J Neurol (2003) 250 : 1307–1312DOI 10.1007/s00415-003-0201-6 ORIGINAL COMMUNICATION

Barbara M. van der SluijsLies H. HoefslootGeorge W. PadbergSilvère M. van der MaarelBaziel G. M. van Engelen

Oculopharyngeal muscular dystrophywith limb girdle weakness as major complaint

Introduction

Oculopharyngeal muscular dystrophy (OPMD) is an es-tablished entity clinically, histologically as well as genet-ically. The disease was first described as an independentclinical entity in a kinship of French-Canadian lineagein 1915 [19]. Later this muscle disorder was described invarious ethnic groups [1–3,8,14–16].OPMD is a late-on-set autosomal dominant dystrophy, and is clinicallycharacterised by slowly progressive ptosis of the upper-eyelids, dysphagia, and dysphonia [23]. Symptoms suchas external ophthalmoplegia, and facial and proximallimb weakness develop subsequently [7, 21]. Sporadic

limb girdle weakness has been described as the initialsymptom of OPMD [10, 12].

OPMD is histologically characterised by unique nu-clear filamentous inclusions within skeletal muscle fi-bres observed by electron microscopy [20].A typical,butnot specific, finding in muscle biopsy specimens ofOPMD patients is the presence of basophilic-rimmedvacuoles of autophagic nature [24].

Genetic investigation in OPMD patients has revealedclose linkage to chromosome 14q11.2-q13 [4, 9]. A(GCG)-repeat expansion has been found in exon 1 of thepolyadenylate binding protein nuclear 1 (PABPN1) gene(previously called poly (A) binding-protein 2, PABP2,gene) at this locus. It has been suggested that the

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Received: 23 December 2002Received in revised form: 29 May 2003Accepted: 11 June 2003

B. M. van der Sluijs, MD (�) · G. W. Padberg, MD, PhD · B. G. M. van Engelen, MD, PhDNeuromuscular Centre NijmegenDept. of NeurologyUniversity Medical Centre NijmegenPO Box 91016500 HB Nijmegen, The NetherlandsTel.: +31-24/3615202Fax: +31-24/3541122E-Mail: b.vandersluijs@neuro.umcn.nl

L. H. Hoefsloot, PhDDept. of Human GeneticsUniversity Medical Centre NijmegenNijmegen, The Netherlands

S. M. van der Maarel, PhDDept. of Human GeneticsLeiden University Medical CentreLeiden, The Netherlands

■ Abstract This first descriptionof the oculopharyngeal musculardystrophy (OPMD) phenotype inDutch patients shows that limb gir-dle weakness can occur early in thecourse of disease and can give thefirst and major complaint inOPMD patients. The aim of thisstudy was to examine clinically,histologically and genetically allDutch OPMD patients known atthe Neuromuscular Centre Nij-megen, to measure the limb girdleweakness (MRC scale) and toquantify the consequences of thelimb girdle weakness on daily ac-tivities (Rankin scale). Remarkablein this population was the early on-set and the severity of the limb gir-dle weakness. We found a higherpercentage of patients with limbgirdle weakness than reported be-

fore in non-Dutch OPMD popula-tions. This limb girdle weaknesscaused limitations in daily activi-ties more than the other symptomsof OPMD. It was difficult to com-pare the severity of the limb girdleweakness of Dutch patients withother patients because of the lackof data related to quantification oflimb girdle weakness in non-DutchOPMD patients. Because of the in-fluence of the limb girdle weaknesson the daily activities of the pa-tients, we recommend that more at-tention is paid to the proximal limbmuscles in OPMD patients early inthe course of the disease.

■ Key words oculopharyngealmuscular dystrophy · limb girdleweakness · Dutch phenotype · dailyactivities

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(GCG)n-repeat, encoding a polyalanine tract, could beresponsible for the accumulation of undegradablepolyalanine rich molecules forming the unique nuclearfilaments [5]. In 2000 Uyama et al. did confirm that theintranuclear filamentous inclusions indeed contain mu-tated PABPN1 protein [22]. How the accumulation ofmutated PABPN1 protein in the nucleus of the skeletalfibre leads to the symptoms of OPMD is still the subjectof research.

