Movement Disorders

Vol. 17, No. 6, 2002, pp. 1271–1277

© 2002 Movement Disorder Society

Phenomenology of “Lubag” or X-Linked

Dystonia–Parkinsonism

Virgilio Gerald H. Evidente, MD,1,2* Joel Advincula, MD,3 Raymund Esteban, PT,2 Paul Pasco, MD,4
Jhoe Anthony Alfon, BS,5 Filipinas F. Natividad, PhD,5 Joven Cuanang, MD,2 Amado San Luis, MD,6
Katrina Gwinn-Hardy, MD,7 John Hardy, PhD,7 Dena Hernandez, BS,7 and Andrew Singleton, PhD7
1
Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA
2
Institute for Neurosciences, St. Luke’s Medical Center, Quezon City, Philippines
3
Western Visayas State University Medical Center, Iloilo City, Philippines
4
Department of Neurology, Philippine General Hospital, Manila, Philippines
5
Research & Biotechnology Division, St. Luke’s Medical Center, Quezon City, Philippines
6
University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines
7
National Institutes of Health, Bethesda, Maryland, USA

Abstract: X-linked dystonia–parkinsonism (XDP), or Lubag
syndrome, is known to cause progressive dystonia, with or
without parkinsonism, among Filipino male adults with mater-
nal roots from the Philippine island of Panay. We present cin-
ematographic material of 11 cases of Lubag carrying the XDP
haplotypes who manifest with a wide spectrum of movement
disorders, including dystonia, tremor, parkinsonism, myoclo-
nus, chorea, and myorhythmia. Because of overlapping fea-
tures, Lubag patients are commonly misdiagnosed as idiopathic
dystonia, essential tremor, Parkinson’s disease, or Parkinson’s-
plus syndromes. Thus, it is imperative to elicit an exhaustive
family history in any Filipino male adult who presents with a
movement disorder. © 2002 Movement Disorder Society
Key words: dystonia; Lubag; XDP; parkinsonism

Lubag syndrome, or X-linked dystonia–parkinsonism
(XDP), is believed to have originated ancestrally in the
Philippine island of Panay, through a founder mutation
some 50 meiotic generations ago (1–2,000 years ago).1
In the local dialect, “Lubag” describes intermittent twist-
ing or posturing, whereas “Wa-eg” and “Sud-sud” refer
to sustained postures and shuffling gait, respectively.1–3
The age of onset of Lubag ranges from 12 to 48 years
(mean, 31.5 years).3 The presenting feature is usually
focal dystonia, most commonly blepharospasm, torticol-
lis, distal limb dystonia, oromandibular, lingual, or pha-
A videotape accompanies this article.
*Correspondence to: Virgilio Gerald H. Evidente, Department of
Neurology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, Arizona
85259. E-mail: evidente.virgilio@mayo.edu
Received 3 December 2001; Revised 28 April 2002; Accepted 5
May 2002
Published online 24 June 2002 in Wiley InterScience (www.
interscience.wiley.com). DOI 10.1002/mds.10271
ryngeal dystonia. Alternatively, the presenting symptom
is an action or resting tremor of a limb. Previous groups
have noted that only 14% develop frank parkinsonism;
these patients typically have a later mean age of onset of
40.5 years.3 Once focal dystonia sets in, progression to
multifocal or generalized dystonia typically occurs
within 5 to 6 years in most patients.
Because of overlapping features, Lubag can be misdi-
agnosed as Parkinson’s disease (PD), Parkinson’s-plus
syndrome, or essential tremor (ET). Such misdiagnosis is
most likely in those with equivocal family histories,
those born and raised outside the endemic areas, or those
who fail to recall any maternal ancestral roots from the
Panay Islands. Because Filipinos are one of the most
migrant ethnic groups in the globe, some Lubag patients
inevitably are evaluated in medical institutions outside of
the Philippines. For these reasons, and because Lubag is
a movement disorder that many practitioners have not
had the chance to see, we present cinematographically
the phenotypic spectrum of XDP. Toward this goal, we

1271
1272 V.G.H. EVIDENTE ET AL.
present 11 cases that represent the wide spectrum of
neurological findings that may be seen in Lubag.
PATIENTS AND METHODS
Clinical assessment of each subject was done by a
movement disorder specialist (V.G.H.E.) and included
the motor Unified Parkinson’s Disease Rating Scale
(UPDRS), Burke-Fahn-Marsden (BFM) dystonia scale,
and standard neurological examination. For further char-
acterization and verification of phenotype, videotaped
segments of the patients were reviewed by another
movement disorder specialist (K.G.H.). Blood was ob-
tained by means of venipuncture for genotyping. The
clinical evaluations were performed blind to the geno-
type information.
