Singular DYT6 phenotypes in association with new THAP1 frameshift mutations


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Singular DYT6 phenotypes in association with new
THAP1 frameshift mutations

Arnaud Blanchard, Agathe Roubertie, Marion Simonetta-Moreau, Vuthy Ea,
Coline Coquart, Melissa Y. Frederic, Gael Gallouedec, Jean-Paul Adenis,

Isabelle Benatru, Michel Borg, et al.

To cite this version:
Arnaud Blanchard, Agathe Roubertie, Marion Simonetta-Moreau, Vuthy Ea, Coline Coquart, et al..
Singular DYT6 phenotypes in association with new THAP1 frameshift mutations. Movement Disor-
ders, Wiley, 2011, 26 (9), pp.1775 - 1776. �10.1002/mds.23641�. �hal-01670065�

https://hal.archives-ouvertes.fr/hal-01670065
https://hal.archives-ouvertes.fr


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Singular DYT6 Phenotypes in
Association with New THAP1

Frameshift Mutations

DYT6 dystonia is an autosomal dominant disorder
with incomplete penetrance (�60%) characterized by
early-age onset (median, 13 years) and slight female pre-
dominance.1 The upper limb is a common site of onset, with
progressive extension of the disease to other body parts. The
cranial region is affected in almost two thirds of patients, and
the functional repercussions of the disease are perceived by
patients as mainly a result of disturbances in this region and
particularly to the speech problems present in more than half
of the patients; functional impairment is moderate overall
(patients remain ambulatory). THAP1 gene mutations have
now been identified in numerous DYT6 families. Here we
describe 2 new THAP1 mutations identified in non-Amish
patients with primary non-DYT1 dystonia.
Patients were selected among those followed in outpatient

clinics by trained neurologists from the French Dystonia net-
work. Eight index patients were recruited from Polish outpa-
tient clinics through an international collaboration. A set of
178 independent index patients with primary non-DYT1 dys-

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*Correspondence to: Gwenaelle Collod-Béroud, INSERM, U827,
Montpellier, France; gwenaelle.collod-beroud@inserm.fr
Arnaud Blanchard and Agathe Roubertie contributed equally to this
work.

Relevant conflicts of interest/financial disclosures: Nothing to report.
This study was supported by grants from the French Ministry of Health
(National PHRC 2007-A00614-49), AMADYS-LFCD, Alliance France
Dystonie, Lions Club, French Dystonia Network, Université Montpellier 1
and INSERM. Arnaud Blanchard and Vuthy Ea are supported by a grant
from the Ministère de l’Enseignement Supérieur et de la Recherche
(MESR).
Full financial disclosures and author roles may be found in the online
version of this article.

Published online 25 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23641

FIG. 1. Family tree demonstrating index cases with SGCE deletion (III:1 and III:2) who had cognitive impairment and mild myoclonus dystonia (black
fill). The father of index cases had the same SGCE deletion (II:3) but had adult-onset psychosis without myoclonus dystonia. Three of his siblings
had a history of psychosis without movement disorders (II:1, II:5, and II:6), but were unavailable for clinical examination or SGCE testing.

tonia were included. Patients with a mean age at onset of
20.4 6 16.7 years were diagnosed as having ‘‘generalized,
segmental, or multifocal dystonia’’ (54% of patients), or
‘‘oromandibular or cervical dystonia’’ (21.3%). Moreover, as
clinical expression of DYT6 has been redefined as ‘‘broad and
overlapping with non-DYT6 dystonia subtypes,’’2 we also
included patients with ‘‘blepharospasm’’ (7.3%) or with
‘‘other focal dystonia’’ such as writer’s cramp (17.4%). Sixty-
three percent were isolated cases, and autosomal dominant
transmission with sometimes incomplete penetrance was
observed in families. Informed consent and blood samples
were collected and DNA extracted from peripheral lympho-
cytes according to standard procedures. Direct sequencing of
the 3 THAP1 coding regions and their exon boundaries was
carried out. In the group of ‘‘generalized, segmental, or multi-
focal dystonia,’’ we identified 2 novel THAP1 heterozygous
mutations (c.377_378delCT deletion [p.Pro126ArgFsX2]
in patient 1; c.514dupA insertion [p.Arg172LysFsX7] in
patient 3) (Supplementary Figure 1). The same THAP1 dele-
tion was identified in the dystonic sibling of patient 1 (patient
2). These new frameshift mutations result in the formation of
premature STOP codons at positions 127 and 178,



respectively, and suggest, as previously reported, a loss-of-
function mechanism by haploinsufficiency.
The clinical picture of these 3 patients (Table 1) fits with

