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.
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.
eTable 1. Mutations of the DCTN1 Gene in Patients With ALS and FTD
eTable 2. Presence or Absence (+/-) of the Clinical Diagnostic Criteria for Perry Syndrome in the 2 Patients With PSP-Like Phenotype
Caroppo P, Le Ber I, Clot F, Rivaud-Péchoux S, Camuzat A, De Septenville A, Boutoleau-Bretonnière C, Mourlon V, Sauvée M, Lebouvier T, Bonnet A, Levy R, Vercelletto M, Brice A, for the French Clinical and Genetic Research Network on Frontotemporal Dementia/Frontotemporal Dementia–Amyotrophic Lateral Sclerosis. DCTN1 Mutation Analysis in Families With Progressive Supranuclear Palsy–Like Phenotypes. JAMA Neurol. 2014;71(2):208-215. doi:10.1001/jamaneurol.2013.5100
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.
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.
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.
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by the presence of an akinetic-rigid parkinsonian syndrome associated with postural instability, frontal lobe dysfunction, and vertical supranuclear gaze palsy.1 The National Institute of Neurological Disorders–Society for Progressive Supranuclear Palsy clinical diagnostic criteria rely on (1) age at onset older than 40 years and (2) the presence of a gradually progressive disorder, combined with (3) slow vertical saccades or supranuclear gaze palsy and (4) early postural instability and falls during the first year of the disease.1 Modified clinical diagnostic criteria have been recently proposed (Neuroprotection and Natural History in Parkinson Plus Syndromes criteria) that allow an age at onset older than 30 years, postural instability or falls within 3 years from disease onset, and a disease duration ranging from 1 to 8 years.2 Five distinct clinical phenotypes have been described according to the predominant symptoms.3 Pathological diagnosis is based on the presence of neuropil threads, neurofibrillary tangles, and tau-positive astrocytes.4 Progressive supranuclear palsy is usually sporadic; a familial aggregation of Parkinson disease and other neurodegenerative disorders, such as tremor, dementia, and parkinsonism remain controversial, having been observed in only one recent PSP case-control study.5 Few pedigrees with familial clustering of PSP-like phenotypes have been described.5- 7 The genetic cause is unknown in most familial cases. Mutations in the MAPT (Online Mendelian Inheritance in Man [OMIM] 157140)5,8,9 gene have been identified in a few families, and TARDBP (OMIM 605078)10 and C9ORF72 (OMIM 614260)11,12 mutations are extremely rare in patients with PSP. A locus has been mapped on chromosome 1, but the disease-causing gene has not been identified.13 In this study, we analyzed the DCTN1 (OMIM 601143) gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype).
This study was approved by the ethics committee of Assistance Publique–Hôpitaux de Paris, Paris, France. All participants signed an informed consent form for genetic studies. During the past several years, we evaluated 21 families with PSP-like phenotypes. A PSP phenotype was clinically diagnosed using National Institute of Neurological Disorders–Society for Progressive Supranuclear Palsy international diagnostic criteria.1 The diagnosis of PSP was confirmed by pathological examination in 2 families. A positive family history was defined by at least 1 first- or second-degree relative manifesting a clinical phenotype of PSP. We recorded familial histories of related disorders, including Parkinson disease, frontotemporal dementia (FTD), and corticobasal degeneration syndrome, diagnosed according to international criteria. Clinical data and biological samples were collected for all the patients. The genealogy of the families was reconstructed, and clinical data and biological samples of relatives were collected whenever possible.
Blood genomic DNA was extracted from peripheral white blood cells using standard methods. Point mutations, as well as gene deletions and duplications, were previously searched for in the main genes responsible for FTD (C9ORF72, PGRN, MAPT, VCP, and TARDBP) and for Parkinson disease (SNCA, LRRK2, parkin, ATP13A2, and FBXO7) by direct sequencing or repeat-primed polymerase chain reaction (for C9ORF72). MAPT and C9ORF72 mutations were identified in one family each (7%, respectively).8,11
No mutations were found in the 19 remaining families. The 32 exons and exon-intron junctions of the DCTN1 gene were then amplified by polymerase chain reaction, as previously described.14 The purified amplified fragments were sequenced on an automated system with a cycle kit (ABI 3730, Big Dye 3.1; Applied Biosystems). The sequencing data were analyzed using available software (SeqScape 2.5; Applied Biosystems).
