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 NEUROLOGICA SCANDINAVICA
Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M, Milea D, Vissing J. Ocular, bulbar, limb, and cardiopulmonary involvement 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 as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). Materials and methods – Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical history, ptosis, ophthalmoplegia, facial and limb strength, and swallowing capability. Cardiopulmonary function was evaluated using forced expiratory capacity 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 the first symptom in 8/13 patients followed by limb weakness in the remaining 5 patients Dysphagia was never the presenting symptom. At the time of examination, all affected patients had ptosis or had previously been operated for ptosis, while ophthalmoplegia was found in 9 patients. Dysphagia, tested by cold-water swallowing test, was abnormal in 9 patients (17-116 s, ref 7 s was 126
considered abnormal. Pulmonary function was assessed by measuring forced expiratory vital (FEV1) capacity using a spirometer type T01A and a facial mask in all, due to facial weakness in some. Three measurements were carried out, and the best FEV1 was noted. Percentage reduction compared to expected values was calculated from normal values adjusted for height, sex, and age (14). A reduction of ≥20% was considered abnormal. Cardiac function was assessed by electrocardiography (ECG), transthoracic echocardiography, and a 48-h Holter monitoring. The cardiac examinations were obtained and analyzed by trained cardiologists (LK, HB, HP). Limb muscle strength was examined using a handheld dynamometer (Citec CT 301). Strength in shoulder abduction (SA), elbow flexion/extension (EF/EE), hip flexion/extension (HF/HE), knee flexion/extension (KF/KE), and ankle dorsiand plantar flexion (AdF/ApF) were assessed. Values were compared to an age- and sexmatched group of 23 healthy individuals. All dynamometer tests in patients and healthy controls were performed by the same examiner (NW). A handgrip dynamometer (Smedley, Stoeltinger) was used to assess the handgrip force. Normal values reported by Schl€ ussel et al. (15) were used as reference. Three repetitions were performed for each measurement of handheld and handgrip dynamometry, and average values are reported. Ambulatory participants were also tested with a 10-step staircase test, measuring time in seconds to climb 10 steps on a standardized staircase (normal L 7 None Mild Y/1 4 3.3 3.4 4
61 8 14 M 14 GCG 51 O>P>L 7 None
67 6 11 M 13 GCG 59 O>P>L 54 Liquids, meat Mild Y/2 5 3.3 3.3 1
Men 60–69 years
None Y/1 4 4.5 3.3 34
66 3 6 M 13 GCG 58 O>P>L 21 Meat
60 3 13 F 13 GCG 51 O>P>L 18 Cold liquids Mild Y/2 4 1.9 3.0 39 Mild Y/2 4+ 1.7 2.7 23
69 7 12 F 13 GCG 58 O>L>P 66 Liquids
Women 60–69 years
FEV1, forced expiratory volume in 1 s; O, ptosis/ophthalmoplegia; P, pharyngeal (dysphagia); L, limb weakness. *Very mild weakness (provided strength levels). † A normal swallowing test should be below 7 s or less.
41 3 4 F 13 GCG 41 (L,O)* 3 None
Age at exam (years) Family no. Participant no. Gender Repeat
Women 40–49 years
Table 1 Baseline data, symptom evolution, cranial nerve examination, and ventilation in Danish OPMD patients
Mild Y/4 4 2.6 2.5 4
65 2 3 F 13 GCG 37 O>P>L 62 NI Mild Y/5 4 2.3 2.7 15
64 1 2 F 15 GCG 50 O>P>L 7 NI
70 4 9 M 13 + 2 GCA+GCG 53 O>P>L 24 Liquids, meat, bread crumps Mild Y/4 4 1.3 3.2 59
Men 70–79 years 70 3 5 M 13 GCG 51 L>O>P 17 Liquids, meat, bread crumps Mild Y/2 4 2.3 3.7 38
72 1 1 F 15 GCG 56 L>O>P 116 Liquids, meat, bread crumps Severe Y/5 4 1.5 2.3 34
Women 70–79 years
None Y/1 4 2.3 3.0 24
80 5 10 M 13 GCG 63 L>O>P 46 Liquids, meat, bread crumps
Men 80–89 years
OPMD phenotype
127
Witting et al. Molecular genetic investigation
Limb function
Genetic analysis showed that two patients (sisters) were heterozygous for a 15 GCN repeat expansion, one patient for a 14 GCN repeat expansion, eight (five families) for a 13 GCN repeat expansion, and two (one family) were heterozygous for a 12 GCN expansion.
