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(Circulation. 1995;91:955-961.)
© 1995 American Heart Association, Inc.

Articles

Cardiac Involvement in Mitochondrial Diseases

A Study on 17 Patients With Documented Mitochondrial DNA Defects

Ryuichiro Anan, MD; Masanori Nakagawa, MD; Masaaki Miyata, MD; Itsuro Higuchi, MD; Shoichiro Nakao, MD; Masahito Suehara, MD; Mitsuhiro Osame, MD; Hiromitsu Tanaka, MD

From the First (R.A., M.M., S.N., H.T.) and Third (M.N., I.H., M.S., M.O.) Departments of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.

Correspondence to Hiromitsu Tanaka, MD, First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890, Japan.

	Abstract

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Background Mutations of mitochondrial DNA have been demonstrated as causes of human mitochondrial diseases. While these disorders typically involve multiple organs, the effect of mitochondrial mutations on the heart has not been systematically studied.

Methods and Results We studied mitochondrial mutations and cardiac changes in 17 patients with Kearns-Sayre syndrome; ocular myopathy; myoclonus epilepsy with ragged red fibers (MERRF); and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Cardiac involvement was evaluated by chest radiograph, ECG, His-bundle electrogram, and echocardiogram. All 3 patients with Kearns-Sayre syndrome had large deletions of mitochondrial DNA and disturbances in cardiac conduction. ECG abnormalities were found in 2 of 6 patients with ocular myopathy who showed large deletions of mitochondrial DNA. All 3 patients with MERRF had an A-to-G mutation at nucleotide position 8344; 2 had cardiomegaly, asymmetrical septal hypertrophy, and diffuse hypokinesis of the left ventricle. One patient with asymmetrical septal hypertrophy developed dilated cardiomyopathy 2 years later. All 5 patients with MELAS had an A-to-G mutation at nucleotide position 3243, and 2 had symmetrical left ventricular hypertrophy with or without abnormal wall motion.

Conclusions The clinical features of cardiac involvement in mitochondrial diseases vary in the different subgroups of these disorders. Particular mitochondrial mutations can cause characteristic cardiac abnormalities.

Key Words: genetics • hypertrophy • myocardium • heart block • mitochondria

	Introduction

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Mitochondrial diseases are a heterogeneous group of disorders in which a primary mitochondrial dysfunction is proven by morphological, biochemical, and genetic examinations.¹ Several clinically distinct subgroups exist,² including Kearns-Sayre syndrome; myoclonus epilepsy with ragged-red fibers (MERRF)³ ; and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS).⁴ Recent studies have demonstrated that deletions and point mutations in the mitochondrial genome can cause these disorders. Most of patients with Kearns-Sayre syndrome had large deletions of the mitochondrial genome,⁵ whereas mutations in the mitochondrial tRNA^Lys gene or tRNA^Leu gene account for MERRF^{6 7} or MELAS,^{8 9 10} respectively.

Cardiac conduction disturbance has been recognized in the Kearns-Sayre syndrome,¹¹ which is characterized as progressive external ophthalmoplegia and retinopathy. To clarify the characteristic clinical features of cardiac involvement and the effect of mitochondrial mutations on the heart in patients with mitochondrial diseases, we clinically evaluated cardiac structure and function in patients with mitochondrial diseases.

	Methods

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Clinical Evaluations
All patients gave informed consent for participation in the study. Patients were evaluated generally, neurologically, and cardiologically. A family survey was made clinically in all patients.