Based on our observation of large variation of theOPMD phenotype in Dutch patients, with a remarkablefrequency of complaints of limb girdle weakness, wewondered if the limb girdle weakness is indeed an im-portant complaint in Dutch OPMD-patients, and if thisgroup differs from the previously reported OPMD-pa-tients. The aim of this study was to examine clinically,histologically as well as genetically all Dutch OPMD-pa-tients known at the Neuromuscular Centre Nijmegen, tomeasure the limb girdle weakness and to quantify theconsequences of the limb girdle weakness on daily ac-tivities.

Methods

■ Patients

A review of the patient database of the Neuromuscular Centre Nij-megen yielded eight patients from six families recorded havingOPMD.All these patients were visited and a family tree of all six fam-ilies was drawn up. The relatives of the patients, who had the samesymptoms as the patients already known to us, were also contacted

and asked to participate in this study. All participating persons gavetheir informed consent before they were included in this study.

To verify the diagnosis of OPMD we have used the diagnostic cri-teria described by Brais [6]: the three major criteria being 1) positivefamily history, 2) ptosis or previous surgical correction, and 3) dys-phagia. Other minor criteria were analysed, such as age at onset (af-ter 40 years), limitation of eye movements,and facial, tongue and limbweakness. Exclusion criteria were also checked: severe external oph-thalmoplegia before the age of 60 and the presence of myotonia.

Using these clinical diagnostic criteria of Brais one family with 2affected siblings of non-consanguineous healthy parents, was ex-cluded from this study owing to the early appearance of symptoms (at20 and 25 years), severe external ophthalmoplegia before the age of60, limb weakness which was more distal than proximal and presum-ably autosomal recessive inheritance. PABPN1 mutation screening inboth patients showed a normal GCG repeat of 6. These two siblingssuffered from oculopharyngodistal myopathy, and have previouslybeen described in a case report [11].

The five remaining families with 6 patients from our centre ful-filled the Brais criteria. These families included 50 members knownto be affected clinically, 22 of whom were still alive. Sixteen (10 menand 6 women) of the 22 OPMD patients agreed to participate in thisstudy (Table 1).

■ Medical history

A standardised questionnaire was developed for this study in whichspecial attention was paid to the age at onset, the initial symptom, theprogression of clinical symptoms, drooping of the upper eyelid,swallowing difficulties, location of weakness, difficulty climbingstairs, rising from a low seat, difficulty combing hair and lifting some-thing above the head. The questionnaire was completed by all pa-tients.

Because of the results of the questionnaire we wondered if pa-tients who were said to have weakness of the proximal muscles oftheir legs before the ptosis appeared, really did not have a ptosis whenthe complaints of their legs started. To investigate this photographs of

Table 1 Clinical features of the presented 16 patients from 5 OPMD families

Family Patient Sex Age at onset First complaint First symptom GCG repeat Histology of muscle Rankin scorenumber in proband

LM EM

1 III 7 M 49 years limb girdle weakness ptosis 10 2

1 III 4 M 53 years ptosis ptosis 10 + (a) + 3

2 III 1 M 58 years limb girdle weakness ptosis 10 4

2 III 8 M 50 years limb girdle weakness ptosis 10 1

2 III 10 M 52 years limb girdle weakness ptosis 10 + 2

2 III 4 M 49 years ptosis ptosis 10 + + 4

2 III 28 M 45 years limb girdle weakness limb girdle weakness 10 + 2

2 III 16 F 43 years ptosis ptosis 10 1

2 III 18 F 50 years limb girdle weakness ptosis 10 3

2 III 13 F 48 years limb girdle weakness ptosis 10 4

3 III 19 M 52 years dysphagia dysphagia 10 + 3

3 IV 3 M 52 years dysphagia dysphagia 10 2

3 IV 11 M 45 years ptosis ptosis 10 2

3 IV 31 F 41 years dysphagia dysphagia 10 1

4 III 11 F 58 years ptosis ptosis 10 + + 3

5 II 1 F 44 years ptosis and dysphagia ptosis and dysphagia NA + + 2

NA not available; + has been performed; LM Light microscopy; EM Electron microscopy; (a) m. constrictor pharyngis

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the face of these patients were studied at the age of onset of com-plaints of limb girdle weakness.