We identified a point mutation in exon 2 of the DCTN1 gene in a large French family. Our findings enlarge the genetic causes of familial PSP and the phenotypic spectrum associated with DCTN1 mutations.
In the patient (III-5) of one family (F187), we identified a heterozygous missense mutation, c.212G>A, p.Gly71Glu (NM_004082.4), in exon 2 of the DCTN1 gene. These results are shown in Figure 1.
Two patients (III-5 and II-7) of family F187 manifested a PSP-like phenotype at disease onset. Other patients had clinical diagnoses of Perry syndrome (II-3), Parkinson disease (III-3 and II-2), and behavioral variant of FTD (bvFTD) (III-7 and III-12). Two patients (III-5 and III-12) were independently referred to us by their neurologist, and genealogical extension of the family allowed us to link the 2 patients to the same pedigree.
The mutation segregated with the disease: patients III-3, III-7, and III-12 carried the mutation, whereas 4 asymptomatic relatives older than 60 years (II-5, II-6, III-4, and III-6) did not carry the mutation. The DNA of patients II-2, II-3, and II-7, who were obligate carriers, was unavailable.
The c.212G>A, p.Gly71Glu mutation has been previously identified in an apparently unrelated French family with a phenotype of Perry syndrome.14,15 The glycine at codon 212 is conserved among multiple species. This mutation is located in the cytoskeleton-associated protein, glycine-rich domain, which contains the most conserved GKNDG motif (Gly-Lys-Asn-Asp-Gly). In silico analysis of missense substitutions pathogenicity revealed that p.Gly71Glu was classified as pathogenic using the following 4 algorithms: (1) PolyPhen-2 (Polymorphism Phenotyping version 2) software (http://genetics.bwh.harvard.edu/pph2), (2) Align GVGD (http://agvgd.iarc.fr/), (3) SIFT (Sorting Intolerant From Tolerant) (http://sift.jcvi.org), and (4) Mutation Taster (http://www.mutationtaster.org). It was not detected in 949 control subjects from another study14 and was not present in 6503 individuals from an available database (Exome Variant Server [http://evs.gs.washington.edu/EVS/]), supporting its pathogenicity.
Detailed clinical features were available for 8 patients of the family (Table 1). Four patients (III-3, III-5, III-7, and III-12) were examined and followed up by one of us (C.B.B., M.S., T.L., A.-M.B., R.L., or M.V.). Clinical data of deceased patients (I-1, II-2, II-3, and II-7) were collected from their medical records and by interview with their relatives.
In 6 patients, the mean (SD) age at onset was 47 (7) years (age range, 39-59 years). The first symptom was parkinsonism in 4 of 8 patients. Parkinsonism was predominantly of rigid-akinetic type; asymmetric tremor was present in one patient. Beneficial effect of levodopa was variable and often mild. It was often not well tolerated, rapidly causing levodopa-induced delirium, dyskinesias, and hallucinations. Initial depression and behavioral disorders (each in 2 of 8 patients) were less frequent. None of the patients developed clinical symptoms of amyotrophic lateral sclerosis (ALS). Among 8 patients, the mean (SD) age at death was 52 (6) years (age range, 43-64 years). Among 7 patients, the mean (SD) duration of disease was 6 (4) years (range, 3-14 years). The disease duration was long (14 years) in one patient (Table 1).
Four patients (III-5, II-7, III-12, and III-7) had uncommon presentations. Patient III-5 manifested apathy at age 59 years. At age 61 years, he developed bilateral blepharospasm, environmental adherence, and predominant axial akinetic-rigid parkinsonism. Brain magnetic resonance imaging revealed mild midbrain atrophy (Figure 2A), and brain ethyl cysteinate dimer–single-photon emission computed tomography showed prefrontal superior hypoperfusion. At age 62 years, the patient manifested anxiety, collectionism, and loss of interest, in the absence of depression. Examination showed marked axial rigid-akinetic parkinsonism with perseverations, buccolingual apraxia, bilateral grasping reflex, and severe postural instability. Examination of gaze showed slowing of voluntary vertical saccades. An electroneuromyogram was normal. Eye movement recording showed severe hypometry (gain = 0.75) but normal latency and velocity of horizontal visually guided saccades (225 milliseconds for right latency, 221 milliseconds for left latency; normal value 130–220). Saccade velocity was slightly reduced in downward vertical movements. Antisaccades were mildly abnormal (errors of 47% on the right side and 20% on the left side). A dysexecutive syndrome with perseverations, poor lexical phonological evocation, and attention and working memory deficits was present (Table 2). A diagnosis of PSP was made based on the clinical phenotype. The disease rapidly worsened, and death occurred at age 64 years.
