ORIGINAL COMMUNICATION

Executive functions are impaired in heterozygote patientswith oculopharyngeal muscular dystrophy

Raffaele Dubbioso • Pasquale Moretta •

Fiore Manganelli • Chiara Fiorillo •

Rosa Iodice • Luigi Trojano • Lucio Santoro

Received: 19 July 2011 / Revised: 9 September 2011 / Accepted: 14 September 2011 / Published online: 29 September 2011

� Springer-Verlag 2011

Abstract Oculopharyngeal muscular dystrophy (OPMD)

is an autosomal dominant disorder caused by a small

expansion of a short polyalanine tract in poly(A) binding

protein nuclear 1 (PABPN1). It presents with adult onset of

progressive eyelid drooping, swallowing difficulties and

proximal limb weakness, usually without involvement of

central nervous system (CNS). However, cognitive decline

with relevant behavioural and psychological symptoms has

been recently described in homozygous patients. In this

study, we performed for the first time an extensive neuro-

psychological and neuropsychiatric evaluation on 11

OPMD heterozygote patients. We found that they were less

efficient than a matched control sample on several tests,

particularly those tapping executive functions. Moreover,

the presence of negative correlation between GCN expan-

sion size and some neuropsychological scores raises the

issue that CNS involvement might be linked to the genetic

defect, being worse in patients with larger expansion. Our

results might be consistent with the toxic gain-of-function

theory in the pathogenesis of OPMD and hint at a possible

direct role of PABPN1 in the CNS also in heterozygote

patients.

Keywords Oculopharyngeal muscular dystrophy �Heterozygote patients � Executive defects � Psychiatric

disturbances � Central nervous system � GCN expansion

Introduction

Autosomal dominant oculopharyngeal muscular dystrophy

(OPMD) is a late-onset myopathy produced by a stable

trinucleotide expansion from a normal (GCN)10 to

(GCN)12–17 repeats in the first exon of the PABPN1 gene on

chromosome 14q11.1. This gene encodes the small nuclear

isoform of poly(A) binding protein (PABP), which is

required for messenger RNA (mRNA) poly(A) shortening

and translation initiation [1]. The classic clinical features of

OPMD are progressive ptosis, dysphagia and proximal limb

weakness. The disease usually starts insidiously and

becomes manifest in the fifth or sixth decade with a slowly

progressive course in heterozygotes [2, 3]. Homozygous

patients show an early severe form usually with loss of

ambulation, and slow and paretic eye movements [4]. It has

been recently underlined that, apart from disease progres-

sion, the main features distinguishing heterozygotes from

homozygotes are psychological and psychiatric symptoms

[5], since homozygotes tend to develop dementia with rel-

evant behavioural and psychological symptoms. However,

to the best of our knowledge, no specific evaluation of

cognitive, behavioural and psychological disturbances has

been performed on OPMD heterozygote patients. Herein,

we report such a neuropsychological and neuropsychiatric

assessment.

R. Dubbioso � F. Manganelli � R. Iodice � L. Santoro (&)

Department of Neurological Sciences,

University Federico II of Naples,

Via Sergio Pansini, 5, 80131 Naples, Italy

e-mail: lusantor@unina.it

P. Moretta

Salvatore Maugeri Foundation, IRCCS, Scientific Institute

of Telese Terme (BN), Naples, Italy

C. Fiorillo

Molecular Medicine, Neurogenetics and Neurodegenerative

Diseases, IRCCS Fondazione Stella Maris, Pisa, Italy

L. Trojano

Neuropsychology Lab, Department of Psychology,

Second University of Naples, Caserta, Italy

123

J Neurol (2012) 259:833–837

DOI 10.1007/s00415-011-6255-y

Patients and methods

Clinical, molecular and neurophysiological assessment

We recruited 11 OPMD heterozygote patients (7 females;

mean age 59 ± 15.6 years, range 35–83 years; educational

level 9.2 ± 5.5 years) in our Neuromuscular Unit at Uni-

versity of Naples.

The diagnosis of OPMD was based on clinical exami-

nation, electrophysiological study, and the underlying

genetic defects identified by analysis of the GCN repeat in

the first exon of the PABPN1 gene on chromosome 14q11.1

by standard techniques [1]. Muscle strength was evaluated

using the Medical Research Council (MRC) scale, ranging

from 0 to 5 points: 0 = no movement, 1 = flicker per-

ceptible in the muscle, 2 = movement only if gravity

eliminated, 3 = can move limb against gravity, 4 = can

move against gravity and some resistance exerted by

examiner, 5 = normal strength. According to this scale we

adopted the following terms: mild weakness = MRC 4,

moderate weakness = MRC 3 and severe weak-

ness = MRC from 0 to 2; ptosis was graded on a severity

scale as mild for 1–2 mm of lid droop, moderate for 3 mm

of lid droop and severe for 4 mm or more of lid droop.

