Ocular, bulbar, limb, and cardiopulmonaryinvolvement in oculopharyngeal musculardystrophy

Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M,Milea D, Vissing J. Ocular, bulbar, limb, and cardiopulmonaryinvolvement in oculopharyngeal muscular dystrophy.Acta Neurol Scand 2014: 130: 125–130.© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Objectives – To assess skeletal muscle weakness and progression aswell as the cardiopulmonary involvement in oculopharyngealmuscular dystrophy (OPMD). Materials and methods – Cross-sectionalstudy including symptomatic patients with genetically confirmedOPMD. Patients were assessed by medical history, ptosis,ophthalmoplegia, facial and limb strength, and swallowing capability.Cardiopulmonary function was evaluated using forced expiratorycapacity in 1 s (FEV1), electrocardiogram (ECG), Holter monitoring,and echocardiography. Results – We included 13 symptomatic patients(six males, mean age; 64 years (41–80) from 8 families. Ptosis was thefirst symptom in 8/13 patients followed by limb weakness in theremaining 5 patients Dysphagia was never the presenting symptom.At the time of examination, all affected patients had ptosis or hadpreviously been operated for ptosis, while ophthalmoplegia was foundin 9 patients. Dysphagia, tested by cold-water swallowing test, wasabnormal in 9 patients (17-116 s, ref <8 s). Six patients could notclimb stairs of whom two were wheelchair bound and one used arollator. Six patients had reduced FEV1 (range 23%–59%). Nocardiac involvement was identified. Conclusions – Limiting limbweakness is common in OPMD and can even be the presentingsymptom of the disease. In contrast, dysphagia was not the initialsymptom in any of our patients, although it was obligatory fordiagnosing OPMD before genetic testing became available. Mildrespiratory dysfunction, but no cardiac involvement, was detected.

N. Witting1, A. Mensah2,L. Køber3, H. Bundgaard3,H. Petri3, M. Duno4, D. Milea2,5,J. Vissing11Department of Neurology and NeuromuscularResearch Unit, University of Copenhagen,Rigshospitalet, Copenhagen, Denmark; 2Department ofOphthalmology, Glostrup Hospital, Glostrup, Denmark;3Department of Cardiology, The Heart Centre,University of Copenhagen, Rigshospitalet, Copenhagen,Denmark; 4Clinical Genetics, University of Copenhagen,Rigshospitalet, Copenhagen, Denmark; 5SingaporeNational Eye Centre, Singapore Eye Research Instituteand Duke-NUS, Singapore City, Singapore

Key words: muscle disorders; neurogenetics;neurodegenerative disorders; neuroophthalmology

N. Witting, MD, PhD, Neuromuscular Research Unitand Department of Neurology, University ofCopenhagen, Rigshospitalet, Copenhagen, DenmarkTel.: +45 3545 1842Fax: +45 35452626e-mail: nanna.witting@regionh.dk

Accepted for publication February 7, 2014

Introduction

Oculopharyngeal muscular dystrophy (OPMD) isa rare (1:100,000) inherited skeletal muscle dis-ease caused by a stable trinucleotide expansion inthe PAPBN1 gene on chromosome 14. Themajority of cases are inherited in an autosomaldominant manner, but autosomal recessive inheri-tance also exists. Onset of symptoms occurs typi-cally in the fifth decade, and as the name of thedisease implies, ptosis, ophthalmoplegia, and dys-phagia are core symptoms. Additionally, it is wellestablished that limb muscles may also beinvolved (1). According to the diagnostic criteria

defined by Brais in 1995 (2), all of the following3 must be fulfilled to establish the diagnosis: (1)A positive family history; (2) The presence ofptosis or previous corrective surgery for ptosis;(3) The presence of dysphagia, defined as swal-lowing time longer than 7 s when drinking 80 mlof cold water. Since 1995, genetic testing forOPMD has become widely available, and a fam-ily history is therefore no longer mandatory. Theaccessibility of genetic testing has made a fullclinical picture with ptosis and dysphagia lessimportant for diagnosis and has also helped todiagnose atypical cases and presymptomatic indi-viduals. This opportunity makes it essential to be

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Acta Neurol Scand 2014: 130: 125–130 DOI: 10.1111/ane.12244 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

ACTA NEUROLOGICASCANDINAVICA

intimately acquainted with the various diseasepresentations of OPMD. In particular, the timingof onset of the key symptoms, ptosis and dyspha-gia, and onset of additional symptoms (i.e., limbaffection) is important. Involvement of limb mus-culature in OPMD (3–9) is less well characterizedthan the oculopharyngeal involvement. Knowl-edge of the distribution, severity, and evolution-ary pattern of limb weakness is important fordiagnostic evaluation and a prerequisite for opti-mal treatment and planning of follow-up.