To confirm that the 11 cases presented were carriers
of the XDP haplotype, we performed polymerase chain
reaction amplification of microsatellite markers in and
around the previously reported segregating region,
spanning approximately 400 kb.4 The markers used
were DXS7117, DXS6673E 3⬘, ZNF261, DXS10017,
DXS10018, and DXS559. The precise methodology has
been described previously.5
RESULTS
The clinical features of the 11 Lubag patients are sum-
marized in Table 1. We have confirmed that all these
cases possess the disease segregating haplotype found in
34 previously reported cases4 and 20 clinically evaluated
XDP cases.6 Nine of 11 patients had maternal roots from
the Panay Islands, whereas 2 (Cases 6 and 9) could not
trace such roots. All patients had other maternal male
relatives with either dystonia or parkinsonism. The av-
erage age of onset was 35.7 years (range, 21–49 years).
Five patients presented with at least one cardinal feature
of parkinsonism as the initial symptom, 2 of whom were
misdiagnosed as PD or ET in the earlier stages. One
patient (Case 3) presented with ballism as the initial
symptom. Nine of 11 cases had multifocal or generalized
dystonia, 1 of 11 (Case 9) had focal dystonia (last seen at
4th year of disease), and 1 of 11 (Case 10) had no dys-
tonia. Case 10, who was last seen at his 13th year of
disease, only had pure parkinsonism and is discussed in
a separate publication.5 The average time for the dysto-
nia to become multifocal or generalized was 6.7 years
(range, 2–16 years). Two patients had myoclonus: Case
6 had action myoclonus of the hands, whereas Case 8 had
facial action myoclonus. Surface electromyography
(EMG) confirmed myoclonic discharges of less than 50-
msec duration in both cases. Case 6 also had myorhyth-
mia of the distal upper limbs, which on surface EMG
showed 1 to 3 Hz alternating contraction of agonists and
Movement Disorders, Vol. 17, No. 6, 2002
antagonists (with reciprocal inhibition); no co-contrac-
tion of antagonistic muscles was noted.
Monotherapy treatment with various antidystonia
drugs was uniformly ineffective for all patients. Therapy
with a benzodiazepine (e.g., clonazepam or diazepam)
plus an anticholinergic agent (e.g., trihexyphenidyl or
biperiden) was the most common combination to offer
some relief of dystonia (albeit still mild or modest). Zol-
pidem monotherapy was dramatically efficacious in re-
lieving the generalized dystonia in 1 patient (Case 11),
with each dose lasting 2 hours with chronic treatment.
This case is discussed in more detail separately.8 One
patient (Case 7) had dramatic improvement of general-
ized dystonia with tetrabenazine, with no worsening of
parkinsonism (which was being treated with 200 mg/day
levodopa). Levodopa was initiated in 10 of 11 patients; 7
of 10 had mild to moderate improvement of parkinson-
ism, whereas 3 of 10 either had no response or could not
tolerate it. Only 1 patient (Case 1) had worsening of
dystonia with levodopa, but none developed levodopa-
associated dyskinesias.
DISCUSSION
The 11 cases reported in this study represent the wide
array of movement disorders or neurological symptoms
that Lubag patients can present with, including dystonia,
tremor, parkinsonism, myoclonus, and chorea (Table 1).