Dysphagia was assessed using Knyrim’s score [6] as:

0 = able to eat normal diet/no dysphagia, 1 = able to

swallow some solid foods, 2 = able to swallow only semi-

solid foods, 3 = able to swallow liquids only and

4 = unable to swallow anything/total dysphagia.

Needle electromyography (biceps brachii, rectus femori

and tibialis anterior muscles), surface antidromic sensory

(median and superficial peroneal nerves) and orthodromic

motor (median and peroneal nerves) nerve conduction

studies were performed according to standard procedures.

Twelve age-, education-, and sex-matched healthy sub-

jects, not affected by any neurological, psychiatric or other

relevant clinical condition (7 females; mean age

59.1 ± 12.2 years, age range 39–77; educational level

8.5 ± 3.8 years), were evaluated as the control group.

Written consent to participate in the study was obtained

from all subjects. The protocol was approved by the local

ethics committee, and the research was conducted in

accordance with the 1964 Declaration of Helsinki.

Neuropsychological assessment

The neuropsychological evaluation tapped selected cog-

nitive abilities by means of Italian standardized tests.

Mini-Mental State Examination (MMSE) was used to

assess general cognitive abilities [7, 8], and Frontal

Assessment Battery (FAB) [9, 10] to screen frontal

functions. In addition, we used the following specific

neuropsychological tests to evaluate selected cognitive

domains: (1) Corsi’s block-tapping test [11] and verbal

span for words [11] to assess short-term memory, (2)

Rey’s immediate and delayed recall of 15 words [12] and

of a short passage [11] to evaluate long-term memory and

learning, (3) attentional matrices [12] and shortened form

of Stroop Color-Word Test [13] to assess focussed and

selective attention, (4) Raven’s 47 Coloured Progressive

Matrices (RCPM), [12] to evaluate nonverbal intelligence,

(5) semantic [11] and phonological [12] fluency tasks to

assess cognitive flexibility and (6) a copying test for

geometrical figures [11] to assess spatial organization and

visuoconstructional skills.

Neuropsychiatric assessment

All patients also underwent assessment using the following

psychiatric clinical scales: (1) the Beck Depression

Inventory Scale (BDI) [14] to identify clinically relevant

depression and to measure the severity of depressive

symptoms, and (2) the Neuropsychiatric Inventory (NPI) to

evaluate 12 kinds of behavioural disturbances [15],

recording their presence, severity (rated 1–3) and fre-

quency (rated 1–4).

Statistical analysis

Because of the low number of patients enrolled, we

adopted a conservative, distribution-free nonparametric test

(Mann–Whitney U test) to compare groups in terms of

neuropsychiatric and neuropsychological variables. Corre-

lations of neuropsychological results with patients’ demo-

graphic, clinical and genetic features were assessed by

means of Spearman’s rho. The significance level was set at

p \ 0.05.

Results

Clinical, molecular and neurophysiological data

Eleven OPMD patients were molecularly determined with

GCN expansion ranging in size from 13 to 16 repeats in the

first exon of the PABPN1 gene. Age at disease onset ranged

from 37 to 64 years (mean 46.7 ± 18 years), with esti-

mated disease duration of 10 ± 7.5 years.

Ten out of 11 patients were symptomatic, but none of

them showed severe reduction of personal autonomy. The

first clinical manifestation was ptosis in half of them and

dysphagia in the other half. On neurologic examination,

dysphagia was present in all patients but one (E3), who was

the youngest and still asymptomatic. Moreover, dysphagia

was moderate in the majority of patients (7/10) who were

able to swallow only semi-solid foods.

834 J Neurol (2012) 259:833–837

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Eight patients had bilateral ptosis, with a severe degree

of lid droop in four of them. No patient had limitation of

gaze. Proximal muscle weakness was present in six

patients, ranging from mild to severe degree, and two

patients (A1 and C1) needed a cane for walking due to

marked hip girdle weakness (see Table 1 for details).

Neurophysiological investigation showed normal nerve

conduction findings in all patients, while electromyo-

graphic study revealed a variable myopathic pattern in six

patients (A1, B1, B2, C1, C2 and F1), showing reduction of

mean duration of motor unit potentials and increase of

polyphasic action potentials.