Another unexplored area in OPMD iscardiopulmonary function, which has not beensystematically evaluated. Involvement of the car-diopulmonary system is increasingly recognizedas a major cause of morbidity and mortality inseveral other muscular dystrophies, such as dys-trophinopathies, limb girdle muscular dystrophies(10), and myotonic dystrophy type 1 (11). Car-diopulmonary function in patients with musclediseases should be assessed, because well-docu-mented treatment for cardiac and pulmonarydysfunction is available.

We performed a systematic assessment of ocu-lar, bulbar, limb, and cardiopulmonary functionin symptomatic patients with genetically con-firmed OPMD.

Methods

All known patients in Denmark with geneticallyverified OPMD were invited to participate. Thestudy was approved by the local ethics committee(ref. nr. H-A-2009-061). All included patientssigned an informed consent form. Nineteenpatients from 11 OPMD families were invited toparticipate. Five declined to participate due tologistic difficulties. Thus, 14 participants from 8families were included. One of these, a 28-year-old woman, who had requested genetic testing onan earlier occasion, was excluded, because shewas asymptomatic.

Evaluations of ptosis and ophthalmoplegiawere carried out by a trained ophthalmologist(AM). The evaluation methods have beendescribed previously (12). All patients were evalu-ated for symptom evolution over time and for theuse of walking aids. Evaluation of bulbar func-tion was carried out by examining the strength inthe facial muscles and by determining the level ofdysphagia. Facial muscle strength was assessedusing the Medical Research Council (MRC) 0–5scale, in which 0 signifies complete palsy, and 5 isnormal strength. Swallowing function wasassessed by measuring the time to swallow 80 mlof 5° cold water (13), and a duration >7 s was

considered abnormal. Pulmonary function wasassessed by measuring forced expiratory vital(FEV1) capacity using a spirometer type T01Aand a facial mask in all, due to facial weakness insome. Three measurements were carried out, andthe best FEV1 was noted. Percentage reductioncompared to expected values was calculated fromnormal values adjusted for height, sex, and age(14). A reduction of ≥20% was considered abnor-mal.

Cardiac function was assessed by electrocardi-ography (ECG), transthoracic echocardiography,and a 48-h Holter monitoring. The cardiac exam-inations were obtained and analyzed by trainedcardiologists (LK, HB, HP).

Limb muscle strength was examined using ahandheld dynamometer (Citec CT 301). Strengthin shoulder abduction (SA), elbow flexion/exten-sion (EF/EE), hip flexion/extension (HF/HE),knee flexion/extension (KF/KE), and ankle dorsi-and plantar flexion (AdF/ApF) were assessed.Values were compared to an age- and sex-matched group of 23 healthy individuals. Alldynamometer tests in patients and healthy con-trols were performed by the same examiner(NW). A handgrip dynamometer (Smedley, Sto-eltinger) was used to assess the handgrip force.Normal values reported by Schl€ussel et al. (15)were used as reference. Three repetitions wereperformed for each measurement of handheldand handgrip dynamometry, and average valuesare reported. Ambulatory participants were alsotested with a 10-step staircase test, measuringtime in seconds to climb 10 steps on a standard-ized staircase (normal <8 s).

Statistics

All data were analyzed on a single subject leveland compared to reference material as describedin the methods section. Values are given as meanand range – or standard deviation (SD).

Results

Subjects

Thirteen patients (six men) participated in thestudy [mean age 64 years (41–80)]. The presentingsign of OPMD was ptosis in eight patients andlimb weakness in five patients (Table 1). Dyspha-gia was not the presenting symptom in any of thepatients, but it developed during the course ofthe disease in 11 patients. Dysphagia was absentin the two youngest symptomatic patients (41and 47 years old).

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Table

1Baselinedata,sym

ptom

evolution,

cranialnerve

exam

ination,andventilationinDanish

OPMDpatients

Wom

en40–49years

Men

60–69years

Wom

en60–69years

Men

70–79years

Wom

en70–79years

Men

80–89years

Ageat

exam

(years)

4147

6167

6660

6965

6470

7072

80Family

no.

34

86

33

72

14

31

5Participant

no.