Standard 12-lead ECGs were obtained in all patients and interpreted according to standard criteria.¹² Chest radiographs were obtained in all patients and also interpreted according to standard criteria.¹³ Cardiomegaly was diagnosed when the cardiothoracic ratio exceeded 0.55. Congestion was diagnosed when obvious abnormality of the vascular shadow was present.¹⁴

Echocardiography was performed in 13 patients with Toshiba SSH-60A, 65A, or 160A. Measurements of chamber and wall thickness were obtained at the mitral valve level on cross-sectional guided M-mode echocardiograms and reviewed according to established criteria for the patient's age and body surface area.¹⁵ Left ventricular fractional shortening was also calculated as the shortening of the ventricular end-diastolic diameter, and hypokinesis was defined as fractional shortening <0.26.¹⁶ Left ventricular wall motion was also evaluated with visual interpretation.¹⁷ Regurgitation of valves was estimated with pulsed or color Doppler echocardiography and graded as mild, moderate, or severe according to standard criteria.^{18 19 20} Mitral valve prolapse was diagnosed according to standard criteria.²¹ Asymmetrical septal hypertrophy was diagnosed when the ratio of thickness of the septum to the free wall exceeded 1.3.²²

Intracardiac electrophysiological studies were performed in 2 patients. His-bundle recordings were performed according to standard methods.²³ Measurements were interpreted according to standard criteria, and the His-ventricular (HV) interval was defined as abnormal when it exceeded 55 milliseconds.²³

Skeletal muscle biopsy was performed in all patients. Frozen thin sections of the biceps brachii or quadriceps femoris were studied with hematoxylin-eosin stain, Gomori-trichrome stain,²⁴ and cytochrome c oxidase activity.

Genetic Analysis
DNA was isolated from 50 mg of frozen biopsied skeletal muscle in all patients as described.⁵ Southern blotting was performed to detect deletions with total mitochondrial DNA isolated from human liver mitochondria as a probe.^{5 25} DNA (5 µg) was linearized by digestion with a battery of restriction enzymes: Pvu II, Xba I, HindIII, BamHI, and EcoRI. The digested DNAs were electrophoresed on a 0.8% agarose gel and transferred to nylon membranes. The nylon membranes were hybridized with [-³²P]-ATP-labeled whole mitochondrial DNA. The deleted mitochondrial DNAs were mapped by analysis for the absence of known restriction sites in the mitochondrial DNA. After the deletion site was mapped, the DNA fragment encompassing the deletion junction was amplified by polymerase chain reaction (PCR).

DNA samples were assayed for a transition of A to G at nucleotide position 3243 by the methods of Kobayashi et al,⁹ a transition of A to G at nucleotide position 8344 by the method of Yoneda et al,⁷ a transition of T to C at nucleotide position 3271 by the method of Goto et al,¹⁰ a transition of T to C at nucleotide position 3250 by the method of Goto et al,²⁶ and a transition of A to G at nucleotide position 3260 by the method of Zeviani et al.²⁷ Mothers of two patients with MERRF were also studied.

The proportion of deleted mitochondrial DNA was estimated from densitometric scanning (Ultra Scan XL, Pharmacia) of the autoradiogram after correction by molecular weight. The amount of mutant DNA in MERRF and MELAS was expressed as the percentage of Apa I or Nae I cleaved material to total PCR product. Patient 1 was reported elsewhere.²⁸

	Results

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Clinical Results
Seventeen unrelated patients with mitochondrial diseases were studied (Table 1). The 11 men and 6 women ranged in age from 12 to 54 (mean, 31) years. Diagnoses of particular mitochondrial disease subtypes were based on typical clinical features and the presence of ragged- red fibers on skeletal muscle biopsy specimen.^{1 4}

View this table: [in this window] [in a new window]   Table 1. Results of Cardiac and Genetic Analyses in Patients With Mitochondrial Diseases

Two patients had typical features of Kearns-Sayre syndrome: onset before age 20; progressive external ophthalmoplegia; pigmentary retinopathy; and/or complete heart block, cerebrospinal fluid protein levels above 1 g/L, and cerebellar syndrome. One patient was diagnosed as probably having Kearns-Sayre syndrome because disease signs and symptoms began at the age of 33 years.² Six patients had ocular myopathy, often accompanied by proximal limb weakness. No patients with Kearns-Sayre syndrome or ocular myopathy had a relative with any of these manifestations.

Three patients diagnosed with MERRF showed myoclonus, ataxia, epilepsy, and ragged-red fibers. None of the mothers had symptoms that suggested mitochondrial encephalomyopathy. Five patients with MELAS had mitochondrial encephalomyopathy, lactic acidosis, strokelike episodes, intermittent vomiting, proximal limb weakness, and ragged-red fibers. The mother of patient 15 had severe sensory neural hearing impairment, but four other mothers had no clinical symptoms of mitochondrial encephalomyopathy.