The dystonia is often focal at onset and may involve the
eyes, jaw, tongue, oropharyngeal region, neck, or distal
limb. Lower facial and oromandibular dystonia are par-
ticularly common in Lubag patients, particularly jaw-
opening/closing, and tongue dystonia (either involuntary
protrusion or limitation in voluntary movement). Dysto-
nia usually does not involve the trunk in the early stages
but may cause truncal hyperextension or arching, rota-
tion, flexion, or lateral bending if present. Those with
retrocollis also commonly develop truncal hyperexten-
sion. Patients with blepharospasm may have associated
apraxia of eyelid opening, or may develop Meige syn-
drome, with dystonia spreading to the lips (pursing), jaw
(opening or closing), or tongue (spontaneous outward
protrusion or difficulty with protruding). Lubag patients
may also present with laryngopharyngeal dystonia,
which can produce dysphonia or audible respiratory ab-
normalities. Case 7 had inspiratory sounds (similar to
wheezing or stridor) that were associated with involun-
tary jaw-opening, eye closure, and turning of the head to
the right. Case 11 emitted moaning sounds in association
with oromandibular dystonia. In severe cases, laryngeal
dystonia may lead to respiratory stridor and require tra-
cheostomy.7 Patients with dystonia of the lips, tongue, or
oropharyngeal region not surprisingly become dysarthric
 TABLE 1. Clinical profile of the 11 Lubag patients
Case Age of
no. onset (yr) Initial symptoms Description of parkinsonism
1 34 Resting tremor of RLE, Parkinsonism present at onset; by
hyperextension of 3rd year, parkinsonism was
neck, change in severe (hypophonic speech,
handwriting shuffling gait, resting and
postural tremor of RLE, diffuse
rigidity, bradykinesia,
breakdown of RAMs of all 4
limbs, reduced arm swing
bilaterally, slowness in arising
from a seated position, and
postural instability)
2 36 Stiffness of LEs, Parkinsonism was present at onset;
shuffling gait, and by 3rd year, parkinsonism was
bending of knees moderate (hypophonic speech,
on walking shuffling gait, diffuse rigidity,
bradykinesia, breakdown in
RAMs in all 4 limbs, slowness
in arising from a seated
position, reduced arm swing
bilaterally, and postural
instability)
3 36 Ballism of RUE Mild to moderate parkinsonism
developed at 15th year
(hypophonic speech, shuffling
gait, postural and terminal
tremor of LUE, mild rigidity of
the neck, bradykinesia,
breakdown of RAMs of all 4
limbs, reduced arm swing
bilaterally, and postural
instability)
4 40 Twisting of RLE on Resting tremor of RUE noted at
walking 7th year; shuffling gait and
postural instability at 8th year;
by 9th year, parkinsonism was
mild to moderate (dysarthria,
dysphagia, hypominia,
breakdown in RAMs in all 4
limbs, rigidity of UEs and neck,
slowness in arising from a
seated position, micrographia,
and postural instability)
5 33 Fingers hyperextend Moderate parkinsonism noted at
involuntarily 7th year (stooped posture,
diffuse rigidity, bradykinesia,
breakdown of RAMs in all 4
limbs, slowness in arising from
a seated position, shuffling gait,
reduced arm swing bilaterally,
micrographia)
Movement Disorders, Vol. 17, No. 6, 2002
Description of dystonia
Focal cervical dystonia at onset;
generalized dystonia by 2nd
year (jaw opening, retrocollis,
extension of UEs, trunk
hyperextension, twisting of
distal LEs); (+) sensory trick
for cervical dystonia
Focal action dystonia of LEs at
onset; generalized dystonia by
3rd year (torticollis, trunk
dystonia, extension of LEs at
rest and flexion on walking);
(+) sensory trick for cervical
dystonia
Focal dystonia (blepharospasm)
noted at 2nd year; segmental
dystonia by 9th year
(additional jaw-opening and
tongue protrusion dystonia);
multifocal dystonia by 16th
year (severe tongue
protrusion, jaw-opening,
blepharospasm, twisting of
distal LEs at rest)
Focal distal RLE action dystonia
at onset; multifocal dystonia
by 16th year (torticollis,
flexion of the fingers at rest,
dorsiflexion of distal RLE);
generalized dystonia by 18th
year (with additional
blepharospasm, truncal
dystonia, and severe dystonia
of UEs and LEs)
Segmental dystonia (jaw forward
displacement and torticollis)
at 4th year; multifocal
dystonia by 7th year (forward
displacement of jaw,
torticollis, inversion of distal
LLE, dorsiflexion of left big
toe); (+) sensory trick for jaw
dystonia
Course of treatment
Other clinical features Course of treatment of dystonia of parkinsonism
Dysphagia and severe Failed monotherapy with 375 mg/day levodopa
drooling coincided with diphenhydramine, tetrabenazine, offered moderate
onset of jaw dystonia, reserpine, baclofen, tizanidine, improvement of resting
and led to 30-lb. weight trihexyphenidyl, clonazepam, and tremor, but worsened
loss haloperidol; mild improvement with the cervical dystonia
10 mg/day trihexyphenidyl + 2
mg/day clonazepam; BTX injections
for cervical dystonia were effective,
but worsened dysphagia
Walking backwards allows Failed maximally tolerated doses of Tolerated 300 mg/day of
the patient to ambulate risperidone and clozapine in levodopa, with
faster monotherapy; 60% improvement of moderate improvment
BFM dystonia scores with of bradykinesia; no
combination of 25 mg/day clozapine effect on dystonia
+ 5 mg/day trihexyphenidyl + 10
mg/day zolpidem
Ballism disappeared Failed various combinations of Levodopa had no effect on
