Progressive Cardiac Dysfunction in Bethlem Myopathy During Pregnancy Anne Flöck, MD, Cornelia Kornblum, MD, Christoph Hammerstingl, MD, Kristl G. Claeys, MD, Ulrich Gembruch, MD, and Waltraut Maria Merz, MD BACKGROUND: Bethlem myopathy is a congenital myopathy presenting with muscle weakness and joint abnormalities. Although cardiac involvement is frequent in other inherited myopathies, it has not yet been described in Bethlem myopathy. CASE: We report a case of progressive deterioration of left ventricular function during pregnancy in a patient with Bethlem myopathy. Worsening of clinical symptoms, particularly dyspnea, necessitated delivery at 36 2/7 weeks of gestation. Myocardial function recovered postpartum with improvement of clinical symptoms. CONCLUSION: Bethlem myopathy may be associated with progressive left ventricular dysfunction during pregnancy and may require early delivery. (Obstet Gynecol 2014;123:436–8) DOI: 10.1097/AOG.0000000000000101
D
uring pregnancy, organs are subject to multiple changes that can worsen symptoms of existing diseases or create new problems with necessity of treatment. We report progressive deterioration of left ventricular function during pregnancy in a patient with Bethlem myopathy. Bethlem myopathy (OMIM #158810; Online Mendelian Inheritance in Man, www.omim.org) is an autosomal-dominantly inherited congenital myopathy with variable age of onset, presenting with generalized predominantly proximal muscle weakness and joint laxity or contractures. The From the Departments of Obstetrics and Prenatal Medicine, Neurology, and Cardiology, University Medical School, Bonn, and the Department of Neurology and the Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. Correspondence to: Dr. Waltraut Maria Merz, Department of Obstetrics and Prenatal Medicine, University Medical School Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
436
Flo¨ck et al
Bethlem Myopathy Heart and Pregnancy
disease is associated with mutations in the genes that encode collagen VI subunits. The collagen VI protein is primarily associated with the extracellular matrix of skeletal muscle. Although cardiac involvement is frequent in inherited myopathies and is one of the most life-threatening complications of muscle diseases, cardiomyopathies have not been described in Bethlem myopathy.
CASE A 30-year-old primigravid woman with Bethlem myopathy was referred to our department at 21 2/7 weeks of gestation. Molecular diagnosis had revealed a heterozygous pathogenic mutation in COL6A3, exon 17 (p.Gly2080Asp) (c.6239G.A); COL6A1 and COL6A2 sequencing did not yield other mutations. Her mother and sister were symptomatic carriers of the same mutation, with a less pronounced clinical phenotype. Her medical history included hip dislocations secondary to dysplasia with degenerative osteoarthritis of the right hip joint that necessitated arthroplasty 9 years previously. Physical examination revealed moderate-to-severe muscle weakness that was accentuated in lower limbs and proximal muscle groups, with gait instability and difficulties in walking on heels. Severe weakness of thigh muscles and hip abductors required the patient to use hand support to push herself to an upright position (Gowers sign) and resulted in a Trendelenburg gait pattern (waddling gait). She had lumbar hyperlordosis, distal joint hyperlaxity, and finger contractures. Follicular hyperkeratosis and multiple keloid scars were present on her skin. The patient reported dyspnea during normal daily activities (New York Heart Association II classification) and an occasionally irregular heart beat since the beginning of her pregnancy. At 31 0/7 weeks of gestation, semiquantitative transthoracic echocardiography1 revealed moderate global restriction of left ventricular systolic function without valvular heart disease (Table 1). Mild tachycardia (mean 104 beats per minute; range, 79–148 beats per minute) was present on Holter electrocardiogram, and pulmonary function tests showed moderate restrictive lung disease. Treatment with metoprolol 47.5 mg/d was initiated. At 33 1/7 weeks of gestation, deterioration to New York Heart Association III had occurred. Auscultation and Holter electrocardiogram results were normal. Transthoracic echocardiography revealed myocardial hypokinesia accentuated in the interventricular septum with stable ejection fraction. At 36 0/7 weeks of gestation, the patient presented with shortness of breath at rest. At that time, beginning left ventricular dilatation with stable ejection fraction was diagnosed for the first time in transthoracic echocardiography (Fig. 1). Laboratory test results (aspartate aminotransferase, alanine aminotransferase, troponin, and n-terminal pro-B-type natriuretic peptide) were within normal ranges. Because of progressive clinical