From age 49 years, patient II-7 demonstrated obsessional personality traits; severe panic attacks characterized his disease, which led to a diagnosis of hypochondria. At age 51 years, the patient developed severe axial parkinsonian rigidity with postural instability associated with right upper limb dystonia. Parkinsonism only partially responded to levodopa treatment. An examination revealed a massive frontal syndrome with grasping reflex. Eye movement recording showed saccade hypometry. A diagnosis of PSP was made based on the clinical presentation. The disease rapidly worsened. Death occurred from pulmonary infection and acute respiratory failure at age 52 years.
Patient III-12 had depression and anxiety associated with behavioral changes at age 39 years. He progressively developed apathy, hyperorality, personal neglect, loss of initiative, indifference to others, and eating conduct changes. An examination at age 41 years revealed severe psychomotor slowness and reduction of speech output. Perseverative errors were present on the Wisconsin Card Sorting Test19 (Table 2). Mild frontal atrophy was seen on brain magnetic resonance imaging, and brain single-photon emission computed tomography showed bilateral frontal hypoperfusion (Figure 2B and C). A diagnosis of bvFTD was made. An electroneuromyogram was normal. A polysomnographic recording revealed a sleep apnea syndrome. At age 42 years, he developed predominant axial rigidity associated with moderate right upper and lower limb tremor and rigidity. Levodopa treatment was complicated by drug-induced dyskinesia and hallucinations. The patient manifested severe depression with suicidal ideation (score of 20 on the Montgomery-Åsberg Depression Rating Scale22) that was resistant to antidepressant treatment. He later developed alcohol abuse, motor stereotypies, and progressive weight loss. Death occurred at age 43 years during an episode of acute alcoholism.
Patient III-7 had a long history of depression with numerous suicide attempts. He demonstrated loss of balance, a gait in small steps, and falls at age 40 years. A behavioral disorder with puerilism, coarseness, hyperorality, anosognosia, bizarre conduct, and disinhibition with seductress behavior was consistent with a diagnosis of bvFTD. The patient died at age 54 years of respiratory arrest.
Other patients (I-1, II-2, II-3, and III-3) are summarized in Table 1. Patients I-1, II-2, and III-3 had a diagnosis of early-onset parkinsonism. The phenotype of the other patient (II-3) included hypoventilation, severe depression, and associated parkinsonism with respiratory failure, which was consistent with the diagnostic criteria of Perry syndrome.
We have described herein a French family characterized by high intrafamilial variability with different phenotypes, including bvFTD, Perry syndrome, PSP-like phenotype, and isolated parkinsonism caused by the p.Gly71Glu mutation in exon 2 of the DCTN1 gene. Another apparently unrelated French family carried the p.Gly71Glu mutation14,15 (Table 3). Although these 2 families originated from different regions of France, we cannot firmly exclude a founder effect for this mutation.
