Five members of the same family, along three generations, presented with hypertrophic cardiomyopathy. Neurological examination, muscle strength, electromyography, and serum creatine kinase were normal. Skeletal muscle biopsy showed abnormal lipid accumulation and carnitine deficiency. In three patients the cardiac symptoms and echocardiographic findings improved after treatment with L-carnitine, 3-4 g daily, and a long-chain fattyacid-free diet. Key words: familial cardiomyopathy carnitine deficiency skeletal muscle biopsy MUSCLE & NERVE 13:192-194 1990
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY AND MU S CL E CARNlTlNE DEFICIENCY J. BAUTISTA, MD, E. RAFEL, MD, A. MARTINEZ, MD, 1. SAINZ, MD, J. HERRERA, MD, L. SEGURA, MD, and I. CHINCHON, MD
Hypertrophic cardiomyopathy (HCM) is a disease of unknown etiology, often familial with dominant autosomal transn~ission.~ Involvement of skeletal muscle is rare, and only nonspecific morphological changes have been reported on a few occasions.' We report a family affected with HCM and muscle carnitine deficiency. MATERIALS AND METHODS
We studied six individuals from the same family in three consecutive generations (Fig. 1). T h e patients' ages ranged from 12 to 74 years, and three were males. Cardiological examination and two-dimensional doppler echocardiograms were carried out in all patients. Electromyographic studies of the biceps, deltoid, and quadriceps muscles and motor and sensory responses of the peroneal nerve were recorded. Deltoid muscle biopsies
From the Departments of Neurology, Pathology, Cardiology, and Biochemistry. Hospital Virgen del Rocio, Sevilla, Spain. Acknowledgments. We thank Prof S. DiMauro for his helpful suggestions and for reviewing the manuscript. This work was supported in part by grant 87/1211 from the Fondo de lnvestigaciones Sanitarias de la Seguridad Social (FISSS) del Ministerio de Sanidad y Consumo. Presented in part at the International Symposium on Inherited Diseases of the Nervous System and Skeletal Muscle: Molecular and Genetic Aspects, Aosta, Italy, 1986 Address reprint requests to Dr.J. Bautista at the Departamento de Neurologia, Hospital Virgen del Rocio, 41013, Sevilla, Spain. Accepted for publication February 21, 1989 0148-639X1030192-03 $04 00,' 0 1990 John Wiley & Sons, Inc
192
Hypertrophic Myopathy
were studied in all patients with conventional histochemistry and electron microscopy according to D ~ b o w i t z .Tissue ~ fragments from the biopsies were used for the biochemical determination^.^ Follow-up studies were performed after 1 year. RESULTS
The clinical data are summarized in Table 1. Four patients, 11-2, 11-4, 11-5, and 111-5, fulfilled the clinical and echocardiographic criteria for HCM. Obstructive HCM (OHCM) became clinically evident in all four patients between the ages of 12 and 25. T h e more common symptoms were shortness of breath, chest pain and throbbing, dizziness, and sudden loss of consciousness. The disease was not equally severe in all patients, and the severity had no relation to the age of the patients or the duration of the disease. According to the criteria given by the New York Heart Association (NYHA), patients with HCM in grades 2 (cases 112 and 11-4) manifest symptoms in association with mild exercise. Patients in grade 4 (cases 11-5 and 111-5) are symptomatic at rest. The fifth patient (case I- 1) had subclinical HCM which corresponds to grade 1 of NYHA classification. The sixth case (11-3)was normal. None of the patients had muscular symptoms. The muscle strength, creatine kinase levels, and EMG studies were normal. In all patients the muscle biopsy disclosed, in more than half of the fibers, abundant, small lipid vacuoles which were oil red positive and PAS negative. Electron microscopic studies confirmed the lipid
MUSCLE 8, NERVE
March 1990
I
II
0
HYPERTROPHIC MYOCARMOPATHY LIPID STORAGE MYOPATHY
FIGURE 1. Pedigree.