Three patients used assistive devices for walking. Two men, aged 70 and 80 years, were confined to a wheelchair, and a 72-year-old woman used a rollator. Another three patients, aged 60, 64, and 65 years, could not climb stairs (Table S1). Of the remaining eight, a 70-year-old patient spent 12 -s climbing the stairs (normal 20 kg).
Ophthalmologic examination
All 13 symptomatic patients were affected by ptosis, and 12 of them had had surgery for ptosis. Impaired eye movements were found in nine patients, but severe ophthalmoplegia was diagnosed in only one (Table 1). Bulbar function
Only two patients (aged 41 and 67 years) had normal strength in facial muscles, and four patients (aged 41, 47, 61, and 64 years) had a normal cold-water swallowing test (Table 1). The two oldest patients with normal cold-water test (2, 13) complained of dysphagia; hence, no patients older than 47 years had subjective normal swallowing. Mean cold-water swallowing time was 34 s. This covered a wide variability in swallowing capacity, ranging from a normal capacity to abnormal swallowing times between 17–116 s for the 61–80year-old patients. None of the patients had had cricopharyngeal myotomy performed, or a percutaneous endoscopic gastrostomy tube inserted.
Figure 1. Percentage muscle strength in 13 patients with oculopharyngeal muscle dystrophy compared to 23 age- and sex-matched controls. Error bars indicate standard deviation.
128
OPMD phenotype Pulmonary function
None of the patients complained of respiratory symptoms. FEV1 was on average reduced by 16% from reference values, and 6, all more than 60 years old, had more than a 20% reduction in FEV1. Cardiac function
Three of the 13 patients (two men, 80 and 61 years old and a woman, 72 years old) did not have the energy to come to the hospital the next day for cardiac investigation. They were contacted by phone and had no medical history or symptoms of cardiac disease. Cardiac investigations were performed in the remaining 10 patients. None had any cardiac symptoms. A 67-yearold man had known ischemic heart disease and previous myocardial infarction, but had preserved left ventricular ejection fraction of 55%. Two patients, a 71-year-old man and a 65-year-old woman, had diastolic dysfunction grade 1 (abnormal left ventricular diastolic relaxation pattern) and mild aortic insufficiency, respectively, assessed by echocardiography. These findings were considered within the normal range according to age. The remaining patients had normal findings on echocardiography, and all patients had normal findings on ECG and Holter monitoring. Discussion
This is the first Danish study to assess ocular, bulbar, limb, and cardiopulmonary involvement in patients with OPMD. We report several findings, which provide new insights to the phenotype and evolution of symptoms in OPMD. First, severe and functionally limiting proximal and distal weakness is present in the majority older than 60 years. Despite the name of the disorder, limb weakness is a frequent presenting symptom of OPMD, but the variability in limb affection is high. Second, OPMD does not appear to be associated with cardiac, involvement and respiratory insufficiency is only mild and present as a subclinical finding in patients older than 60 years. Third, swallowing function, whether subjectively reported or assessed by cold-water swallowing test, was normal until the 60-ties in the majority and was not a presenting symptom in any of the patients. Age, gender, and time of symptom onset matched other described populations (3–5, 16, 17).