DCTN1 mutations were first identified in patients with distal spinal and bulbar muscular atrophy33,34 and in patients with ALS.35,36 A cluster of mutations in exon 2 of the DCTN1 gene was identified later in 11 families with Perry syndrome, a rare autosomal dominant form of parkinsonism associated with weight loss, severe depression, and central hypoventilation (Table 3).14,15,23- 32 Clinical diagnostic criteria of Perry syndrome, as defined by Wider and Wszolek,37 include 5 cardinal characteristics (weight loss, parkinsonism, hypoventilation, psychiatric symptoms, and familial autosomal dominant history) and 5 supportive features (rapid progression, suicidal thoughts or attempts, no or transient response to levodopa, onset between the ages of 30 and 60 years, and dyspnea or apnea with night predominance). The phenotypes associated with DCTN1 mutations are correlated with the genotype because all the mutations located in exon 2 except one (p.Gly59Ser) are responsible for Perry syndrome. The p.Gly59Ser mutation led to slowly progressive distal spinal and bulbar muscular atrophy with vocal cord paralysis.33 All other mutations producing ALS are in the other exons of the gene (see eTable 1 in the Supplement).35,36
The patient of family F187 (III-5) and his relative (II-7) manifested a clinical phenotype that matched the criteria for PSP, which is an uncommon presentation in families with DCTN1. A clinical diagnosis of Perry syndrome could not be considered in the 2 patients at early stages of disease. Indeed, the phenotype of III-5, with only 2 cardinal features (parkinsonism and autosomal dominant inheritance) without weight loss, hypoventilation, or psychiatric symptoms was inconsistent with probable or possible criteria for Perry syndrome (see eTable 2 in the Supplement). The phenotype of II-7 was ultimately consistent with a probable diagnosis of Perry syndrome but not at the early stage of disease. Initially, both patients manifested a progressive rigid-akinetic syndrome after age 40 years, combining early postural instability with falls, slow vertical saccades, or supranuclear gaze palsy and a disease duration shorter than 8 years, which fit well with criteria for PSP by the National Institute of Neurological Disorders–Society for Progressive Supranuclear Palsy,1 as well as criteria by the Neuroprotection and Natural History in Parkinson Plus Syndromes.2 Oculomotor recordings in both patients showed hypometric horizontal saccades and a speed reduction downward in vertical movements, which were unusual in Perry syndrome but were characteristic of PSP. In addition, both patients had frontal syndrome and dystonia (blepharospasm or upper limb dystonia), and midbrian atrophy was present in patient III-5; these symptoms are uncommon in Perry syndrome but suggest the diagnosis of PSP. One other patient carrying a p.Gly71Arg DCTN1 mutation demonstrated slowing of vertical downward saccades and progressive midbrain atrophy on neuroimaging that were suggestive of PSP.31 This patient and our series support that PSP-like phenotypes may be included in the clinical spectrum of disorders associated with DCTN1 mutations. These cases also suggest that phenotypic presentations are related to an anatomical distribution of the lesions rather than to a specific histopathological condition because DCTN1 mutations are associated with pathological transactive response DNA-binding protein 43 (TDP-43),32 although most other PSP phenotypic presentations are tauopathies.4
Two other patients had unusual presentations of predominant behavioral disorders consistent with the diagnostic criteria of bvFTD.38 Only mild to moderate frontal atrophy was present at brain imaging, although single-photon emission computed tomography showed marked bilateral frontal hypoperfusion in one patient. Neither patient had clinical symptoms of ALS. Another patient having FTD with a family history of ALS carried a p.Arg1101Lys mutation in exon 27. Frontotemporal type of dementia is not included in the clinical criteria for Perry syndrome,37 but our cases showed that it may be the predominant initial phenotype in patients with DCNT1 mutations.
It has recently been shown that Perry syndrome is a genetically and pathologically heterogeneous syndrome; however, neuropathological investigations demonstrated severe neuronal loss in the substantia nigra without Lewy bodies but with TDP-43–positive inclusions in Perry syndrome caused by DCTN1 mutations.32MAPT mutations have also recently been identified in 2 families with associated weight loss, parkinsonism, and central hypoventilation, a phenotype resembling Perry syndrome, and with a pathological 4-repeat tau suggestive of PSP.39DCTN1 codes for the large subunit p150glued of the dynein-dynactin motor protein complex are involved in retrograde axonal transport. Tau is a microtubule-binding protein that strongly interacts with tubulin to assemble and stabilize the microtubule and is crucial for axonal transport. Mutations in DCTN1 and MAPT in dementia, parkinsonism, and motor neuron disorder support that axonal transport injury might have a key role in the pathogenesis of these conditions.33
The frequency of DCTN1 mutations was low (1 of 21 patients) in our series of familial forms of PSP-like phenotypes. However, our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-phenotypes, especially when bvFTD, psychiatric disturbances, associated parkinsonism, or a familial history of an autosomal dominant disorder is present.