nature of the vacuoles (Fig. 2). T h e ATPase activity showed that the vacuoles were present in both types of fibers. There was predominance of type 1 fibers in cases 1-1, 11-3, and 11-5. Atrophy of type 1 fibers was seen in case 11-3 and atrophy of type 2 fibers was present in case 1-1. Biochemical studies of cases 11-3, 11-4, and 11-5 showed low levels of carnitine in the muscle, while levels of serum carnitine were normal. Cases 11-2, 11-4, and 11-5 were treated with oral L-carnitine, 3-4 g daily, and a long-chain fatty-acid-free diet for 1 year. Cases 1-1 and 11-3 were asymptomatic and refused therapy, and case 111-5 did not tolerate treatment because of severe gastric discomfort. Clinical improvement was achieved according to the NYHA guidelines (Table 2) in cases 11-2, 11-4, and 11-5. Echocardiographic studies showed improvement in cases 11-2, 11-4, and 11-5, in the following findings: asymmetrical septa1 hypertrophy (ventricular septumlposterior wall ratio), ventricular expansion (“a” index and EF slope in the mitral valve register), and doppler transmitral flow. There has been
FIGURE 2. Longitudinal section showing strings of lipid vacuoles and normal myofibrilar apparatus. Bar = 1 pm.
also a reduction in the amount of the hemodynamic obstruction (systolic anterior motion and midsystolic aortic valve notching) in cases 11-4 and 11-5. DISCUSSION
Hypertrophic cardiomyopathy is a disease of unknown origin characterized by hypertrophy of the
Table 1. Clinical data. ~
Cardiac symptoms Case 1-1 11-2 11-3 11-4 11-5
111-5
Muscle biopsy
Sex/age (years)
Echo
Grade*
Duration (years)
Carnitine (3 6 2 0 2 pmollg)
Morphology
Fl74 MI49 F147 MI41 MI31 Ff12
HCMt OHCMS Normal OHCM OHCM OHCM
0 2 0 2 4 4
0 3 0 16 8 1
NT§ NT 14 14 09 NT
Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy
*Nomenclature and criteria for diagnosis of diseases of the heart and great vessels (functional capacity) according to the New York Heart Association (NYHA) THypertrophic cardiomyopathy #Obstructive hypertrophic cardiomyopathy §Not tested
Hypertrophic Myopathy
MUSCLE & NERVE
March 1990
193
Table 2. Evolution of the clinical and echocardiographic data after 1 year of treatment with I-carnitine and long-chain fatty-acid-free diet Echocardiogram Cardiac symptoms (NYHA)* Case 11-2 11-4 11-5
VSIPWt
"a" index
EF slope
PVIiTVI*
SAM5
MSAN I(
Pie
Aft
Pre
Aft
Pre
Aft.
Pre
Aft.
Pre
Aft.
Pre
Aft.
Pre
Aft.
2 2 4
1 1 1
1.7 1.8 1.7
1.5 1.5 1
99% 80% 80%
72%
8 20 40
8 70 94
I
I
-
No
~~~~~
'New York Heart Association guidelines tVentricular septumlpostenor wall #Protodiastolic velocity integralltelediastolic velocity integral in the mitral valve flow JSystolic anterior motion (1 Mydsystolic aortic valve notching
ventricular walls and septum and loss of the ability of the heart to expand. Involvement of subjects of both sexes in successive generations suggests an autosomal dominant trait.' Morphological studies of cardiac muscle showed fiber d i ~ a r r a y .How~ ever, no specific changes have been found in skeletal muscle.' Involvement of the heart has been reported in many patients suffering from carnitine deficiency myopathy ," -" but only three reports had familial incidence and systemic carnitine The family described by Tripp et al.' had endocardial fibroelastosis, early onset, and high rate of perinatal death. Waber et a1.I' described two cases: one had congestive heart failure of early onset and later developed muscle weakness; the other child died at 23 months with cardiomegaly.
The siblings with HCM described by Matsuishi et al." showed muscle weakness at 3 years of age. Our patients differ from those previously reported in several ways. The cardiopathy characteristically started late and was the only clinical manifestation; there was muscle carnitine deficiency and autosomal dominant mode of transmission. T h e favorable response to carnitine supplement suggests that carnitine deficiency was the common factor for both the myopathy and the HCM. On the basis of our results, we recommend that muscle biopsies and carnitine levels be considered in patients with cardiomyopathy, both when the disease appears in early infancyg and when it starts in adult life and irrespective of whether or not it is accompanied by muscle weakness.