Limb weakness was severe in most of our patients older than 60 years. Almost half could not walk stairs. As the majority of patients were not bothered by the ophthalmoplegia, and ptosis is amenable to surgery, limb weakness was probably the most troublesome disease manifestation in those without pronounced dysphagia. Although limb weakness does not typically develop before age 60 years, the patients and society will have to live decades with the limitations, dependence on help and socioeconomic implications that limb weakness causes. One other study focused on limb weakness in OPMD and reported that although only 1/16 had limb weakness as the first symptom, it was the main complaint in half (4). Moreover, according to previous observations, limb weakness appears at some stage of the disease in 20–70% (3, 5, 16, 17). These findings underline that limb weakness is prominent in OPMD and causes disability. In addition, we noticed a large individual variation in limb muscle affection, which was only partly explained by age. To our knowledge, detailed data on limb muscle strength in individual OPMD patients has not been published previously. Our OPMD cohort is too small to evaluate whether the size of the trinucleotide expansion in the PAPBN1 gene was related to limb muscle affection, although it is a potential explanation, as is epigenetic modification. Dysphagia and ptosis are the clinical hallmarks of OPMD. In our patient cohort, onset of subjective dysphagia and dysphagia evaluated by coldwater swallowing test was consistently delayed compared with ptosis. A previous study has indicated that retrospective information about timing of initial symptoms can be unreliable (4). The authors showed elegantly, using old photographs, that ptosis was present years before it was noticed by the patients. This finding, however, cannot explain the present observation of a delay between onset of ptosis and onset of dysphagia as the ptosis was recorded long before the dysphagia. Moreover, in contrast to ptosis, dysphagia is a symptom that is most often not overlooked by the patients. Therefore, we believe that the observed delayed onset is correct. Cardiopulmonary function has not previously been addressed systematically in patients with OPMD. We evaluated 10 participants for cardiac involvement, and no cardiac symptoms or significant abnormalities were observed. These findings, combined with the lack of other reports indicating cardiac involvement in OPMD, suggest that the heart is not involved in OPMD. On this basis, we suggest that in contrast to several other 129
Witting et al. muscular dystrophies, cardiac screening and follow-up are not warranted in patients with OPMD. The pulmonary function was examined in all 13 affected patients, and FEV1 was reduced by 20% or more in six patients all in their 60-ties or older. If this finding can be corroborated in a larger group of OPMD patients, we would suggest regular assessment of the respiratory function after age of 60 years. We also observed that subjective dysphagia typically presents later than limb affection. Two patients had normal cold-water swallowing time (although complaining of subjective dysphagia) and were unable to walk stairs due to limb weakness. Therefore, a presentation with ptosis and severe limb weakness, but no increase in swallowing time or significant complaints of dysphagia, does not rule out OPMD. On the contrary, all the patients with increased swallowing time also had limb weakness, although this could be mild. Thus, the pattern of eye muscle affection, dysphagia, and limb weakness can vary substantially in OPMD.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Acknowledgments
The authors have no acknowledgements to declare.
12.
Conflicts of interest and sources of funding statement
The study was not funded, and none of the authors had any conflict of interest Supporting Information Additional Supporting Information may be found in the online version of this article. Table S1. Strength and function in extremities.
References 1. BRAIS B. Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Curr Neurol Neurosci Rep 2009;9:76– 82. 2. BRAIS B, XIE YG, SANSON M et al. The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on
130
13.
14.
15.
16.
17.