spontaneously after first haloperidol, clonazepam, diazepam, his parkinsonism or
2 years; at 9th year, biperiden, and diphenhydramine; dystonia
severe dysphagia combination of 2 mg/day biperiden
developed with + 10 mg/day diazepam offered mild
jaw/tongue dystonia, improvement of lingual/jaw
requiring gastrostomy dystonia; BTX injections into
tube placement genioglossus had no benefit, and
worsened dysphagia significantly
Choreoathetoid movements Tizanidine + levodopa had no benefit; Levodopa had no effect on
of the distal UEs noted 1 mg/day of clonazepam + 5 his parkinsonism,
at 9th year, even before mg/day of trihexyphenidyl offered dystonia, or chorea
PHENOMENOLOGY OF LUBAG OR XDP
levodopa was instituted mild relief of dystonia; BTX
injections offered temporary relief
of torticollis, but worsened
dysphagia
Forced or pathological Failed treatment with clonazepam, Could not tolerate
laughter developed, biperiden, trihexyphenidyl, levodopa even at low
with no spastic tizanidine, clozapine, mexiletine, doses (severe
weakness of and muscle relaxants as headaches)
orophyaryngeal monotherapy or in different
muscles; Mini Mental combinations
score of 27/30; brain
MRI normal
1273

Case Age of
no. onset (yr) Initial symptoms Description of parkinsonism
6 39 Action tremor of UEs Mild parkinsonism noted at 3rd
year (LLE resting tremor,
shuffling gait, and rigidity of
neck and limbs); diagnosed with
PD initially, and
Parkinson’s-plus syndrome later
on when levodopa proved to
have little benefit
Movement Disorders, Vol. 17, No. 6, 2002
7 31 Change in Parkinsonism noted at 3rd year
handwriting (shuffling gait, stooped posture,
dysarthria, RLE resting tremor)
8 37 Blepharospasm Parkinsonism noted at 2nd year
(dysphagia, bradykinesia,
shuffling gait, resting tremor of
LEs and head)
9 49 Hyperextension of Parkinsonism noted at 2nd year
neck (resting and postural tremor of
UEs, rigidity, bradykinesia,
breakdown of RAMs in all 4
limbs, slowness in arising from
a seated position, shuffling gait,
reduced arm swing bilaterally,
and postural instability)
10 21 RUE tremor RUE action tremor from onset;
LUE action tremor noted at 9th
year; mild bradykinesia noted at
10th year; parkinsonism still
mild at 13th year (masked
facies, dysarthria, LUE action
tremor, breakdown of RAMs of
all 4 limbs, diffuse rigidity,
reduced left arm swing, and
micrographia)
11 37 Torticollis and neck Mild parkinsonism noted at 4th
stiffness year (hypomimia, bradykinesia,
diffuse rigidity, stooped posture,
breakdown of RAMs, shuffling
gait, and postural instability)
RLE, right lower extremity; RAM, rapid alternative movement; UE, upper extremity; LE, lower extremity; BTX, botulinum toxin; BFM, Burke-Fahn-Marsden dystonia scale; RUE, right upper extremity; LUE, left
upper extremity; LLE, left lower extremity; MRI, magnetic resonance imaging.
TABLE 1.—(Continued)
Description of dystonia
Multifocal dystonia noted at 9th
year (torticollis, upward
curling of the toes, and
tongue dystonia); generalized
dystonia by 13th year
(additional jaw closing
dystonia, anterocollis, truncal
dystonia, and dystonia of LEs
at rest and action)
Multifocal dystonia noted at 3rd
year (blepharospasm/apraxia
of eyelid opening, torticollis,
and dystonia of distal RLE);
generalized dystonia by 4th
year (additional jaw, tongue,
lower facial, laryngeal, and
truncal dystonia)
Focal dystonia (blepharospasm)
at onset; multifocal dystonia
by 2nd year (additional
dystonia of tongue and LEs)
Focal dystonia (retrocollis) at
onset; dystonic head tremor
noted at 4th year
No dystonia (as of 13th year of
disease)
Focal dystonia (torticollis) at
onset; generalized dystonia by
2nd year (blepharospasm,
posturing of UEs,
jaw-opening, tongue
protrusion, and truncal
dystonia)
1274
Course of treatment
Other clinical features Course of treatment of dystonia of parkinsonism
Myorhythmia of the distal Failed treatment with clonazepam, Levodopa initially helped
UEs noted at rest, trihexyphenidyl, biperiden, the bradykinesia, but
action, and posture, bromocriptine, and propranolol; not the tremor; it had
along with action minimal improvement of dystonia no effect on his
myoclonus of distal with 25 mg/day clozapine + 6 dystonia
UEs mg/day biperiden
Inspiratory sounds (like Failed treatment with clozapine, 200 mg/day of levodopa
wheezing or stridor) mexiletine, quetiapine, zolpidem, produced only mild
and expiratory grunting and baclofen; remarkable improvement of
observed coinciding improvement with 150 mg/day bradykinesia, but no
with torticollis tetrabenazine; BTX injections effect on tremor
around eyes relieved blepharospasm,
but cervical injections worsened
dysphagia
Facial action myoclonus 1 mg/day clonazepam + 10 mg/day 750 mg/day of levodopa
noted on examination trihexyphenidyl gave mild relief of resulted in mild
dystonia; addition of 1,200 mg/day improvement of his
mexiletine further improved the LE tremor, bradykinesia,
dystonia and dysphagia and dysphagia
Zolpidem 10 mg twice daily gave 50% 1,500 mg/day of levodopa
improvement of retrocollis, but + 150 mg/day of
caused significant drowsiness; piribedil (dopamine
biperiden monotherapy had no agonist) resulted in 75%
benefit; BTX injections relieved improvement of his
retrocollis for 3 months tremor; brief trial of
zolpidem 10 mg bid
offered 30%
improvement of his
V.G.H. EVIDENTE ET AL.