To determine whether these mitochondrial diseases have associated cardiac abnormalities, each patient was evaluated by ECG, chest radiograph, and echocardiogram. In addition, two patients underwent electrophysiological studies (see "Methods").

Cardiac Involvement
Table 1 illustrates the results of cardiac analyses. Table 2 illustrates the abnormal results of echocardiograms in patients with MERRF and MELAS.

View this table: [in this window] [in a new window]   Table 2. Abnormal Results of Echocardiography in Patients With MERRF and MELAS

Kearns-Sayre Syndrome
The cardiothoracic ratio was normal in all patients. Echocardiography revealed prolapse of the anterior mitral leaflet without mitral regurgitation in one patient. All three patients exhibited cardiac conduction disturbances, including complete AV block caused by infra-His block, complete right bundle branch block, or left anterior hemiblock with prolongation of the HV interval (Table 1). Patient 1, who had experienced a near-syncopal attack, had complete AV block on the ECG. The ECG recorded 2 years before showed complete right bundle branch block with left anterior hemiblock and Mobitz type 2 second-degree AV block. A His-bundle ECG demonstrated HV block. Long-term monitoring of his ECG demonstrated a long ventricular standstill up to 4.1 seconds. He was improved by implantation of a permanent pacemaker.

Ocular Myopathy
Two of the six patients with ocular myopathy showed ECG abnormalities, including right axis deviation in one patient and ST depression, inverted T wave, and premature ventricular beats in another patient (Table 1). Echocardiographic studies were normal in one of the two patients examined. The other patient had diffuse hypokinetic wall motion of the left ventricle.

Myoclonus Epilepsy With Ragged Red Fibers
Three patients with MERRF had normal blood pressure. Two patients had cardiac involvement (Tables 1 and 2). Patient 10 had symptoms of occasional palpitation and exertional dyspnea. ECG revealed ST depression with T-wave inversion and ventricular premature beats. Holter monitoring revealed multifocal ventricular premature beats. Cardiomegaly was observed on chest x-ray. Echocardiography showed asymmetrical septal hypertrophy with diffuse hypokinesis of the left ventricle.

Patient 11 developed progressive exertional dyspnea; 2 years later, she developed intractable congestive heart failure. Her ECG showed ST depression with T-wave inversion, abnormal Q wave, and left axis deviation. Her chest x-ray showed cardiomegaly with pulmonary congestion. Echocardiography revealed asymmetrical septal hypertrophy and dilatation of the left ventricle with diffuse hypokinetic wall motion. A repeat study obtained 2 years later showed marked dilation of the left ventricle associated with diffuse hypokinetic motion, without evidence of interventricular septum or posterior wall hypertrophy.

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes
Five patients with MELAS had normal blood pressure. Four patients had cardiac involvement (Tables 1 and 2). Patient 14 had occasional palpitations, and ventricular premature beats were observed on the ECG. Patient 15 had symmetrical hypertrophy of the left ventricle by echocardiography, cardiomegaly, and Wolff-Parkinson-White (WPW) syndrome. Patient 16's ECG showed ST depression and T-wave inversion. Patient 17 occasionally had palpitations. His ECG demonstrated occasional atrial premature beats, and echocardiogram demonstrated symmetrical hypertrophy of the left ventricle.

Genetic Results
Table 1 shows the results of genetic analysis.

Kearns-Sayre Syndrome
By Southern blot analysis, all three patients with Kearns-Sayre syndrome showed heteroplasmy of mitochondrial DNA after Pvu II digestion (Fig 1A). All patients with Kearns-Sayre syndrome had a large deletion of mitochondrial DNA (nucleotide positions 8483 to 13 483) that occurs frequently in this syndrome (Fig 2). The proportion of the deleted mitochondrial DNA to total mitochondrial DNA was between 34.2% and 60.3%.