48

1411

613

123

29

51

10Gender

FF

MM

MF

FF

FM

MF

MRepeat

13 GCG

13+2

GCA+

GCG

14 GCG

13 GCG

13 GCG

13 GCG

13 GCG

13 GCG

15 GCG

13+2

GCA+

GCG

13 GCG

15 GCG

13 GCG

Ageat

firstsymptom

(years)

4144

5159

5851

5837

5053

5156

63Symptom

evolution

(L,O)*

O>L

O>P>

LO>

P>L

O>P>

LO>

P>L

O>L>P

O>P>

LO>

P>L

O>P>

LL>O>

PL>O>

PL>O>

PSw

allowingtest(s)†

37

754

2118

6662

724

17116

46Subjectivedysphagia(consistency)

None

None

None

Liquids,

meat

Meat

Cold

liquids

Liquids

NI

NI

Liquids,meat,

breadcrum

psLiquids,meat,

breadcrum

psLiquids,meat,

breadcrum

psLiquids,meat,breadcrum

ps

Ophthalmoplegia

None

None

Mild

Mild

None

Mild

Mild

Mild

Mild

Mild

Mild

Severe

None

Eyelids[ptosis/surgery(times)]

Y/0

Y/1

Y/1

Y/2

Y/1

Y/2

Y/2

Y/4

Y/5

Y/4

Y/2

Y/5

Y/1

Face

(MRC)

54�

4�5

4�4

4+4

44

44�

4FEV1(l)max

of3attempts

3.4

2.4

3.3

3.3

4.5

1.9

1.7

2.6

2.3

1.3

2.3

1.5

2.3

Expected

3.2

2.8

3.4

3.3

3.3

3.0

2.7

2.5

2.7

3.2

3.7

2.3

3.0

%Δ

5�1

4�4

�134

�39

�23

4�1

5�5

9�3

8�3

4�2

4

FEV1,forcedexpiratory

volumein1s;O,

ptosis/ophthalmoplegia;P,pharyngeal(dysphagia);L,lim

bweakness.

*Verymild

weakness(providedstrength

levels).

†Anormalsw

allowingtestshouldbe

below7sor

less.

127

OPMD phenotype

Molecular genetic investigation

Genetic analysis showed that two patients (sis-ters) were heterozygous for a 15 GCN repeatexpansion, one patient for a 14 GCN repeatexpansion, eight (five families) for a 13 GCNrepeat expansion, and two (one family) wereheterozygous for a 12 GCN expansion.

Ophthalmologic examination

All 13 symptomatic patients were affected by pto-sis, and 12 of them had had surgery for ptosis.Impaired eye movements were found in ninepatients, but severe ophthalmoplegia was diag-nosed in only one (Table 1).

Bulbar function

Only two patients (aged 41 and 67 years) hadnormal strength in facial muscles, and fourpatients (aged 41, 47, 61, and 64 years) had a nor-mal cold-water swallowing test (Table 1). The twooldest patients with normal cold-water test (2, 13)complained of dysphagia; hence, no patients olderthan 47 years had subjective normal swallowing.Mean cold-water swallowing time was 34 s. Thiscovered a wide variability in swallowing capacity,ranging from a normal capacity to abnormalswallowing times between 17–116 s for the 61–80-year-old patients. None of the patients had hadcricopharyngeal myotomy performed, or a percu-taneous endoscopic gastrostomy tube inserted.

Limb function

Three patients used assistive devices for walking.Two men, aged 70 and 80 years, were confined toa wheelchair, and a 72-year-old woman used arollator. Another three patients, aged 60, 64, and65 years, could not climb stairs (Table S1). Ofthe remaining eight, a 70-year-old patient spent12 -s climbing the stairs (normal <8 s), but theremaining seven patients (41–69 years old)climbed stairs normally.

Limb muscle strength declined with age bothproximally and distally (Fig. 1) (Table S1), butno clear proximal–distal gradient was observed.The weakness was more severe in legs vs arms.The expected infra-nuclear pattern with an over-weight of flexor weakness in upper extremitieswas seen in the elbow, where 5/13 had more thana 2 SD reduction in strength in elbow flexion,whereas none had more than 1 SD reduction inelbow extensors. However, no such pattern wasobserved in the lower extremities which weremore severely affected. Distally, 7/13 had a hand-grip force/strength which was reduced by 1 ormore SD’s.

Limb weakness was characterized by markedindividual variation, as some in their sixties hadsevere weakness (pt 3, 14), whereas others wereonly mildly affected (pt 2, 11, 12) (Table S1).Furthermore, distal weakness was pronounced ina few patients already in their 60-ties. For exam-ple, pt3 (61 years old) only had a handgripstrength of 3 kg (normal >20 kg).

Figure 1. Percentage muscle strength in 13 patients with oculopharyngeal muscle dystrophy compared to 23 age- and sex-matchedcontrols. Error bars indicate standard deviation.

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Witting et al.

Pulmonary function

None of the patients complained of respiratorysymptoms. FEV1 was on average reduced by16% from reference values, and 6, all more than60 years old, had more than a 20% reduction inFEV1.

Cardiac function

Three of the 13 patients (two men, 80 and61 years old and a woman, 72 years old) did nothave the energy to come to the hospital the nextday for cardiac investigation. They were con-tacted by phone and had no medical history orsymptoms of cardiac disease. Cardiac investiga-tions were performed in the remaining 10patients.