tremors
Diagnosed as ET initially, None Trihexyphenidyl +
then PD later on when selegiline + propranolol
parkinsonian features only offered minimal
appeared change; 900 mg/day
levodopa resulted in
moderate improvement
of his tremor and
bradykinesia
Dystonia was highly Zolpidem 10 mg three times daily Zolpidem had minimal
phasic, with resulted in almost complete effect on his
superimposed resolution of his dystonia for about parkinsonism
choreoathetoid 2 hours per dose
movements of the trunk
and limbs; he had
respiratory sounds
(moaning) with
oromandibular dystonia
 PHENOMENOLOGY OF LUBAG OR XDP
early in the course. Even in the absence of oromandibular
dystonia, many patients develop hypophonic speech (due
to superimposed parkinsonism). Swallowing is impaired
early in patients who develop tongue, jaw, or oropharyn-
geal dystonia. These patients lose weight early and rap-
idly and require feeding tube placement earlier than other
patients. Furthermore, they are prone to aspiration pneu-
monia, which may cause premature death. The tongue
protrusion dystonia is particularly disabling, because it
severely impairs speech and swallowing and causes sig-
nificant dental deformities (as in Case 3).
The dystonia, even in the advanced, generalized state,
is often painless. Patients who complain of pain are those
with cervical dystonia or with fixed contractures of the
limbs. The dystonia in Lubag is commonly the phasic
type. This finding is particularly true for dystonia of the
neck, trunk, and limbs. The tonic type of dystonia is less
common and may lead to joint contractures in chronic,
poorly treated patients. Also, on walking, phasic action
dystonia of the trunk and lower limbs can cause these
areas to bend or fold, thus significantly impairing ambu-
lation (as in Case 2). Some patients may have sensory
tricks (gestes antagonistique, or gegendruckphenom-
enon), particularly those with cervical dystonia. Occa-
sionally, sensory tricks may also alleviate other focal
dystonias in Lubag, such as that of the jaw or eyes. Some
develop other tricks to compensate for the dystonia. Case
2, for instance, had severe impairment of ambulation due
to bending of the knees but was able to walk faster going
backward.
In mild or early cases, the dystonia in Lubag is best
relieved by a combination of benzodiazepines and anti-
cholinergic agents. Levodopa does not improve the dys-
tonia and may occasionally exacerbate it (as in Case 1).
In more severe disease (i.e., multifocal or generalized
state), the dystonia is resistant to traditional antidystonia
regimens. Some may respond to zolpidem (as in Case 11)
in the advanced stages; this response is discussed sepa-
rately.8 Case 8 only responded to 150 mg daily of tetra-
benazine, with no perceptible change in his parkinson-
ism. For focal dystonia, particularly in the cervical re-
gion, botulinum toxin may be effective. Cervical
injections, however, may worsen the dysphagia in pa-
tients with preexisting swallowing difficulty (as in Cases
1 and 4).
The rate of progression of the dystonia is highly vari-
able in Lubag patients. Although generalized dystonia
was reported to occur in most subjects within 5 to 6 years
from onset,3 some may have a slower course. Case 3, for
instance, developed blepharospasm in the 2nd year,
tongue and jaw dystonia in the 9th year, and foot dysto-
nia in the 16th year of disease. On last follow-up in his
1275
18th year of Lubag, no further progression was noted.
His parkinsonian features were mild and developed late.