Group Information: The French Clinical and Genetic Research Network on Frontotemporal Dementia/Frontotemporal Dementia–Amyotrophic Lateral Sclerosis investigators are listed at the end of this article.
Accepted for Publication: September 9, 2013.
Corresponding Author: Alexis Brice, MD, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche_S975, 47 Boulevard de l’Hôpital, 75651 Paris CEDEX 13, France (firstname.lastname@example.org).
Published Online: December 16, 2013. doi:10.1001/jamaneurol.2013.5100.
Author Contributions: Dr Brice 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. Drs Caroppo, Le Ber, and Clot contributed equally to this work.
Study concept and design: Caroppo, Le Ber, Clot, Brice.
Acquisition of data: Caroppo, Le Ber, Rivaud-Péchoux, Camuzat, De Septenville, Boutoleau-Bretonnière, Mourlon, Sauvée, Lebouvier, Bonnet, Levy, Vercelletto.
Analysis and interpretation of data: Caroppo, Le Ber, Clot, Rivaud-Péchoux.
Drafting of the manuscript: Caroppo, Le Ber, Clot, Rivaud-Péchoux, Brice.
Critical revision of the manuscript for important intellectual content: Camuzat, De Septenville, Boutoleau-Bretonnière, Mourlon, Sauvée, Lebouvier, Bonnet, Levy, Vercelletto.
Obtaining funding: Caroppo, Le Ber, Brice.
Administrative, technical, or material support: Clot, Rivaud-Péchoux, Camuzat, De Septenville, Mourlon.
Conflict of Interest Disclosures: None reported.
Funding/Support: The research leading to these results was funded by grant ANR-10-IAIHU-06 from Investissements d’Avenir. Dr Caroppo’s PhD fellowship was supported by Carlo Besta Institute. The study also received funding from PSP-France Association (Dr Le Ber) and France-Alzheimer Association (Dr Le Ber) and was supported by grant R06363DS from the Agence Nationale de la Recherche (Dr Brice).
Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: The French Clinical and Genetic Research Network on Frontotemporal Dementia/Frontotemporal Dementia–Amyotrophic Lateral Sclerosis investigators were Sophie Auriacombe, MD, Centre Hospitalier Universitaire (CHU) Pellegrin, Bordeaux; Frédéric Blanc, MD, Hôpitaux Civils, Strasbourg; Alexis Brice, MD, Hôpital de la Salpêtrière, Paris; Françoise Clerget-Darpoux, MD, PhD, Hôpital Paul Brousse, Villejuif; Philippe Couratier, MD, CHU Limoges, Limoges; Mira Didic, PhD, CHU La Timone, Marseille; Bruno Dubois, MD, PhD, Hôpital de la Salpêtrière, Paris; Charles Duyckaerts, MD, PhD, Hôpital de la Salpêtrière, Paris; Véronique Golfier, MD, CHU Rennes, Rennes; Eric Guedj, MD, PhD, CHU Marseille, Marseille; Marie-Odile Habert, MD, PhD, Hôpital de la Salpêtrière, Paris; Didier Hannequin, MD, PhD, CHU Charles Nicolle, Rouen; Lucette Lacomblez, MD, Hôpital de la Salpêtrière, Paris; Isabelle Le Ber, MD, PhD, Hôpital de la Salpêtrière, Paris; Richard Levy, MD, PhD, CHU St Antoine, Paris; Vincent Meininger, MD, PhD, Hôpital de la Salpêtrière, Paris; Bernard-François Michel, MD, CHU Sainte-Marguerite, Marseille; Florence Pasquier, MD, PhD, CHU Roger Salengro, Lille; Michèle Puel, CHU Rangueil, Toulouse; François Salachas, MD, Hôpital de la Salpêtrière, Paris; François Sellal, MD, CHU Colmar, Colmar; Catherine Thomas-Anterion, MD, CHU Bellevue, Saint-Etienne; Martine Vercelletto, MD, CHU Laennec, Nantes; and Patrice Verpillat, MD, PhD, Hôpital de la Salpêtrière, Paris.
Additional Contributions: Lydia Guennec, BS, and the DNA and Cell Bank of the Research Center–Brain and Spine Institute, Hôpital de la Salpêtrière, provided excellent technical assistance.