REFERENCES 1. Maron BJ, Bonow RO, Cannon RO, Leon MB, Epstein SE: Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy (first of two parts). N Engl J Med 1987;316:780-789. 2. Smith ER, Heffernan LP, Sangalang VE, Vaughan LM, Flemington S: Voluntary muscle involvement in hypertrophic cardiomyopathy. A study of eleven patients. Ann Intern Med 1976;85:566-572. 3. Dubowitz V: Muscle Bzopsy: A Practtcal Approach, 2nd ed. London, Balliere Tindall, 1985, pp 19-40, 82-94. 4. McGarry JD, Foster DW: An improved and simplified radioisotopic assay for the determination of free and sterified carnitine. J Lzpzd Res 1976;17:227-228. 5. Van Der Eel-Kahn J: Muscle fiber disarray in common heart diseases. Am J Cardtol 1977;40:355-364. 6. Vandyke DH, Griggs RC, Markesbery W, DiMauro S: Hereditary carnitine-aeficiency of muscle. Neurology 1975; 251154- 159. 7. Cornelio F, DiDonato S, Peluchetti D, Bizzi A, Bertagnolio
194
Hypertrophic Myopathy
B, DAngelo A, Wiesmann U : Fatal cases of lipid storage myopathy with carnitine deficiency.J Neurol Neurosurg Psychiatry 1977;40:170- 178. 8. Hart ZH, Chang CH, DiMauro S, Farroki Q, Ayyar R: Muscle carnitine deficiency and fatal cardiomyopathy. Neurology 1978;28:147- 151. 9. Tripp ME, Katcher ML, Peters HA, Gilbert EF, Arya S, Hodach RJ, Shug AL: Systemic carnitine deficiency presenting as familial endocardia] fibroelastosis. A treatable cardiomyopathy. N EnglJ Med 1981;305:385-390. 10. Wdber LJ, Valle D, Neil1 C , DiMauro S, Shug A: Carnitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport. J Pediatr 1982;10 1 :700705. 11. Matsuishi T, Hirata K, Terasawa K, Kato H, Yoshino M, Ohtaki E, Hirose F: Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy. Neuropediatrics 1985;16:6- 12.
MUSCLE & NERVE
March 1990
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY AND MU S CL E CARNlTlNE DEFICIENCY J. BAUTISTA, MD, E. RAFEL, MD, A. MARTINEZ, MD, 1. SAINZ, MD, J. HERRERA, MD, L. SEGURA, MD, and I. CHINCHON, MD
Hypertrophic cardiomyopathy (HCM) is a disease of unknown etiology, often familial with dominant autosomal transn~ission.~ Involvement of skeletal muscle is rare, and only nonspecific morphological changes have been reported on a few occasions.' We report a family affected with HCM and muscle carnitine deficiency. MATERIALS AND METHODS
We studied six individuals from the same family in three consecutive generations (Fig. 1). T h e patients' ages ranged from 12 to 74 years, and three were males. Cardiological examination and two-dimensional doppler echocardiograms were carried out in all patients. Electromyographic studies of the biceps, deltoid, and quadriceps muscles and motor and sensory responses of the peroneal nerve were recorded. Deltoid muscle biopsies
From the Departments of Neurology, Pathology, Cardiology, and Biochemistry. Hospital Virgen del Rocio, Sevilla, Spain. Acknowledgments. We thank Prof S. DiMauro for his helpful suggestions and for reviewing the manuscript. This work was supported in part by grant 87/1211 from the Fondo de lnvestigaciones Sanitarias de la Seguridad Social (FISSS) del Ministerio de Sanidad y Consumo. Presented in part at the International Symposium on Inherited Diseases of the Nervous System and Skeletal Muscle: Molecular and Genetic Aspects, Aosta, Italy, 1986 Address reprint requests to Dr.J. Bautista at the Departamento de Neurologia, Hospital Virgen del Rocio, 41013, Sevilla, Spain. Accepted for publication February 21, 1989 0148-639X1030192-03 $04 00,' 0 1990 John Wiley & Sons, Inc
192
Hypertrophic Myopathy
were studied in all patients with conventional histochemistry and electron microscopy according to D ~ b o w i t z .Tissue ~ fragments from the biopsies were used for the biochemical determination^.^ Follow-up studies were performed after 1 year. RESULTS