In contrast, some patients progress rapidly. Cases 1 and
2 developed generalized dystonia within 2 years from
onset. Unlike the other patients presented, these 2 cases
had parkinsonism and dystonia from the onset.
The tremor in Lubag can be at rest, posture, or action
(usually a terminal tremor on finger-to-nose). The pres-
ence of an asymmetric resting limb tremor or oroman-
dibular tremor can lead to a misdiagnosis of PD, particu-
larly when accompanied by bradykinesia, shuffling gait,
rigidity, and postural instability. Like tremor in PD, the
resting tremor in Lubag can reemerge in sustained pos-
ture after a latency of a few seconds (like Cases 1 and 9).
A coarse head tremor similar to ET head tremor may
develop but may actually represent dystonic head tremor
if cervical dystonia is present. At times, the limb tremor
can be very similar to ET in frequency and is evident on
sustained posture or at the terminal portion of an action
(as in finger-to-nose). Because of overlapping features
between PD, ET, and Lubag, it is imperative that a thor-
ough family history be elicited.
Aside from having tremors similar to PD or ET, Lubag
patients may also present with myorhythmia. This term
refers to a slow, 1 to 3-Hz, rhythmic, pendular, periodic
tremor at rest, which may be exacerbated or attenuated
by muscle activation or sustained posture.9 The tremor
may vary considerably in rate, rhythm, or amplitude, and
disappears during sleep. When seen in the oculomasti-
catory muscles, myorhythmia is considered pathogno-
monic of cerebral Whipple’s disease.10 Case 6 had a
slow, fluctuating, rhythmic tremor of the upper limbs at
rest, action, and posture, which was more pronounced on
standing or walking. On electrophysiology, myorhyth-
mia was suggested by 1 to 3 Hz alternating contraction
(with reciprocal inhibition) of agonist and antagonist
muscles; this finding is in contrast to co-contraction of
antagonistic muscles in dystonia. This tremor was resis-
tant to levodopa, dopamine agonists, anticholinergic
agents, and propranolol. Myorhythmia of the limbs may
occur with ipsilateral dentate nucleus or superior cerebel-
lar peduncle lesions or contralateral inferior olive in-
volvement.11 Typically, in Lubag, only the caudate and
lateral putamen exhibit neuronal loss and astrocytosis.12
Neuropathological examination of Case 6 in the future
would help elucidate any extrastriatal pathology.
Definite parkinsonism, defined as the presence of at
least two cardinal parkinsonian features (which must in-
clude a resting tremor or bradykinesia or both, with or
without rigidity, postural instability, or shuffling gait),
was previously reported to afflict only 14% of Lubag
patients.3 Our observations suggest that parkinsonism is
Movement Disorders, Vol. 17, No. 6, 2002
1276 V.G.H. EVIDENTE ET AL.
more common than previously reported. In fact, all 11
patients presented in this study had definite parkinson-
ism. Most Lubag patients exhibit some degree of parkin-
sonism early in the course. Five of 11 patients we de-
scribed presented with a parkinsonian feature (i.e., rest-
ing tremor, rigidity, bradykinesia, or postural instability)
as an initial or early symptom, with or without focal
dystonia. Thus, not surprisingly, Lubag patients are mis-
diagnosed as PD or Parkinson’s-plus syndrome (as in
Case 6). Some may even present with parkinsonism
alone with no dystonia for a protracted period (e.g., Case
10). Wilhelmsen and colleagues previously reported a
large Filipino kindred with Lubag.13 Of 8 affected indi-
viduals they examined, 3 had pure parkinsonism without
dystonia, 1 of whom had this isolated phenotype 19 years
after onset of symptoms. We presented separately 3
Lubag patients (including 1 of those reported here) with
predominant parkinsonism, with late-onset or no dysto-
nia.5 Thus, pure or predominant parkinsonism may be a
phenotypic presentation of Lubag; it is uncertain whether
dystonia will universally develop in these cases with
time. Those with predominant parkinsonism tend to have
a milder course and later onset of disability. The parkin-
sonism is often at least mildly or moderately responsive
to levodopa.
The highly phasic dystonia of the limbs, trunk, and
neck in Lubag patients may appear choreiform, or be
admixed with true chorea. Case 3, at onset, had ballism
of the right arm, which disappeared after 2 years. Case 4,
on his 9th year of disease, had upper limb choreoathetoid
movements at rest and on posture. Case 11 had axial and
limb choreiform movements together with the phasic
dystonia. None of these 3 cases were on levodopa when
chorea/ballism was observed. In the series of 42 Lubag
patients reported by Lee and colleagues,3 chorea was not
described as a presenting feature. Waters and associates,
however, reported a sister of an affected male Lubag
patient who presented with generalized chorea.2 It ap-
pears that chorea may be admixed with dystonia in
Lubag patients or may occur independent of the dystonia.