OBSTETRICS & GYNECOLOGY
Table 1. Transthoracic Echocardiography Measurements in Pregnancy and Postpartum Weeks of Gestation Measurement 8
Ejection fraction, %* (normal range ) † Left ventricular volume, mL (normal range8)
Postpartum
31 0/7
33 1/7
36 0/7
4d
2 mo
45 (—) 131 (—)
50 (6264) 138 (94614)
45 (—) 162 (—)
50 (—) 114 (—)
56 (6464) 111 (70615)
* Normal third-trimester ejection fraction (%) is 6264, and normal 2-month postpartum ejection fraction (%) is 6464.8 † Normal third-trimester left ventricular volume (mL) is 92614, and normal 2-month postpartum left ventricular volume (mL) is 70615.8
deterioration, a decision for delivery was made at 36 2/7 weeks of gestation. Because of the decreased range of motion in her hip joints, her muscle weakness, and shortness of breath, cesarean delivery was performed, even though cesarean delivery may predispose patients with left ventricular dysfunction to increased risk of heart failure. An apparently healthy boy (birth weight 2,570 g; Apgar scores 9, 10, and 10 at 1, 5, and 1 minutes.; umbilical artery pH 7.30) was delivered. Dyspnea and tachycardia improved during the early postpartum period. Transthoracic echocardiography on day 4 postpartum showed normal left ventricular dimensions with unchanged ejection fraction. The patient was discharged on postoperative day 5 with metoprolol. At follow-up 2 months after delivery, the patient was asymptomatic and echocardiography findings had resolved.
COMMENT We report heart failure attributable to progressive cardiac dysfunction in a patient with Bethlem myopathy during pregnancy. Although COL6 is expressed in myocardial tissue, cardiac involvement in Bethlem myopathy has not been described.2,3 Cardiac abnormalities, mostly conduction defects, have been reported in up to 10% of patients with Bethlem myopathy, although a relationship to the myopathy seems to be unlikely.4–6 van der Kooi et al4 described three family members with Bethlem myopathy and abnormal findings during echocardiography; however, the left atrial dilatation present in these patients could be attributed to other predisposing conditions (atrial fibrillation and hypertension).4,5 Our patient did not show any comorbidities predisposing to
Fig. 1. Left ventricular volumes and function antepartum and postpartum. LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction. Flo¨ck. Bethlem Myopathy Heart and Pregnancy. Obstet Gynecol 2014.
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Bethlem Myopathy Heart and Pregnancy 437
myocardial remodeling, and cardiac conduction disturbances were not present. Other possible causes of cardiac dysfunction include peripartum cardiomyopathy and viral myocarditis. However, diagnostic criteria were not fulfilled for either of these differential diagnoses.7 Respiratory muscle involvement may have contributed to the clinical presentation, particularly because other symptoms of cardiac failure were subtle and results of pulmonary function tests during early pregnancy revealed moderate restrictive lung function. Familial predisposition, although unlikely, cannot be ruled out because the patient’s mother had myocarditis with transient conduction abnormalities at the age of 37 years, her maternal grandmother had died of cardiac insufficiency, and her maternal great-grandmother had died unexpectedly at the age of 62 years. Myocardial biopsy was not performed because of normal electrocardiogram results, absent signs of infection, and excellent and immediate recovery after delivery. In conclusion, we report a patient with progressive and transient cardiac dysfunction with Bethlem myopathy during pregnancy. We assume this finding to be related to the underlying myopathy rather than viral or obstetric causes. Therefore, we recommend close monitoring of these patients during pregnancy
because of the increased myocardial preload during pregnancy, which may unmask or worsen a hitherto subclinical myocardial disorder.
Obstetric Outcome in a Primigravid Patient With Autosomal-Recessive Multiminicore Myopathy
patients. Little is known about pregnancy outcomes, although patients with other neuromuscular disorders may experience a postpartum decline.