the clinical phenotype associated with THAP1 mutations,
but some clinical aspects are singular. In patient 3, dystonia
initially implicated the right upper limb at the age of 9, with
progressive axial involvement; at 14 years of age, the right
upper limb and the cervical region were clearly dystonic,
with writer’s cramp and torticolis. The patient was not
treated. At the age of 18 the patient reported spontaneous,
complete remission (cervical and upper limb). This remission
was transient, and after a free interval of 4 years, without
any obvious triggering factor, dystonia rapidly recurred with
right arm and cervical involvement. Afterward, dystonia did
not spread to other body parts; upper limb dystonia remained
moderate and stable, and disability was mainly due to cervical
involvement. No worsening or remission has been reported
since the age of 22, except for partial improvement after tri-
hexiphenydyl treatment and botulinum toxin injections in the
neck. Such transient improvement, or ‘‘honeymoon,’’ is not
uncommon in other primary dystonias, particularly in cervical
dystonia,3 but usually occurs within the first 5 years after
onset. To our knowledge, such a honeymoon has never been
observed in other known DYT6 patients.
Patient 1 is remarkable because of the lower limb onset of

the disease at an early age, thus mimicking DYT1 dystonia.
Nevertheless, upper limb onset is reported in more than half
of DYT6 patients, and cranial onset occurs in one quarter of
the cases (Table 1). In patients 1 and 2, who are siblings,
dystonia became progressively generalized, with prominent
cranial involvement, as described in almost half the DYT6
patients reported in the literature.

Although the 3 patients did not report any family history
of motor disabilities or movement disorders (except for the
sibling of patient 1), unfortunately, other family members
could not be examined or tested for THAP1 mutations.
Patient 3 was thus considered a sporadic case.

The occurrence of cognitive and psychiatric disorders is an
area of uncertainty in rare genetic forms of dystonia. Standar-
dized cognitive and psychiatric assessments were not performed
in our 3 patients; they were all university graduates, and their
past medical histories was uneventful for psychiatric disturban-
ces. Paisan-Ruiz4 reported cognitive changes in 1 DYT6
patient. Cognitive or psychiatric functions among THAP1
mutation carriers will need to be better analyzed.

In conclusion, THAP1 implication in primary dystonia is
rare in non-Amish patients (about 1.5% of tested dystonic
patients reported in the literature). The DYT6 phenotype over-
laps with that of other forms of primary early-onset dystonia,
especially DYT1 dystonia. Good candidates for THAP1 screen-
ing might be patients with onset in childhood or during adoles-
cence who present cervicocranial and upper limb involvement
or generalized dystonia and cranial involvement.

Acknowledgments: We thank all patients and family mem-
bers for participation in this study.

Note that during the reviewing process, several new
THAP1 mutations were reported (Zittel et al, Groen et al.,
Söhn et al, Cheng et al, and De Carvalho et al).

Arnaud Blanchard, MS,1,2 Agathe Roubertie, MD, PhD,1,2,3

Marion Simonetta-Moreau, MD, PhD,4 Vuthy Ea, MS,1,2

Coline Coquart,5 Melissa Y. Frederic, PhD,1,2

Table 1. Clinical characteristics of carriers of THAP1 mutations

Patient 1 Patient 2 Patient 3 Amish families* n ¼ 25 Non-Amish patients** n ¼ 50

Sex F M M F 15 (60%) F 30 (60.0%)
Age at onset (y) 4 7 9 Median, 14.5 (5–38) 2–62
Age at last examination (y) 52 50 38 Median, 40 (10–66) 13–79
Family history þ þ No 1 0.656
Site at onset 48 patientsa

Upper limb þ þ 11 (44%) 28 of 48 (58.3%)
Lower limb þ 1 (4%) 5 of 48 (10.4%)
Cervical 5 (20%) 6 of 48 (12.5%)
Cranial 8 (32%) 12 of 48 (25.0%)

Site at examination 41 patientsb

Upper limb þ þ þ 22 (88%) 35 of 41 (85.4%)
Lower limb þ þ No 12 (48%) 22 of 41 (53.7%)
Cervical þþ þ þ 14 (56%) 29 of 41 (70.7%)
Cranial þ þ No 17 (68%) 27 of 41 (65.8%)
Speech þ þ No 16 (64%) 28 of 50 (56.0%)

Distribution G G S Fo: 3 (12%) Fo: 10/50 (20.0%)
S: 10 (40%) S: 14/50 (28.0%)
Mu: 4 (16%) Mu: 2/50 (4.0%)
G: 8 (32%) G: 24/50 (48.0%)

Sex: F, female; M, male. Dystonia distribution: G, generalized; Fo, focal; Mu, multifocal; S, segmental.
*4 Families, 25 patients.1

**21 Families, 11 sporadic cases, 50 patients including our 3 patients.2,4–8
a48 Patients, as data were not available for patients reported by Djarmati et al.6
b41 Patients, as data were not available for patients reported by Houlden et al.7



Gael Gallouedec, MD,6 Jean-Paul Adenis, MD,7

Isabelle Benatru, MD,8 Michel Borg, MD,9

Pierre Burbaud, MD, PhD,10 Patrick Calvas, MD, PhD,11

Laura Cif, MD,12 Philippe Damier, MD, PhD,13

Alain Destee, MD, PhD,14 Laurence Faivre, MD, PhD,15

Lucie Guyant-Marechal, MD,16 Piotr Janik, MD, PhD,17

Samer Janoura, MD,18 Alexandre Kreisler, MD, PhD,14 ,
Anna Lusakowska, MD, PhD,17 Sylvie Odent, MD, PhD,19