The clinical data are summarized in Table 1. Four patients, 11-2, 11-4, 11-5, and 111-5, fulfilled the clinical and echocardiographic criteria for HCM. Obstructive HCM (OHCM) became clinically evident in all four patients between the ages of 12 and 25. T h e more common symptoms were shortness of breath, chest pain and throbbing, dizziness, and sudden loss of consciousness. The disease was not equally severe in all patients, and the severity had no relation to the age of the patients or the duration of the disease. According to the criteria given by the New York Heart Association (NYHA), patients with HCM in grades 2 (cases 112 and 11-4) manifest symptoms in association with mild exercise. Patients in grade 4 (cases 11-5 and 111-5) are symptomatic at rest. The fifth patient (case I- 1) had subclinical HCM which corresponds to grade 1 of NYHA classification. The sixth case (11-3)was normal. None of the patients had muscular symptoms. The muscle strength, creatine kinase levels, and EMG studies were normal. In all patients the muscle biopsy disclosed, in more than half of the fibers, abundant, small lipid vacuoles which were oil red positive and PAS negative. Electron microscopic studies confirmed the lipid
MUSCLE 8, NERVE
March 1990
I
II
0
HYPERTROPHIC MYOCARMOPATHY LIPID STORAGE MYOPATHY
FIGURE 1. Pedigree.
nature of the vacuoles (Fig. 2). T h e ATPase activity showed that the vacuoles were present in both types of fibers. There was predominance of type 1 fibers in cases 1-1, 11-3, and 11-5. Atrophy of type 1 fibers was seen in case 11-3 and atrophy of type 2 fibers was present in case 1-1. Biochemical studies of cases 11-3, 11-4, and 11-5 showed low levels of carnitine in the muscle, while levels of serum carnitine were normal. Cases 11-2, 11-4, and 11-5 were treated with oral L-carnitine, 3-4 g daily, and a long-chain fatty-acid-free diet for 1 year. Cases 1-1 and 11-3 were asymptomatic and refused therapy, and case 111-5 did not tolerate treatment because of severe gastric discomfort. Clinical improvement was achieved according to the NYHA guidelines (Table 2) in cases 11-2, 11-4, and 11-5. Echocardiographic studies showed improvement in cases 11-2, 11-4, and 11-5, in the following findings: asymmetrical septa1 hypertrophy (ventricular septumlposterior wall ratio), ventricular expansion (“a” index and EF slope in the mitral valve register), and doppler transmitral flow. There has been
FIGURE 2. Longitudinal section showing strings of lipid vacuoles and normal myofibrilar apparatus. Bar = 1 pm.
also a reduction in the amount of the hemodynamic obstruction (systolic anterior motion and midsystolic aortic valve notching) in cases 11-4 and 11-5. DISCUSSION
Hypertrophic cardiomyopathy is a disease of unknown origin characterized by hypertrophy of the
Table 1. Clinical data. ~
Cardiac symptoms Case 1-1 11-2 11-3 11-4 11-5
111-5
Muscle biopsy
Sex/age (years)
Echo
Grade*
Duration (years)
Carnitine (3 6 2 0 2 pmollg)
Morphology
Fl74 MI49 F147 MI41 MI31 Ff12
HCMt OHCMS Normal OHCM OHCM OHCM
0 2 0 2 4 4
0 3 0 16 8 1
NT§ NT 14 14 09 NT
Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy Lipid myopathy
*Nomenclature and criteria for diagnosis of diseases of the heart and great vessels (functional capacity) according to the New York Heart Association (NYHA) THypertrophic cardiomyopathy #Obstructive hypertrophic cardiomyopathy §Not tested
Hypertrophic Myopathy
MUSCLE & NERVE
March 1990
193
Table 2. Evolution of the clinical and echocardiographic data after 1 year of treatment with I-carnitine and long-chain fatty-acid-free diet Echocardiogram Cardiac symptoms (NYHA)* Case 11-2 11-4 11-5
VSIPWt
"a" index
EF slope
PVIiTVI*
SAM5
MSAN I(
Pie
Aft
Pre
Aft
Pre
Aft.