Caitlyn Klaska, BS, and Bernard Gonik,
MD
BACKGROUND: Multiminicore disease is a congenital myopathy characterized by muscle weakness and respiratory impairment. Predilection for the development of malignant hyperthermia has been reported in select
REFERENCES 1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. 2. McClain PE. Characterisation of cardiac muscle collagen: molecular heterogeneity. J Biol Chem 1974;249:2303–11. 3. de Visser M, de Voogt WG, la Rivière GV. The heart in Becker muscular dystrophy, facioscapulohumeral dystrophy, and Bethlem myopathy. Muscle Nerve 1992;15:591–6. 4. van der Kooi AJ, de Voogt WG, Bertini E, Merlini L, Talim FB, Ben Yaou R, et al. Cardiac and pulmonary investigations in Bethlem myopathy. Arch Neurol 2006;63:1617–21. 5. Finsterer J, Stöllberger C. Cardiac involvement in Bethlem myopathy. Arch Neurol 2007;64:916. 6. Pepe G, Bertini E, Bonaldo P, Bushby K, Giusti B, de Visser M, et al. Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 2324 November 2001, Naarden, the Netherlands. Neuromuscul Disord 2002;12:984–93. 7. Johnson-Coyle L, Jensen L, Sobey A. Peripartum cardiomyopathy: review and practice guidelines. Am J Crit Care 2012;21:89–98. 8. Savu O, Jurcut R, Giusca S, van Mieghem T, Gussi I, Popescu BA, et al. Morphological and functional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging 2012;5:289–97.
CASE: We report a case of pregnancy associated with autosomal-recessive multiminicore disease. Genetic implications of this condition were addressed. Orthopedic complications were managed through physical medicine and rehabilitation consultation. Under epidural anesthesia, a healthy full-term neonate was delivered through spontaneous vaginal delivery. There was no evidence of malignant hyperthermia or functional decline in the puerperium. CONCLUSION: A successful pregnancy outcome was achieved in a patient with multiminicore myopathy by proactively addressing potential genetic, orthopedic, and anesthetic concerns associated with this condition.
From the Wayne State University School of Medicine and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
(Obstet Gynecol 2014;123:438–40)
Corresponding author: Bernard Gonik, MD, 6071 West Outer Drive, Suite M541, Detroit, MI 48235; e-mail: [email protected].
ultiminicore disease is a congenital core myopathy. Classic multiminicore disease is associated with recessive mutations in the selenoprotein N gene (SEPN1) and is characterized by respiratory impairment.1 Other phenotypic variants of multiminicore disease are associated with recessive or dominant mutations
Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
438
Klaska and Gonik
DOI: 10.1097/AOG.0000000000000003
M
Multiminicore Disease in Pregnancy
OBSTETRICS & GYNECOLOGY
D
uring pregnancy, organs are subject to multiple changes that can worsen symptoms of existing diseases or create new problems with necessity of treatment. We report progressive deterioration of left ventricular function during pregnancy in a patient with Bethlem myopathy. Bethlem myopathy (OMIM #158810; Online Mendelian Inheritance in Man, www.omim.org) is an autosomal-dominantly inherited congenital myopathy with variable age of onset, presenting with generalized predominantly proximal muscle weakness and joint laxity or contractures. The From the Departments of Obstetrics and Prenatal Medicine, Neurology, and Cardiology, University Medical School, Bonn, and the Department of Neurology and the Institute of Neuropathology, RWTH Aachen University, Aachen, Germany. Correspondence to: Dr. Waltraut Maria Merz, Department of Obstetrics and Prenatal Medicine, University Medical School Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
436
Flo¨ck et al
Bethlem Myopathy Heart and Pregnancy
disease is associated with mutations in the genes that encode collagen VI subunits. The collagen VI protein is primarily associated with the extracellular matrix of skeletal muscle. Although cardiac involvement is frequent in inherited myopathies and is one of the most life-threatening complications of muscle diseases, cardiomyopathies have not been described in Bethlem myopathy.