To quantify the consequences of OPMD on daily activities of thepatients we used the Modified Rankin scale (0 to 5) [18].

■ Clinical evaluation

Each patient underwent a structured clinical neurological examina-tion performed by one of us (B vd S), including a standardised mea-surement of muscle strength of the arms and legs, proximal and dis-tal, using the Medical Research Council (MRC) grading scale (0 to 5).The following muscles were measured: m.deltoideus, m.tricepsbrachii, m. biceps brachii, extensors and flexors of the hand, m. glu-teus maximus, m. iliopsoas, m. quadriceps femoris, m. tibialis ante-rior, m. soleus.

■ Muscle Biopsies

Quadriceps muscle biopsy specimens from each of these families’proband were studied with histochemical reactions routinely per-formed at our laboratory. Specimens were also prepared for electronmicroscopy according to standard procedures [13].

■ Genetic investigations

To screen and sequence the PABPN1 gene genomic DNA was ex-tracted from the blood lymphocytes according to standard protocols,and amplified by polymerase chain reactions essentially as described[5] using forward primer 5’-TGGCGCAGTGCCCGCCTTAGA-3’ andreverse primer 5’-ACAAGATGGCGCCGCCGCCCCGGC-3’. After pu-rification the same primers were used for sequence analysis of theamplified fragment on an ABI 3700 sequence analyser with theBigDye terminator kit (version 2,Applied Biosystems,Nieuwekerk a/dYssel, The Netherlands).

Results

■ Medical history

The data obtained from the questionnaire showed thatthe presenting symptom had been limb girdle weaknessin 7 (44 %) patients, bilateral ptosis in 5 (30 %) and dys-phagia in 3 (19 %) patients. In one patient bilateral pto-sis and dysphagia appeared at the same time. The meanage at symptom appearance was 49 years (range, 41–58years). Assessing the exact age at onset was difficult be-cause of the very slow progression of the symptoms. Thetime lag between the first symptom of OPMD and the

second varied considerably (mean 3 years, range 1–11).Different patterns of progression of the clinical features(revealed by completing the questionnaire) were ob-served (Table 2).

Because of the relatively large percentage of patientswho reported limb girdle weakness as first symptom wehave studied photographs of their faces made at the timeof onset of the complaints of limb girdle weakness andfound that 6 of the 7 patients already had ptosis whenthey started complaining of weakness of the limb girdlemuscles (Table 2). Thus, although ptosis appeared ear-lier than weakness of the limb girdle, the first complaintmade by the patients was the loss of strength of the prox-imal leg muscles.

At the time of this study all patients suffered fromptosis. Seven patients had undergone surgery for bilat-eral ptosis and in three cases surgical correction wasplanned.All patients complained of dysphagia. They atevery slowly compared with others, and needed moretime to chew and swallow to avoid choking. Four pa-tients lost weight as a result of severe dysphagia, 2 pa-tients were on a high-caloric diet, and 2 others had un-dergone a cricopharyngeal myotomy.

The Rankin scale quantifies the independence of pa-tients. Even though ptosis and dysphagia give limita-tions both do not influence the independence of the pa-tient, but limb girdle weakness does. In our population 4of 16 patients had Rankin score 3, i. e. these patients hadmoderate disability, required some help, but were able towalk without assistance (Table 1). Three other patientsscored 4, they had moderately severe disability, were un-able to walk without assistance, and unable to attend totheir own bodily needs without assistance. Thus thelimb girdle weakness is really an important complaint,which influences the daily activities and independenceof the OPMD patients.