Because the neuropathology in Lubag involves the cau-
date nucleus,12 chorea is not an unexpected finding.
Myoclonus has not been reported previously in Lubag
patients; however, 2 of the cases described in this study
had action myoclonus confirmed by surface electromy-
ography (EMG). Case 6 presented with myoclonus of the
upper limbs upon raising his arms up and on finger-to-
nose, whereas Case 8 presented with facial myoclonus on
grimacing and jaw opening. Neither of these 2 individu-
als had myoclonic jerks at rest nor stimulus-sensitive
myoclonus. Surface EMG studies on both patients re-
vealed myoclonic discharges of less than 50-msec dura-
Movement Disorders, Vol. 17, No. 6, 2002
tion in the affected muscles. Full neurophysiological
characterization of the myoclonus in Lubag is the subject
of another ongoing study. Myoclonus is not known to
occur in pure striatal lesions but can be seen in cortical,
thalamic, brainstem, spinal cord, peripheral nerve, and
even cerebellar lesions.14 This, again, suggests that ex-
trastriatal structures may be affected, at least function-
ally, in Lubag patients.
Pathological or forced emotions (forced laughing or
crying) usually signify either a focal or diffuse subcor-
tical brain pathology and is most commonly due to de-
generative, vascular, or demyelinating disorders.15,16
When coupled with spastic or upper motor neuron weak-
ness of voluntary muscles of the face, tongue, larynx, or
pharynx, the term “pseudobulbar palsy” is used. Of the
degenerative brain disorders, progressive supranuclear
palsy (PSP) most commonly presents with pseudobulbar
palsy. Case 5 demonstrated pathological or forced laugh-
ing, which could be either spontaneous or inappropriate
to the situation or conversation. No spastic weakness of
the craniofacial muscles was seen. With the brain mag-
netic resonance imaging and mental status examination
being unremarkable, it is likely that the forced laughter
was a manifestation of Lubag.
In summary, the phenotypic presentation of Lubag is
more diverse than previously thought, and may include a
combination of parkinsonism, dystonia, myoclonus,
tremor, myorhythmia, chorea, and pathological or forced
emotions. Tremor and parkinsonism are common in
Lubag and may even precede or overshadow the dystonic
symptoms. In such cases, Lubag may be easily mistaken
for PD, ET, or Parkinson’s-plus syndrome. It is impera-
tive, therefore, to elicit a detailed family history in any
Filipino man who presents with dystonia, tremor, or par-
kinsonism in isolation or in combination with other neu-
rological symptoms or movement disorders.
Acknowledgments: This research was supported by the Re-
search and Biotechnology Division of St. Luke’s Medical Cen-
ter (Quezon City, Philippines) and the Dystonia Medical Re-
search Foundation. Thanks to the family members for their
participation.
LEGENDS TO THE VIDEOTAPE
Segment 1. Case 1 presents with severe retrocollis,
truncal hyperextension, jaw-opening dystonia, resting
and postural tremor of the distal right lower limb, bra-
dykinesia, shuffling gait, and reduced arm swing. As a
sensory trick to lessen the cervical dystonia, the patient
puts both hands behind his head.
Segment 2. Case 2 has dystonic flexion of the legs on
walking. He is able to ambulate faster walking backward.
 PHENOMENOLOGY OF LUBAG OR XDP
Segment 3. Case 3 has severe tongue protrusion dys-
tonia, along with involuntary jaw-opening and blepharo-
spasm.
Segment 4. Case 4 presents with dystonia and cho-
reoathetoid movements of the distal upper limbs on rais-
ing his arms up.
Segment 5. Case 5 presents with forward dystonic jaw
displacement and torticollis. He also has forced laughing
or giggling, most evident while counting.
Segment 6. Case 6 has myorhythmia of the upper
limbs, most prominently in the left.
Segment 7. Case 7 presents with blepharospasm or
apraxia of eyelid opening. He produces respiratory
sounds similar to wheezing or stridor in inspiration and
grunting on expiration. These sounds are associated with
involuntary eye closing, jaw-opening, and turning of the
head to the right.
Segment 8. Case 8 has prominent facial myoclonus on
opening his mouth.
Segment 9. Case 9 presents with a coarse postural
tremor of both upper limbs, retrocollis, and a dystonic
head tremor.