Neuropsychological and neuropsychiatric assessment

On most neuropsychological tests, OPMD patients

obtained lower scores than matched controls. The Mann–

Whitney U test showed a significant difference between

normal controls and OPMD patients on tests for cognitive

flexibility (semantic and phonological fluency tasks) and

short-term memory (spatial and verbal spans), and on one

test for selective attention (Stroop test), whereas the dif-

ference on the screening battery for frontal functions (FAB

total score) did not reach statistical significance (Table 2).

In reference to age- and education-adjusted normative

scores of single neuropsychological tests, three OPMD

patients showed deficits in cognitive flexibility (patholog-

ical score on phonological fluency task), four patients had a

spatial working memory defect (pathological score on

spatial span), five had impairments of selective attention

(pathological score on Stroop test) and five achieved a

pathological score on the screening battery for frontal

functions (FAB); the number of pathological scores on the

other tasks ranged from zero to two. The oldest OPMD

patient (F1) obtained five pathological scores on neuro-

psychological tests, whereas no other patient had more than

three pathological scores.

Correlation analysis between neuropsychological results

and the genetic expansion revealed a significant negative

correlation of GCN length with MMSE (q = -0.735,

p = 0.01), spatial span (q = -0.856, p = 0.001) and

semantic fluency (q = -0.756, p = 0.007). No other sig-

nificant correlation was found between disease duration

and neuropsychological measures.

BDI revealed more depressive symptoms in OPMD

patients (mean score 12.9 ± 6.9) with respect to controls

(mean score 7.3 ± 3.9), but the difference between groups

did not reach the significance level (p = 0.059). The cor-

relations between BDI total score and neuropsychological

measures were not significant. The neuropsychiatric

inventory (NPI) in patient E1 revealed visual hallucina-

tions, occurring predominantly in the evening or at night,

and characterized by animal shadows passing sideways or

by presence of an undefined person nearby. Patient C1

showed apathy (NPI composite score 4) and depression

(NPI composite score 2). All the remaining patients did not

show psychiatric or behavioural disturbances.

Discussion

In the present study we performed for the first time an

extensive neuropsychological evaluation in heterozygote

OPMD patients, and observed that patients were less

Table 1 Clinical and genetic features of oculopharyngeal muscular dystrophy heterozygote patients

Family Case Sex GCN

expansion

Age at

examination,

years

Age at

onset,

years

Disease

duration,

years

First

symptom

Ptosis Dysphagia Proximal

upper limb

weakness

Proximal

lower limb

weakness

A 1 F 10/13 GCN 66 56 10 Ptosis 2 2 ?? ???

B 1 M 10/13 GCN 68 64 4 Ptosis 3 2 – –

2 F 10/13 GCN 70 60 10 Dysphagia 2 2 ?? ??

C 1 M 10/14 GCN 79 56 23 Ptosis 3 2 ?? ???

2 F 10/14 GCN 47 46 1 Dysphagia 0 1 – –

D 1 M 10/14 GCN 55 49 6 Ptosis 1 1 – –

E 1 F 10/15 GCN 56 41 15 Dysphagia 2 2 ? ?

2 F 10/15 GCN 38 37 1 Dysphagia 0 1 – –

3 F 10/15 GCN 35 NA NA None 0 0 – –

F 1 M 10/15 GCN 83 63 20 Dysphagia 3 2 ? ?

G 1 F 10/16 GCN 52 42 10 Ptosis 3 2 ? ?

Dysphagia assessed using Knyrim’s score: 0, able to eat normal diet/no dysphagia; 1, able to swallow some solid foods; 2, able to swallow only

semi-solid foods; 3, able to swallow liquids only; 4, unable to swallow anything/total dysphagia. Ptosis graded as absence of ptosis (0), mild

ptosis of 1–2 mm lid droop (1), moderate ptosis of 3 mm of lid droop (2) and severe ptosis of 4 mm or more of lid droop (3)

F female, M male, NA not applicable, ? mild, ?? moderate, ??? severe, – no involvement

J Neurol (2012) 259:833–837 835

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efficient than a matched control sample on several tests,

particularly those tapping executive functions (working

memory, cognitive flexibility and selective attention).