CASE A 30-year-old primigravid woman with Bethlem myopathy was referred to our department at 21 2/7 weeks of gestation. Molecular diagnosis had revealed a heterozygous pathogenic mutation in COL6A3, exon 17 (p.Gly2080Asp) (c.6239G.A); COL6A1 and COL6A2 sequencing did not yield other mutations. Her mother and sister were symptomatic carriers of the same mutation, with a less pronounced clinical phenotype. Her medical history included hip dislocations secondary to dysplasia with degenerative osteoarthritis of the right hip joint that necessitated arthroplasty 9 years previously. Physical examination revealed moderate-to-severe muscle weakness that was accentuated in lower limbs and proximal muscle groups, with gait instability and difficulties in walking on heels. Severe weakness of thigh muscles and hip abductors required the patient to use hand support to push herself to an upright position (Gowers sign) and resulted in a Trendelenburg gait pattern (waddling gait). She had lumbar hyperlordosis, distal joint hyperlaxity, and finger contractures. Follicular hyperkeratosis and multiple keloid scars were present on her skin. The patient reported dyspnea during normal daily activities (New York Heart Association II classification) and an occasionally irregular heart beat since the beginning of her pregnancy. At 31 0/7 weeks of gestation, semiquantitative transthoracic echocardiography1 revealed moderate global restriction of left ventricular systolic function without valvular heart disease (Table 1). Mild tachycardia (mean 104 beats per minute; range, 79–148 beats per minute) was present on Holter electrocardiogram, and pulmonary function tests showed moderate restrictive lung disease. Treatment with metoprolol 47.5 mg/d was initiated. At 33 1/7 weeks of gestation, deterioration to New York Heart Association III had occurred. Auscultation and Holter electrocardiogram results were normal. Transthoracic echocardiography revealed myocardial hypokinesia accentuated in the interventricular septum with stable ejection fraction. At 36 0/7 weeks of gestation, the patient presented with shortness of breath at rest. At that time, beginning left ventricular dilatation with stable ejection fraction was diagnosed for the first time in transthoracic echocardiography (Fig. 1). Laboratory test results (aspartate aminotransferase, alanine aminotransferase, troponin, and n-terminal pro-B-type natriuretic peptide) were within normal ranges. Because of progressive clinical
OBSTETRICS & GYNECOLOGY
Table 1. Transthoracic Echocardiography Measurements in Pregnancy and Postpartum Weeks of Gestation Measurement 8
Ejection fraction, %* (normal range ) † Left ventricular volume, mL (normal range8)
Postpartum
31 0/7
33 1/7
36 0/7
4d
2 mo
45 (—) 131 (—)
50 (6264) 138 (94614)
45 (—) 162 (—)
50 (—) 114 (—)
56 (6464) 111 (70615)
* Normal third-trimester ejection fraction (%) is 6264, and normal 2-month postpartum ejection fraction (%) is 6464.8 † Normal third-trimester left ventricular volume (mL) is 92614, and normal 2-month postpartum left ventricular volume (mL) is 70615.8
deterioration, a decision for delivery was made at 36 2/7 weeks of gestation. Because of the decreased range of motion in her hip joints, her muscle weakness, and shortness of breath, cesarean delivery was performed, even though cesarean delivery may predispose patients with left ventricular dysfunction to increased risk of heart failure. An apparently healthy boy (birth weight 2,570 g; Apgar scores 9, 10, and 10 at 1, 5, and 1 minutes.; umbilical artery pH 7.30) was delivered. Dyspnea and tachycardia improved during the early postpartum period. Transthoracic echocardiography on day 4 postpartum showed normal left ventricular dimensions with unchanged ejection fraction. The patient was discharged on postoperative day 5 with metoprolol. At follow-up 2 months after delivery, the patient was asymptomatic and echocardiography findings had resolved.
COMMENT We report heart failure attributable to progressive cardiac dysfunction in a patient with Bethlem myopathy during pregnancy. Although COL6 is expressed in myocardial tissue, cardiac involvement in Bethlem myopathy has not been described.2,3 Cardiac abnormalities, mostly conduction defects, have been reported in up to 10% of patients with Bethlem myopathy, although a relationship to the myopathy seems to be unlikely.4–6 van der Kooi et al4 described three family members with Bethlem myopathy and abnormal findings during echocardiography; however, the left atrial dilatation present in these patients could be attributed to other predisposing conditions (atrial fibrillation and hypertension).4,5 Our patient did not show any comorbidities predisposing to
Fig. 1. Left ventricular volumes and function antepartum and postpartum. LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction. Flo¨ck. Bethlem Myopathy Heart and Pregnancy. Obstet Gynecol 2014.