Anna Potulska-Chromik, MD, PhD,17

Monika Rudzińska, MD, PhD,20 Stephane Thobois, MD, PhD,21

Isabelle Vuillaume, MD, PhD,22 Christine Tranchant, MD,23

Sylvie Tuffery-Giraud, PhD,1,2 Philippe Coubes, MD, PhD,12

Bernard Sablonnière, MD, PhD,22

Mireille Claustres, MD, PhD,1,2,5,
Gwenaelle Collod-Béroud, PhD,1,2*

1INSERM, U827, Montpellier, France; 2Université
Montpellier 1, UFR Médecine, Montpellier,
France; 3CHU Montpellier, Hôpital Gui de

Chauliac, Service de Neuropédiatrie, Montpellier,
France; 4Hôpitaux de Toulouse, Pôle
Neurosciences, Toulouse, France;

5CHU Montpellier, Hôpital Arnaud de Villeneuve,
Laboratoire de Génétique Moléculaire,

Montpellier, France; 6CHU Dupuytren, Service de
Neurologie, Limoges, France; 7CHU Dupuytren,

Service d’Ophtalmologie, Limoges, France;
8CHU de Dijon, Hôpital Général, Service de

Neurologie, Dijon, France; 9CHU de Nice, Service
de Neurologie, Nice, France; 10CHU Pellegrin,

Service de Neurophysiologie, Clinique, Bordeaux,
France; 11CHU Toulouse, Hôpital Purpan, Service

de Génétique Médicale, Toulouse, France;
12CHU Montpellier, Hôpital Gui de Chauliac,
Service de Neurochirurgie, Montpellier, France;

13CHU Nantes, CIC0004, Service de Neurologie,
Nantes, France; 14CHU de Lille, Service de

Neurologie, et Pathologie du Mouvement, Lille,
France; 15CHU de Dijon, Hôpital d’Enfants,

Centre de Génétique, Dijon, France; 16CHU de
Rouen, Hôpital Charles Nicolle, Département de
Neurologie, Rouen, France; 17Department of
Neurology, Medical University of Warsaw,

Poland; 18CHG Roanne, Service de Neurologie,
Roanne, France; 19Service de Génétique Clinique,
CHU de Rennes, Hôpital Sud, Rennes, France;

20Department of Neurology, Jagiellonian
University Medical College, Poland;

21Hospices Civils de Lyon, Hôpital Neurologique,
Service de Neurologie C, Lyon, France;

22CHRU de Lille, Département de Biochimie, et
de Biologie Moléculaire, Lille, France;

23Hôpitaux Universitaires de Strasbourg, Service
de Neurologie, Strasbourg, France

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6. Djarmati A, Schneider SA, Lohmann K, et al. Mutations in THAP1
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7. Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations
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Pantothenate Kinase–Associated
Neurodegeneration: Clinical

Description of 10 Patients and
Identification of New Mutations

Pantothenate kinase–associated neurodegeneration
(PKAN) is a rare autosomal recessive neurodegenerative dis-
order of childhood onset, characterized by progressive dysto-
nia and iron accumulation in the brain, mainly in the globus
pallidus and the pars reticulata of the substantia nigra.1

Patients have mutations in the gene encoding pantothenate
kinase 2 (PANK2), a key regulatory enzyme in the biosyn-
thesis of coenzyme A.2

We ascertained 10 patients from 3 unrelated Algerian fami-
lies between 1997 and 2008; all were examined at different
stages of the disease and presented with early-onset, typical,3–5

and rarely described clinical PKAN features (Table 1 and Sup-
plementary Fig. 1). Hyperactivity (Video) and attention deficit
rarely described in previous series5 but observed in most of our
patients were inaugural signs of the disease, as demonstrated
by the absence of any other clinical signs in patient F2P4 at the
age of 3 years. Pigmentary retinopathy, present in all our
patients, was also considered as an early sign because it was al-
ready detectable in the neurologically asymptomatic patient
(F2P4). The phenotype thereafter extended with abnormal falls

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Additional Supporting Information may be found in the online version of
this article.

*Correspondence to: Meriem Tazir, Department of Neurology, CHU
Mustapha Bacha and Laboratoire de Neurosciences, Université d’Alger,
Algérie, Algeria; meriem.tazir@sante.dz

Relevant conflicts of interest/financial disclosures: Nothing to report.
This work received support from the Ministère de la Santé, de la
Population et de la Réforme Hospitalière (Algeria), the Ministère de
l’Enseignement Supérieur et de la Recherche Scientifique (Algeria), the
Agence National de la Recherche (France, to A.D. and G.S.), the
Association Française contre les Myopathies (AFM, France; to H.A.) and
the Verum Foundation (Germany; to A.B.).
Full financial disclosures and author roles may be found in the online
version of this article.

Published online 25 March 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23648