chromosome 14q11.2-q13. Hum Mol Genet 1995;4:429– 34. BOUCHARD JP, BRAIS B, BRUNET D, GOULD PV, ROULEAU GA. Recent studies on oculopharyngeal muscular dystrophy in Quebec. Neuromuscul Disord 1997;7(Suppl 1): S22–9. VAN DER SLUIJS BM, HOEFSLOOT LH, PADBERG GW, VAN DER MAAREL SM, VAN ENGELEN BG. Oculopharyngeal muscular dystrophy with limb girdle weakness as major complaint. J Neurol 2003;250:1307–12. MEDICI M, PIZZAROSSA C, SKUK D, YORIO D, EMMANUELLI G, MESA R. Oculopharyngeal muscular dystrophy in Uruguay. Neuromuscul Disord 1997;7(Suppl 1):S50–2. FARDEAU M, TOME FM. Oculopharyngeal muscular dystrophy in France. Neuromuscul Disord 1997;7(Suppl 1): S30–3. UYAMA E, NOHIRA O, TOME FM et al. Oculopharyngeal muscular dystrophy in Japan. Neuromuscul Disord 1997;7(Suppl 1):S41–9. MEOLA G, SANSONE V, ROTONDO G, TOME FM, BOUCHARD JP. Oculopharyngeal muscular dystrophy in Italy. Neuromuscul Disord 1997;7(Suppl 1):S53–6. HILL ME, CREED GA, MCMULLAN TF et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 2001;124:522–6. SVEEN ML, THUNE JJ, KOBER L, VISSING J. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy. Arch Neurol 2008;65:1196–201. PETRI H, VISSING J, WITTING N, BUNDGAARD H, KOBER L. Cardiac manifestations of myotonic dystrophy type 1. Int J Cardiol 2012;160:82–8. MENSAH A, WITTING N, DUNO M, MILEA D, VISSING J. Delayed diagnosis of oculopharyngeal muscular dystrophy in Denmark: from initial ptosis to genetic testing. Acta Ophthalmol 2013; doi:10.1111/aos.12243. [Epub ahead of print]. BOUCHARD JP, MARCOUX S, GOSSELIN F, PINEAULT D, ROULEAU GA. A simple test for the detection of dysphagia in members of families with oculopharyngeal muscular dystrophy (OPMD). Can J Neurol Sci 1992;19: 296–7. HANKINSON JL, ODENCRANTZ JR, FEDAN KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159:179–87. SCHLUSSEL MM, DOS ANJOS LA, DE VASCONCELLOS MT, KAC G. Reference values of handgrip dynamometry of healthy adults: a population-based study. Clin Nutr 2008;27:601–7. BLUMEN SC, NISIPEANU P, SADEH M, ASHEROV A, TOME FM, KORCZYN AD. Clinical features of oculopharyngeal muscular dystrophy among Bukhara Jews. Neuromuscul Disord 1993;3:575–7. BECHER MW, MORRISON L, DAVIS LE et al. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA 2001;286:2437–40.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M, Milea D, Vissing J. Ocular, bulbar, limb, and cardiopulmonary involvement 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 as well as the cardiopulmonary involvement in oculopharyngeal muscular dystrophy (OPMD). Materials and methods – Cross-sectional study including symptomatic patients with genetically confirmed OPMD. Patients were assessed by medical history, ptosis, ophthalmoplegia, facial and limb strength, and swallowing capability. Cardiopulmonary function was evaluated using forced expiratory capacity 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 the first symptom in 8/13 patients followed by limb weakness in the remaining 5 patients Dysphagia was never the presenting symptom. At the time of examination, all affected patients had ptosis or had previously been operated for ptosis, while ophthalmoplegia was found in 9 patients. Dysphagia, tested by cold-water swallowing test, was abnormal in 9 patients (17-116 s, ref 7 s was 126
considered abnormal. Pulmonary function was assessed by measuring forced expiratory vital (FEV1) capacity using a spirometer type T01A and a facial mask in all, due to facial weakness in some. Three measurements were carried out, and the best FEV1 was noted. Percentage reduction compared to expected values was calculated from normal values adjusted for height, sex, and age (14). A reduction of ≥20% was considered abnormal. Cardiac function was assessed by electrocardiography (ECG), transthoracic echocardiography, and a 48-h Holter monitoring. The cardiac examinations were obtained and analyzed by trained cardiologists (LK, HB, HP). Limb muscle strength was examined using a handheld dynamometer (Citec CT 301). Strength in shoulder abduction (SA), elbow flexion/extension (EF/EE), hip flexion/extension (HF/HE), knee flexion/extension (KF/KE), and ankle dorsiand plantar flexion (AdF/ApF) were assessed. Values were compared to an age- and sexmatched group of 23 healthy individuals. All dynamometer tests in patients and healthy controls were performed by the same examiner (NW). A handgrip dynamometer (Smedley, Stoeltinger) was used to assess the handgrip force. Normal values reported by Schl€ ussel et al. (15) were used as reference. Three repetitions were performed for each measurement of handheld and handgrip dynamometry, and average values are reported. Ambulatory participants were also tested with a 10-step staircase test, measuring time in seconds to climb 10 steps on a standardized staircase (normal L 7 None Mild Y/1 4 3.3 3.4 4
61 8 14 M 14 GCG 51 O>P>L 7 None
67 6 11 M 13 GCG 59 O>P>L 54 Liquids, meat Mild Y/2 5 3.3 3.3 1
Men 60–69 years
None Y/1 4 4.5 3.3 34
66 3 6 M 13 GCG 58 O>P>L 21 Meat
60 3 13 F 13 GCG 51 O>P>L 18 Cold liquids Mild Y/2 4 1.9 3.0 39 Mild Y/2 4+ 1.7 2.7 23
69 7 12 F 13 GCG 58 O>L>P 66 Liquids
Women 60–69 years
FEV1, forced expiratory volume in 1 s; O, ptosis/ophthalmoplegia; P, pharyngeal (dysphagia); L, limb weakness. *Very mild weakness (provided strength levels). † A normal swallowing test should be below 7 s or less.