None had any cardiac symptoms. A 67-year-old man had known ischemic heart disease andprevious myocardial infarction, but had preservedleft ventricular ejection fraction of 55%. Twopatients, a 71-year-old man and a 65-year-oldwoman, had diastolic dysfunction grade 1 (abnor-mal left ventricular diastolic relaxation pattern)and mild aortic insufficiency, respectively,assessed by echocardiography. These findingswere considered within the normal range accord-ing to age. The remaining patients had normalfindings on echocardiography, and all patientshad normal findings on ECG and Holter moni-toring.

Discussion

This is the first Danish study to assess ocular,bulbar, limb, and cardiopulmonary involvementin patients with OPMD. We report several find-ings, which provide new insights to the phenotypeand evolution of symptoms in OPMD. First,severe and functionally limiting proximal and dis-tal weakness is present in the majority older than60 years. Despite the name of the disorder, limbweakness is a frequent presenting symptom ofOPMD, but the variability in limb affection ishigh. Second, OPMD does not appear to be asso-ciated with cardiac, involvement and respiratoryinsufficiency is only mild and present as a sub-clinical finding in patients older than 60 years.Third, swallowing function, whether subjectivelyreported or assessed by cold-water swallowingtest, was normal until the 60-ties in the majorityand was not a presenting symptom in any of thepatients.

Age, gender, and time of symptom onsetmatched other described populations (3–5, 16, 17).

Limb weakness was severe in most of ourpatients older than 60 years. Almost half couldnot walk stairs. As the majority of patients werenot bothered by the ophthalmoplegia, and ptosisis amenable to surgery, limb weakness was proba-bly the most troublesome disease manifestation inthose without pronounced dysphagia. Althoughlimb weakness does not typically develop beforeage 60 years, the patients and society will have tolive decades with the limitations, dependence onhelp and socioeconomic implications that limbweakness causes. One other study focused onlimb weakness in OPMD and reported thatalthough only 1/16 had limb weakness as the firstsymptom, it was the main complaint in half (4).Moreover, according to previous observations,limb weakness appears at some stage of the dis-ease in 20–70% (3, 5, 16, 17). These findingsunderline that limb weakness is prominent inOPMD and causes disability.

In addition, we noticed a large individual vari-ation in limb muscle affection, which was onlypartly explained by age. To our knowledge,detailed data on limb muscle strength in individ-ual OPMD patients has not been published previ-ously. Our OPMD cohort is too small to evaluatewhether the size of the trinucleotide expansion inthe PAPBN1 gene was related to limb muscleaffection, although it is a potential explanation,as is epigenetic modification.

Dysphagia and ptosis are the clinical hallmarksof OPMD. In our patient cohort, onset of subjec-tive dysphagia and dysphagia evaluated by cold-water swallowing test was consistently delayedcompared with ptosis. A previous study has indi-cated that retrospective information about timingof initial symptoms can be unreliable (4). Theauthors showed elegantly, using old photographs,that ptosis was present years before it wasnoticed by the patients. This finding, however,cannot explain the present observation of a delaybetween onset of ptosis and onset of dysphagiaas the ptosis was recorded long before the dys-phagia. Moreover, in contrast to ptosis, dyspha-gia is a symptom that is most often notoverlooked by the patients. Therefore, we believethat the observed delayed onset is correct.

Cardiopulmonary function has not previouslybeen addressed systematically in patients withOPMD. We evaluated 10 participants for cardiacinvolvement, and no cardiac symptoms or signifi-cant abnormalities were observed. These findings,combined with the lack of other reports indicat-ing cardiac involvement in OPMD, suggest thatthe heart is not involved in OPMD. On this basis,we suggest that in contrast to several other

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OPMD phenotype

muscular dystrophies, cardiac screening and fol-low-up are not warranted in patients withOPMD.

The pulmonary function was examined in all13 affected patients, and FEV1 was reduced by20% or more in six patients all in their 60-ties orolder. If this finding can be corroborated in a lar-ger group of OPMD patients, we would suggestregular assessment of the respiratory functionafter age of 60 years.

We also observed that subjective dysphagiatypically presents later than limb affection. Twopatients had normal cold-water swallowing time(although complaining of subjective dysphagia)and were unable to walk stairs due to limb weak-ness. Therefore, a presentation with ptosis andsevere limb weakness, but no increase in swallow-ing time or significant complaints of dysphagia,does not rule out OPMD. On the contrary, allthe patients with increased swallowing time alsohad limb weakness, although this could be mild.Thus, the pattern of eye muscle affection, dyspha-gia, and limb weakness can vary substantially inOPMD.

Acknowledgments

The authors have no acknowledgements to declare.

Conflicts of interest and sources of funding statement

The study was not funded, and none of theauthors had any conflict of interest

Supporting Information

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

Table S1. Strength and function in extremities.

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