Segment 10. Case 10 presents with pure parkinsonism
without dystonia. Note the masked facies, terminal
tremor on finger-to-nose in the left, asymmetric break-
down of rapid alternating movements of the limbs (worse
in left), and reduced arm swing in the left. He also has a
tongue postural tremor.
Segment 11. Case 11 has abundant phasic dystonic
movements of the facial, cervical, truncal, and limb
muscles. He has superimposed axial and limb choreiform
and athetoid movements. He also emits a moaning sound
along with the oromandibular dystonia.
REFERENCES
1. Lee LV, Pascacio FM, Fuentes FD, Viterbo GH. Torsion dystonia
in Panay, Philippines. Adv Neurol 1976;14:137–151.
2. Waters CH, Takahashi H, Wilhelmsen KC, Shubin R, Snow BJ,
Nygaard TG, Moskowitz CB, Fahn S, Calne DB. Phenotypic ex-
pression of X-linked dystonia–parkinsonism (Lubag) in two
women. Neurology 1993;43:1555–1558.
1277
3. Lee LV, Kupke KG, Caballar-Gonzaga F, Hebron-Ortiz M, Müller
U. The phenotype of the X-linked dystonia–parkinsonism syn-
drome: an assessment of 42 cases in the Philippines. Medicine
1991;70:179–187.
4. Nemeth AH, Nolte D, Dunne E, Niemann S, Kostrzewa M, Peters
U, Fraser E, Bochukova E, Butler R, Brown J, Cox RD, Levy ER,
Ropers HH, Monaco AP, Müller U. Refined linkage dysequilib-
rium and physical mapping of the gene locus for X-linked dysto-
nia–parkinsonism (DYT3). Genomics 1999;60:320–329.
5. Evidente VGH, Gwinn-Hardy K, Hardy J, Hernandez D, Singleton
A. X-linked dystonia (“Lubag”) presenting predominantly with
parkinsonism: a more benign phenotype? Mov Disord 2002;17:
200–202.
6. Hernandez D, Evidente VGH, Alfon JA, Gwinn-Hardy K, Nativi-
dad FF, Hussey J, Gibbs R, Lincoln S, Adam A, Grover A, Hutton
M, Drafta C, Brin M, Doheny D, Marjama-Lyons J, Farrer M,
Hardy J, Singleton A. Identification and screening of candidate
genes within the X-linked dystonia–parkinsonism critical region
(submitted).
7. Lew MF, Shindo M, Moskowitz CB, Wilhelmsen KC, Fahn S,
Waters CH. Adductor laryngeal breathing dystonia in a patient
with Lubag (X-linked dystonia–parkinsonism syndrome). Mov
Disord 1994;9:318–320.
8. Evidente VGH. Zolpidem improves dystonia in “Lubag” or
X-linked dystonia-parkinsonism syndrome. Neurology 2002;58:
662–663.
9. Ahlskog JE. Patients with movement disorders. In: Adler CH, Ahl-
skog JE, editors. Parkinson’s disease and movement disorders:
diagnosis and treatment guidelines for the practicing physician.
Totowa, NJ: Humana Press, 2000. p 31–32.
10. Schwartz MA, Selhorst JB, Ochs AL, Beck RW. Oculomasticatory
myorhythmia: a unique movement disorder occurring in Whipple’s
disease. Ann Neurol 1986;20:677–683.
11. Masucci EF, Kurtzke JF, Saini N. Myorhythmia: a widespread
movement disorder. Clinicopathological correlations. Brain 1984;
107:53–79.
12. Waters CH, Faust PL, Powers J, Vinters H, Moskowitz C, Nygaard
T, Hunt AL, Fahn S. Neuropathology of Lubag (X-linked dysto-
nia–parkinsonism). Mov Disord 1993;8:387–390.
13. Wilhelmsen KC, Weeks DE, Nygaard TG, Moskowitz CB, Rosales
RL, dela Paz DC, Sobrevega EE, Fahn S, Gilliam TC. Genetic
mapping of “Lubag” (X-linked dystonia–parkinsonism) in a Fili-
pino kindred to the pericentromeric region of the X chromosome.
Ann Neurol 1991;29:124–131.
14. Shibasaki H. Electrophysiological studies of myoclonus. AAEE
minimonograph no. 30. Muscle Nerve 1988;11:899–907.
15. The limbic lobes and the neurology of emotion. In: Victor R,
Ropper AH, editors. Adams Victor’s Principles of Neurology. 7th
ed. New York: McGraw-Hill; 2001. p 541–542.
16. Black DW. Pathological laughter. A review of literature. J Nerv
Ment Dis 1982;170:67–71.
Movement Disorders, Vol. 17, No. 6, 2002