41 3 4 F 13 GCG 41 (L,O)* 3 None
Age at exam (years) Family no. Participant no. Gender Repeat
Women 40–49 years
Table 1 Baseline data, symptom evolution, cranial nerve examination, and ventilation in Danish OPMD patients
Mild Y/4 4 2.6 2.5 4
65 2 3 F 13 GCG 37 O>P>L 62 NI Mild Y/5 4 2.3 2.7 15
64 1 2 F 15 GCG 50 O>P>L 7 NI
70 4 9 M 13 + 2 GCA+GCG 53 O>P>L 24 Liquids, meat, bread crumps Mild Y/4 4 1.3 3.2 59
Men 70–79 years 70 3 5 M 13 GCG 51 L>O>P 17 Liquids, meat, bread crumps Mild Y/2 4 2.3 3.7 38
72 1 1 F 15 GCG 56 L>O>P 116 Liquids, meat, bread crumps Severe Y/5 4 1.5 2.3 34
Women 70–79 years
None Y/1 4 2.3 3.0 24
80 5 10 M 13 GCG 63 L>O>P 46 Liquids, meat, bread crumps
Men 80–89 years
OPMD phenotype
127
Witting et al. Molecular genetic investigation
Limb function
Genetic analysis showed that two patients (sisters) were heterozygous for a 15 GCN repeat expansion, one patient for a 14 GCN repeat expansion, eight (five families) for a 13 GCN repeat expansion, and two (one family) were heterozygous for a 12 GCN expansion.
Three patients used assistive devices for walking. Two men, aged 70 and 80 years, were confined to a wheelchair, and a 72-year-old woman used a rollator. Another three patients, aged 60, 64, and 65 years, could not climb stairs (Table S1). Of the remaining eight, a 70-year-old patient spent 12 -s climbing the stairs (normal 20 kg).
Ophthalmologic examination
All 13 symptomatic patients were affected by ptosis, and 12 of them had had surgery for ptosis. Impaired eye movements were found in nine patients, but severe ophthalmoplegia was diagnosed in only one (Table 1). Bulbar function
Only two patients (aged 41 and 67 years) had normal strength in facial muscles, and four patients (aged 41, 47, 61, and 64 years) had a normal cold-water swallowing test (Table 1). The two oldest patients with normal cold-water test (2, 13) complained of dysphagia; hence, no patients older than 47 years had subjective normal swallowing. Mean cold-water swallowing time was 34 s. This covered a wide variability in swallowing capacity, ranging from a normal capacity to abnormal swallowing times between 17–116 s for the 61–80year-old patients. None of the patients had had cricopharyngeal myotomy performed, or a percutaneous endoscopic gastrostomy tube inserted.
Figure 1. Percentage muscle strength in 13 patients with oculopharyngeal muscle dystrophy compared to 23 age- and sex-matched controls. Error bars indicate standard deviation.