Moreover, by adopting standardized tests, we also verified

that some scores were below the normal range, thus sug-

gesting the presence of clinically relevant cognitive defects

in these patients. However, only the oldest patient (F1) had

a diffuse cognitive impairment, although he was still

autonomous in personal and social activities. The neuro-

psychiatric assessment revealed that visual hallucinations

(patient E1) and apathy and depressive symptoms (C1) can

be present in heterozygote OPMD patients.

Taken together, the present data suggest that heterozy-

gote OPMD patients may show some cognitive impair-

ments and psychological disorders often related to

alteration of prefrontal-subcortical circuits [16]; in partic-

ular, dysfunction of the dorsolateral prefrontal circuit leads

to impairments of executive functions, whereas dysfunc-

tion of the orbital and frontomesial prefrontal circuits is

related to defects of selective attention, and, on behavioural

grounds, to disinhibition and personality changes. These

considerations seem to fit well with the observation that a

few homozygote OPMD patients have been reported to

develop subcortical dementia [5], a clinical syndrome

mainly characterized by frontal executive impairment,

personality changes and affective disorders [17]. However,

neuropsychological and psychiatric disturbances in het-

erozygote OPMD seem to be less severe and to show

slower progression with respect to homozygote OPMD. In

our sample, the presence of negative correlation between

GCN expansion size and some neuropsychological scores

raises the issue that CNS involvement might be linked to

the genetic defect, being worse in homozygous patients and

in heterozygote patients with larger expansion. We did not

find significant correlations between disease duration and

neuropsychological performance, but only a longitudinal

study would provide strong evidence on the evolution of

the cognitive defects in OPMD patients.

The present findings concur with data on homozygote

OPMD patients [5] underlining the previously unsuspected

neurodegenerative component, also described in transgenic

mice [18], although the primary origin of OPMD symptoms

was thought to be related to damage of muscular tissue.

The clear involvement of the CNS in all homozygote

cases demonstrates that two doses of the mutant PABPN1

allele cause, in the long run, toxicity to other postmitotic

cells such as neurons. In fact, the pathogenesis of OPMD is

related to the toxic effect of elongated polyalanine domains

that aggregate as typical intranuclear inclusions (INIs) and

represent the histologic hallmark of this disease [19–21].

Abnormal polyalanine peptides are encoded by the

expanded trinucleotide sequence in the first exon of the

PABPN1 gene, and it was demonstrated that ubiquitinated

PABPN1-positive INIs were produced in neurons of

transgenic mice expressing the expanded form of human

PABPN1 with its native promoter [21]. INIs were also

found in post mortem brain sections from a heterozygote

patient with OPMD [20].

Table 2 Neuropsychological

data of OPMD patients versus

controlsa

OPMD oculopharyngeal

muscular dystrophy, NS not

significant, FAB Frontal

Assessment Battery, RCPMRaven’s 47 Coloured

Progressive Matrices;

significance level was set at

p \ 0.05a Values are mean ± standard

deviation (SD)

Neuropsychological measures OPMD Controls p values

Screening tests

Mini-Mental State Examination 27.3 ± 1.8 27.2 ± 1.3 NS

FAB 14.2 ± 1.9 15.8 ± 1.1 0.056

Spatial and verbal working memories

Corsi’s test 3.4 ± 0.8 4.6 ± 0.9 0.007

Verbal span 3.3 ± 0.5 3.9 ± 0.3 0.009

Long-term memory

15-Word immediate recall 36.4 ± 6.3 40.4 ± 7.5 NS

15-Word delayed recall 8.2 ± 2.2 9.3 ± 2.5 NS

Story recall test 10.9 ± 1.6 11.7 ± 2.3 NS

Focussed and selective attention

Attentive matrices 39.4 ± 13.5 48.1 ± 9.5 NS

Stroop task 35.3 ± 23.1 10.8 ± 6.3 0.001

Non-verbal intelligence

RCPM 25.3 ± 3.6 28.02 ± 3.4 NS

Cognitive flexibility

Phonological fluency 21.7 ± 4.1 30.6 ± 8.7 0.007

Semantic fluency 10.7 ± 2.4 15.2 ± 5.2 0.011

Visuospatial skill

Copying task 11.6 ± 1.4 12.1 ± 1.0 NS

836 J Neurol (2012) 259:833–837

123

Further studies would be necessary to understand the

neural basis of the (frontal) executive defects that we

demonstrated in heterozygote OPMD patients. However,

we suggest that our data are consistent with the toxic gain-

of-function theory in the pathogenesis of OPMD and hint at

a possible direct role of PABPN1 in the CNS also in het-

erozygote patients.

Conflict of interest None.

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