Pre
Aft.
Pre
Aft.
Pre
Aft.
Pre
Aft.
2 2 4
1 1 1
1.7 1.8 1.7
1.5 1.5 1
99% 80% 80%
72%
8 20 40
8 70 94
I
I
-
No
~~~~~
'New York Heart Association guidelines tVentricular septumlpostenor wall #Protodiastolic velocity integralltelediastolic velocity integral in the mitral valve flow JSystolic anterior motion (1 Mydsystolic aortic valve notching
ventricular walls and septum and loss of the ability of the heart to expand. Involvement of subjects of both sexes in successive generations suggests an autosomal dominant trait.' Morphological studies of cardiac muscle showed fiber d i ~ a r r a y .How~ ever, no specific changes have been found in skeletal muscle.' Involvement of the heart has been reported in many patients suffering from carnitine deficiency myopathy ," -" but only three reports had familial incidence and systemic carnitine The family described by Tripp et al.' had endocardial fibroelastosis, early onset, and high rate of perinatal death. Waber et a1.I' described two cases: one had congestive heart failure of early onset and later developed muscle weakness; the other child died at 23 months with cardiomegaly.
The siblings with HCM described by Matsuishi et al." showed muscle weakness at 3 years of age. Our patients differ from those previously reported in several ways. The cardiopathy characteristically started late and was the only clinical manifestation; there was muscle carnitine deficiency and autosomal dominant mode of transmission. T h e favorable response to carnitine supplement suggests that carnitine deficiency was the common factor for both the myopathy and the HCM. On the basis of our results, we recommend that muscle biopsies and carnitine levels be considered in patients with cardiomyopathy, both when the disease appears in early infancyg and when it starts in adult life and irrespective of whether or not it is accompanied by muscle weakness.
REFERENCES 1. Maron BJ, Bonow RO, Cannon RO, Leon MB, Epstein SE: Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy (first of two parts). N Engl J Med 1987;316:780-789. 2. Smith ER, Heffernan LP, Sangalang VE, Vaughan LM, Flemington S: Voluntary muscle involvement in hypertrophic cardiomyopathy. A study of eleven patients. Ann Intern Med 1976;85:566-572. 3. Dubowitz V: Muscle Bzopsy: A Practtcal Approach, 2nd ed. London, Balliere Tindall, 1985, pp 19-40, 82-94. 4. McGarry JD, Foster DW: An improved and simplified radioisotopic assay for the determination of free and sterified carnitine. J Lzpzd Res 1976;17:227-228. 5. Van Der Eel-Kahn J: Muscle fiber disarray in common heart diseases. Am J Cardtol 1977;40:355-364. 6. Vandyke DH, Griggs RC, Markesbery W, DiMauro S: Hereditary carnitine-aeficiency of muscle. Neurology 1975; 251154- 159. 7. Cornelio F, DiDonato S, Peluchetti D, Bizzi A, Bertagnolio
194
Hypertrophic Myopathy
B, DAngelo A, Wiesmann U : Fatal cases of lipid storage myopathy with carnitine deficiency.J Neurol Neurosurg Psychiatry 1977;40:170- 178. 8. Hart ZH, Chang CH, DiMauro S, Farroki Q, Ayyar R: Muscle carnitine deficiency and fatal cardiomyopathy. Neurology 1978;28:147- 151. 9. Tripp ME, Katcher ML, Peters HA, Gilbert EF, Arya S, Hodach RJ, Shug AL: Systemic carnitine deficiency presenting as familial endocardia] fibroelastosis. A treatable cardiomyopathy. N EnglJ Med 1981;305:385-390. 10. Wdber LJ, Valle D, Neil1 C , DiMauro S, Shug A: Carnitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport. J Pediatr 1982;10 1 :700705. 11. Matsuishi T, Hirata K, Terasawa K, Kato H, Yoshino M, Ohtaki E, Hirose F: Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy. Neuropediatrics 1985;16:6- 12.
MUSCLE & NERVE
March 1990