128
OPMD phenotype Pulmonary function
None of the patients complained of respiratory symptoms. FEV1 was on average reduced by 16% from reference values, and 6, all more than 60 years old, had more than a 20% reduction in FEV1. Cardiac function
Three of the 13 patients (two men, 80 and 61 years old and a woman, 72 years old) did not have the energy to come to the hospital the next day for cardiac investigation. They were contacted by phone and had no medical history or symptoms of cardiac disease. Cardiac investigations were performed in the remaining 10 patients. None had any cardiac symptoms. A 67-yearold man had known ischemic heart disease and previous myocardial infarction, but had preserved left ventricular ejection fraction of 55%. Two patients, a 71-year-old man and a 65-year-old woman, had diastolic dysfunction grade 1 (abnormal left ventricular diastolic relaxation pattern) and mild aortic insufficiency, respectively, assessed by echocardiography. These findings were considered within the normal range according to age. The remaining patients had normal findings on echocardiography, and all patients had normal findings on ECG and Holter monitoring. Discussion
This is the first Danish study to assess ocular, bulbar, limb, and cardiopulmonary involvement in patients with OPMD. We report several findings, which provide new insights to the phenotype and evolution of symptoms in OPMD. First, severe and functionally limiting proximal and distal weakness is present in the majority older than 60 years. Despite the name of the disorder, limb weakness is a frequent presenting symptom of OPMD, but the variability in limb affection is high. Second, OPMD does not appear to be associated with cardiac, involvement and respiratory insufficiency is only mild and present as a subclinical finding in patients older than 60 years. Third, swallowing function, whether subjectively reported or assessed by cold-water swallowing test, was normal until the 60-ties in the majority and was not a presenting symptom in any of the patients. Age, gender, and time of symptom onset matched other described populations (3–5, 16, 17).
Limb weakness was severe in most of our patients older than 60 years. Almost half could not walk stairs. As the majority of patients were not bothered by the ophthalmoplegia, and ptosis is amenable to surgery, limb weakness was probably the most troublesome disease manifestation in those without pronounced dysphagia. Although limb weakness does not typically develop before age 60 years, the patients and society will have to live decades with the limitations, dependence on help and socioeconomic implications that limb weakness causes. One other study focused on limb weakness in OPMD and reported that although only 1/16 had limb weakness as the first symptom, it was the main complaint in half (4). Moreover, according to previous observations, limb weakness appears at some stage of the disease in 20–70% (3, 5, 16, 17). These findings underline that limb weakness is prominent in OPMD and causes disability. In addition, we noticed a large individual variation in limb muscle affection, which was only partly explained by age. To our knowledge, detailed data on limb muscle strength in individual OPMD patients has not been published previously. Our OPMD cohort is too small to evaluate whether the size of the trinucleotide expansion in the PAPBN1 gene was related to limb muscle affection, although it is a potential explanation, as is epigenetic modification. Dysphagia and ptosis are the clinical hallmarks of OPMD. In our patient cohort, onset of subjective dysphagia and dysphagia evaluated by coldwater swallowing test was consistently delayed compared with ptosis. A previous study has indicated that retrospective information about timing of initial symptoms can be unreliable (4). The authors showed elegantly, using old photographs, that ptosis was present years before it was noticed by the patients. This finding, however, cannot explain the present observation of a delay between onset of ptosis and onset of dysphagia as the ptosis was recorded long before the dysphagia. Moreover, in contrast to ptosis, dysphagia is a symptom that is most often not overlooked by the patients. Therefore, we believe that the observed delayed onset is correct. Cardiopulmonary function has not previously been addressed systematically in patients with OPMD. We evaluated 10 participants for cardiac involvement, and no cardiac symptoms or significant abnormalities were observed. These findings, combined with the lack of other reports indicating cardiac involvement in OPMD, suggest that the heart is not involved in OPMD. On this basis, we suggest that in contrast to several other 129
Witting et al. muscular dystrophies, cardiac screening and follow-up are not warranted in patients with OPMD. The pulmonary function was examined in all 13 affected patients, and FEV1 was reduced by 20% or more in six patients all in their 60-ties or older. If this finding can be corroborated in a larger group of OPMD patients, we would suggest regular assessment of the respiratory function after age of 60 years. We also observed that subjective dysphagia typically presents later than limb affection. Two patients had normal cold-water swallowing time (although complaining of subjective dysphagia) and were unable to walk stairs due to limb weakness. Therefore, a presentation with ptosis and severe limb weakness, but no increase in swallowing time or significant complaints of dysphagia, does not rule out OPMD. On the contrary, all the patients with increased swallowing time also had limb weakness, although this could be mild. Thus, the pattern of eye muscle affection, dysphagia, and limb weakness can vary substantially in OPMD.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Acknowledgments
The authors have no acknowledgements to declare.