VOL. 123, NO. 2 PART 2, FEBRUARY 2014
Flo¨ck et al
Bethlem Myopathy Heart and Pregnancy 437
myocardial remodeling, and cardiac conduction disturbances were not present. Other possible causes of cardiac dysfunction include peripartum cardiomyopathy and viral myocarditis. However, diagnostic criteria were not fulfilled for either of these differential diagnoses.7 Respiratory muscle involvement may have contributed to the clinical presentation, particularly because other symptoms of cardiac failure were subtle and results of pulmonary function tests during early pregnancy revealed moderate restrictive lung function. Familial predisposition, although unlikely, cannot be ruled out because the patient’s mother had myocarditis with transient conduction abnormalities at the age of 37 years, her maternal grandmother had died of cardiac insufficiency, and her maternal great-grandmother had died unexpectedly at the age of 62 years. Myocardial biopsy was not performed because of normal electrocardiogram results, absent signs of infection, and excellent and immediate recovery after delivery. In conclusion, we report a patient with progressive and transient cardiac dysfunction with Bethlem myopathy during pregnancy. We assume this finding to be related to the underlying myopathy rather than viral or obstetric causes. Therefore, we recommend close monitoring of these patients during pregnancy
because of the increased myocardial preload during pregnancy, which may unmask or worsen a hitherto subclinical myocardial disorder.
Obstetric Outcome in a Primigravid Patient With Autosomal-Recessive Multiminicore Myopathy
patients. Little is known about pregnancy outcomes, although patients with other neuromuscular disorders may experience a postpartum decline.
Caitlyn Klaska, BS, and Bernard Gonik,
MD
BACKGROUND: Multiminicore disease is a congenital myopathy characterized by muscle weakness and respiratory impairment. Predilection for the development of malignant hyperthermia has been reported in select
REFERENCES 1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. 2. McClain PE. Characterisation of cardiac muscle collagen: molecular heterogeneity. J Biol Chem 1974;249:2303–11. 3. de Visser M, de Voogt WG, la Rivière GV. The heart in Becker muscular dystrophy, facioscapulohumeral dystrophy, and Bethlem myopathy. Muscle Nerve 1992;15:591–6. 4. van der Kooi AJ, de Voogt WG, Bertini E, Merlini L, Talim FB, Ben Yaou R, et al. Cardiac and pulmonary investigations in Bethlem myopathy. Arch Neurol 2006;63:1617–21. 5. Finsterer J, Stöllberger C. Cardiac involvement in Bethlem myopathy. Arch Neurol 2007;64:916. 6. Pepe G, Bertini E, Bonaldo P, Bushby K, Giusti B, de Visser M, et al. Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 2324 November 2001, Naarden, the Netherlands. Neuromuscul Disord 2002;12:984–93. 7. Johnson-Coyle L, Jensen L, Sobey A. Peripartum cardiomyopathy: review and practice guidelines. Am J Crit Care 2012;21:89–98. 8. Savu O, Jurcut R, Giusca S, van Mieghem T, Gussi I, Popescu BA, et al. Morphological and functional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging 2012;5:289–97.
CASE: We report a case of pregnancy associated with autosomal-recessive multiminicore disease. Genetic implications of this condition were addressed. Orthopedic complications were managed through physical medicine and rehabilitation consultation. Under epidural anesthesia, a healthy full-term neonate was delivered through spontaneous vaginal delivery. There was no evidence of malignant hyperthermia or functional decline in the puerperium. CONCLUSION: A successful pregnancy outcome was achieved in a patient with multiminicore myopathy by proactively addressing potential genetic, orthopedic, and anesthetic concerns associated with this condition.
From the Wayne State University School of Medicine and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
(Obstet Gynecol 2014;123:438–40)
Corresponding author: Bernard Gonik, MD, 6071 West Outer Drive, Suite M541, Detroit, MI 48235; e-mail: [email protected].
ultiminicore disease is a congenital core myopathy. Classic multiminicore disease is associated with recessive mutations in the selenoprotein N gene (SEPN1) and is characterized by respiratory impairment.1 Other phenotypic variants of multiminicore disease are associated with recessive or dominant mutations
Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
438
Klaska and Gonik
DOI: 10.1097/AOG.0000000000000003
M
Multiminicore Disease in Pregnancy
OBSTETRICS & GYNECOLOGY