■ Clinical evaluation

At neurological examination all 16 patients (mean age60 years, range 46–79) showed ptosis, which was oftenaccompanied by compensatory contractions of thefrontalis muscles. Four patients had a bilateral symmet-rical ptosis. Three patients over the age of 60 years had

Patterns of progression of the clinical symptoms Result of Results of studyingquestionnaire photographs of the face

Ptosis and dysphagia → Limb girdle weakness 6% (n = 1) 6% (n = 1)

Ptosis → Limb girdle weakness → Dysphagia 30% (n = 5) 69% (n = 11)

Dysphagia → Ptosis → Limb girdle weakness 19% (n = 3) 19% (n = 3)

Limb girdle weakness → Ptosis and dysphagia 25% (n = 4) 0%

Limb girdle weakness → Ptosis → Dysphagia 19% (n = 3) 6% (n = 1)

n number of patients

Table 2 Patterns of progression of muscle weaknessin 10 to 20 years

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minor limitations of eye movements and 13 patients alsoshowed weakness of other facial muscles than externalocular musculature.

Most remarkable in our patients was the limb girdleweakness of the hip and thigh muscles (Fig. 1) found bymeasurement of the muscle strength using the MRCscale. The mean strength of hip and thigh muscles wasMRC 3 (range 1–5). Thirteen patients had difficultyclimbing stairs and nine of them also had problems get-ting up out of a chair. Seven patients also showed weak-ness (MRC 3–4) of the shoulder musculature.

■ Muscle Biopsies

Histological data were available of all five families (Table1): six patients from four families underwent a biopsy ofthe quadriceps muscle. In the other family, we examineda biopsy specimen of the m. constrictor pharyngis,which was obtained during a cricopharyngeal myotomy.All muscle biopsies showed non-specific myopathicfindings, including abnormal variation in fibre size, in-creased endomysial connective tissue, increased per-centage of type 1 fibres, and a larger number of internalnuclei. The typical, but not specific, basophilic-rimmedvacuoles were observed in all specimens. Electron mi-croscopy of the specimens revealed intranuclear inclu-sions typical for OPMD in 4 of the 5 families investi-gated.

■ Genetic investigation

Sequence analysis was performed in patients of families1, 2, 3 and 4, and showed a GCG repeat expansion (from6 to 10 GCG repeats for all patients) in exon 1 of thePABPN1 gene on chromosome 14q11.2-q13. All patientswere heterozygous for the GCG-repeat mutation. Twofamilies [2, 3] showed a perfect repeat, which contained(GCG)10. The patients of the other two families [1, 4] didnot show a perfect one, their repeat contained(GCG)6(GCA)2(GCG)2 [17].

Discussion

This first description of Dutch OPMD patients showsthat limb girdle weakness can occur early in the courseof the disease and can give the first and major complaintin OPMD patients. The diagnosis OPMD was made clin-ically according to the diagnostic criteria of Brais [6]and confirmed histologically and genetically by respec-tively the finding of characteristic intranuclear tubularfilaments and a GCG repeat expansion in the PABPN1gene. The clinical examination of the Dutch patients wascomparable to those of non-Dutch OPMD families de-scribed in the literature [1–3, 8, 14–16], but remarkablewas the early onset and severity of the limb girdle weak-ness. A relatively large percentage of patients had com-plaints of limb girdle weakness before they had noticedptosis themselves. It is important to notice the weaknessof the limb girdle muscles, because this is the symptomthat causes evident limitations in daily activities and in-fluences the independence of OPMD patients.

Information on the course of the disease until this in-vestigation was obtained from the patients themselvesby completing the questionnaire; therefore conclusionshave to be drawn with care. To confirm the data aboutthe initial symptom given by the patients, especially ifpatients whose first complaint was limb girdle weaknessreally did not have ptosis when the complaints of proxi-mal leg weakness started, we studied photographs of thefaces of our patients. We found that even though the pa-tients said to have weakness of the limb girdle musclesbefore having a ptosis, 6 of the 7 patients already had aptosis when they started complaining of limb girdleweakness.The reason that ptosis is noticed relatively lateby the patient might be multifaceted. First complaints ofptosis begin just when the upper eyelid has drooped sofar that it gives limitations of the fields of vision. Secondwhen the upper eyelid droops patients unconsciouslyraise the eyebrows. Third when compensation by con-traction of the muscle frontalis fails patients automati-cally hold their head backwards.

