bvFTD, behavioral variant of frontotemporal dementia; mt, mutation; PD, Parkinson disease; Perry sd, Perry syndrome; PSP, progressive supranuclear palsy; slash, deceased; and wt, wild type. B, Chromatograms of coding exon 2 of the DCTN1 gene. The c.212G>A (p.Gly71Glu) mutation is shown by the arrowhead, and the corresponding normal sequence is shown below.

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Figure 2.
Brain Magnetic Resonance Imaging in Patients III-5 and III-12 and Single-Photon Emission Computed Tomography in Patient III-12

A, Brain magnetic resonance imaging in patient III-5 showing mild midbrain and frontal atrophy. B, Brain magnetic resonance imaging in patient III-12 showing mild frontal atrophy. C, Ethyl cysteinate dimer–single-photon emission computed tomography in patient III-12 showing marked frontotemporal hypoperfusion. According to radiological convention, right is left.

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