12.
Conflicts of interest and sources of funding statement
The study was not funded, and none of the authors had any conflict of interest Supporting Information Additional Supporting Information may be found in the online version of this article. Table S1. Strength and function in extremities.
References 1. BRAIS B. Oculopharyngeal muscular dystrophy: a polyalanine myopathy. Curr Neurol Neurosci Rep 2009;9:76– 82. 2. BRAIS B, XIE YG, SANSON M et al. The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on
130
13.
14.
15.
16.
17.
chromosome 14q11.2-q13. Hum Mol Genet 1995;4:429– 34. BOUCHARD JP, BRAIS B, BRUNET D, GOULD PV, ROULEAU GA. Recent studies on oculopharyngeal muscular dystrophy in Quebec. Neuromuscul Disord 1997;7(Suppl 1): S22–9. VAN DER SLUIJS BM, HOEFSLOOT LH, PADBERG GW, VAN DER MAAREL SM, VAN ENGELEN BG. Oculopharyngeal muscular dystrophy with limb girdle weakness as major complaint. J Neurol 2003;250:1307–12. MEDICI M, PIZZAROSSA C, SKUK D, YORIO D, EMMANUELLI G, MESA R. Oculopharyngeal muscular dystrophy in Uruguay. Neuromuscul Disord 1997;7(Suppl 1):S50–2. FARDEAU M, TOME FM. Oculopharyngeal muscular dystrophy in France. Neuromuscul Disord 1997;7(Suppl 1): S30–3. UYAMA E, NOHIRA O, TOME FM et al. Oculopharyngeal muscular dystrophy in Japan. Neuromuscul Disord 1997;7(Suppl 1):S41–9. MEOLA G, SANSONE V, ROTONDO G, TOME FM, BOUCHARD JP. Oculopharyngeal muscular dystrophy in Italy. Neuromuscul Disord 1997;7(Suppl 1):S53–6. HILL ME, CREED GA, MCMULLAN TF et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 2001;124:522–6. SVEEN ML, THUNE JJ, KOBER L, VISSING J. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy. Arch Neurol 2008;65:1196–201. PETRI H, VISSING J, WITTING N, BUNDGAARD H, KOBER L. Cardiac manifestations of myotonic dystrophy type 1. Int J Cardiol 2012;160:82–8. MENSAH A, WITTING N, DUNO M, MILEA D, VISSING J. Delayed diagnosis of oculopharyngeal muscular dystrophy in Denmark: from initial ptosis to genetic testing. Acta Ophthalmol 2013; doi:10.1111/aos.12243. [Epub ahead of print]. BOUCHARD JP, MARCOUX S, GOSSELIN F, PINEAULT D, ROULEAU GA. A simple test for the detection of dysphagia in members of families with oculopharyngeal muscular dystrophy (OPMD). Can J Neurol Sci 1992;19: 296–7. HANKINSON JL, ODENCRANTZ JR, FEDAN KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159:179–87. SCHLUSSEL MM, DOS ANJOS LA, DE VASCONCELLOS MT, KAC G. Reference values of handgrip dynamometry of healthy adults: a population-based study. Clin Nutr 2008;27:601–7. BLUMEN SC, NISIPEANU P, SADEH M, ASHEROV A, TOME FM, KORCZYN AD. Clinical features of oculopharyngeal muscular dystrophy among Bukhara Jews. Neuromuscul Disord 1993;3:575–7. BECHER MW, MORRISON L, DAVIS LE et al. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA 2001;286:2437–40.
