Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy

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  • Ocular, bulbar, limb, and cardiopulmonaryinvolvement in oculopharyngeal musculardystrophy

    Witting N, Mensah A, Kber 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: 125130. 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 (4180) 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

  • 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 (39) 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) 05scale, 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 Schlussel 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

  • Table

    1Baselinedata,sym

    ptom

    evolution,

    cranialnerve

    exam

    ination,andventilationinDanish

    OPMDpatients

    Wom

    en4049years

    Men

    6069years

    Wom

    en6069years

    Men

    7079years

    Wom

    en7079years

    Men

    8089years

    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

    45

    44

    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

    %

    51

    44

    134

    39

    23

    41

    55

    93

    83

    42

    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 17116 s for the 6180-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 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.

    128

    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 (35, 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 2070% (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

    129

    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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