Although the disease is named oculopharyngealmuscular dystrophy, it is generally stated that the mus-cular weakness is not restricted to the ocular and pha-ryngeal muscles. Symptoms such as facial and proximallimb weakness are reported in different OPMD popula-tions. In the presented Dutch population a relativelyhigh percentage of OPMD patients had proximal weak-ness compared with non-Dutch populations (Table 3),whereas the histological and genetic characteristicswere comparable. From the literature we deduced that innon-Dutch populations OPMD patients complain ofdrooping of upper eyelids several years before they no-tice weakness of the limb girdle muscles, this in contrastto our observations in Dutch patients. We appear to bethe first to systematically quantify the muscle force ofmuscles of the extremities of OPMD-patients. It is diffi-

Fig. 1 The mean (with one SD) muscular strength (MRC scale) of 16 Dutch OPMDpatients, showing that OPMD is a limb girdle syndrome more pronounced in lowerthan upper limbs

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cult to compare the severity of the limb girdle weaknessof our patients with others because of the lack of data re-lated to quantification of this weakness in non-DutchOPMD-patients.

Sporadic limb girdle weakness has been described asan initial symptom of OPMD [10, 12]. Hill described thephenotypical and genetic features of OPMD in a UKpopulation; 3 patients had limb girdle weakness as ini-tial symptom. Lampe et al. described one patient withgenetically proven OPMD, who presented with exercise-induced proximal muscle pain and weakness of thelower limbs. One year later she noticed drooping of herupper eyelids bilaterally and dysphagia. In both papersit is not obvious if the order of presentation of symp-toms is confirmed by the investigator or if the informa-tion is obtained by history taking only; an investigationof photographs of the face of the patients to confirm ifthey really did not have a ptosis when they started com-plaining of weakness of the limb girdle muscles is notmentioned. It might be that all the patients of Hill andLampe also had ptosis before they complained of weak-

ness of the proximal leg muscles, as we found in our ownpatients.

To investigate prospectively the age at onset and thedevelopment of muscle weakness of the extremities inDutch OPMD patients we have to follow up (pre)symp-tomatic patients. During this study we have become ac-quainted with five large OPMD families with many fam-ily-members under the age of 40 years, some of whomwill certainly be presymptomatic carriers of thePABPN1 mutation.Future investigations will be directedtowards prospectively studying the limb girdle weak-ness in Dutch OPMD patients.

On the basis of our findings we conclude that limbgirdle weakness can give the first complaint and the ma-jor complaint in OPMD patients, even before the pa-tients mention ptosis and that limb girdle weakness giveevident limitations in daily activities of these patients.Therefore we recommend that more attention is paid tothe proximal musculature in OPMD patients early in thecourse of the disease.

Table 3 Clinical features of the 16 patients presented compared with 7 other groups of OPMD patients, published in the literature [1–3, 8, 14–16]

Number of patients (%)

Clinical features The presented Italy Uruguay France Quebec Israel Germany New MexicoDutch patients (ref 15) (ref 14) (ref 8) (ref 3) (ref 2) (ref 16) (ref 1)

Ptosis 16 (100) 5 (100) 65 (100) 28 (97) 72 (100) 115 (98) 16 (100) 45 (92)

Dysphagia 16 (100) 4 (80) 65 (100) 20 (69) 72 (100) 87 (73) 10 (62) 37 (76)

Dysphonia 12 (75) ND ND 10 (34) 48 (67) 82 (70) 4 (25) ND

Limitations of the eye movements 3 (19) ND 43 (66) 16 (55) 35 (49) 24 (21) 5 (31) ND

Proximal weakness 13 (81) 3 (60) 22 (34) 15 (52) 51 (71) 23 (20) 9 (56) 32 (65)

Facial weakness 13 (81) 3 (60) 44 (68) ND 31 (43) 20 (17) 2 (13) ND

ND Not Described

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