View larger version (38K): [in this window] [in a new window]   Figure 1. Representation of techniques used to genotype patients for mutations of mitochondrial DNA. A, Kearns-Sayre syndrome and ocular myopathy: Southern blot analysis of mitochondrial DNA from a patient with Kearns-Sayre syndrome (patient 2) and a healthy individual. Heteroplasmy (normal, 16.6-kb band; deleted, 11.6-kb band) of mitochondrial DNA after Pvu II digestion is seen only in the patient with Kearns-Sayre syndrome. B, Myoclonus epilepsy with ragged-red fibers (MERRF): A 174-bp fragment of mitochondrial DNA was amplified and digested with Nae I. Mutant sequence from a patient with MERRF (patient 11) has a novel Nae I site and was cleaved into 156- and 18-bp (not visible) fragments. The patient with MERRF shows heteroplasmy with normal and mutant mitochondrial DNA. C, Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): A 399-bp fragment of mitochondrial DNA was amplified and digested with Apa I. Mutant sequence from a patient with MELAS (patient 17) has a novel Apa I site and was cleaved into 305- and 94-bp fragments. The patient with MELAS shows heteroplasmy with normal and mutant mitochondrial DNA. Pt indicates patient; cont, control; +, after digestion with indicated restriction enzyme; and -, no restriction enzyme digestion.

View larger version (11K): [in this window] [in a new window]   Figure 2. Illustration of the size and site of the deletion of mitochondrial DNA in patients with Kearns-Sayre syndrome or ocular myopathy. Top bar represents the mitochondrial genome; blanks represent the size and the site of the deletion in each patient. ND1 through ND6 indicate subunits of reduced nicotinamide adenine dinucleotide dehydrogenase complex; COI through COIII, subunits of cytochrome c oxidase; and CYTb, cytochrome b.

Ocular Myopathy
All six patients showed heteroplasmy of mitochondrial DNA by Southern blot analysis. Large deletions were detected in all patients. Two patients shared identical deletion; the deletions in the four other patients were at unique sites and of different sizes (Fig 2). The proportion of the deleted mitochondrial DNA to total mitochondrial DNA was between 30.1% and 79.4%.

Myoclonus Epilepsy With Ragged-Red Fibers
An A-to-G mutation at nucleotide position 8344 was detected in all three patients with MERRF. Fig 1B shows representative Nae I digest. Two mothers studied, both clinically normal, had the same mutation as the patients. Transition A to G at nucleotide position 3243, transitions T to C at nucleotide positions 3271 and 3250, transition A to G at nucleotide 3260, and a large deletion were not detected in any patients. The amount of mutant DNA was between 75.6% and 77.9%.

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes
A point mutation at nucleotide position 3243 (A to G) was detected in all five patients. Fig 1C shows representative Apa I digestion. Transition A to G at nucleotide position 8344, transitions T to C at nucleotide positions 3271 and 3250, transition A to G at nucleotide 3260, and a large deletion were not detected in these five patients. The amount of mutant DNA was between 53.3% and 78.3%.

	Discussion

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The human mitochondrial genome is a circular double-stranded DNA of 16.6 kbp.^{29 30} It contains genes for 2 ribosomal RNAs and 22 transfer RNAs, which are all essential for the protein synthesis inside the mitochondria and genes for 13 subunits in 4 complexes participating in mitochondrial oxidative phosphorylation. These 13 subunits include 7 subunits of NADH dehydrogenase, 1 subunit of ubiquinol-cytochrome c oxidoreductase, 3 subunits of cytochrome c oxidase, and 2 subunits of ATP synthase. The remaining subunits of these complexes are encoded by the nuclear DNA.

Mitochondrial diseases involve many but not all organ systems of the body. Differential organ involvement may be due to the heteroplasmy or to the variable proportion of mutant and wild-type DNAs in different tissues. The requirements for oxidative phosphorylation by different organs and environmental factors may also vary the threshold for phenotypic expression.^{6 31} For example, patients with spontaneous cases of Kearns-Sayre syndrome have only one type of deleted mitochondrial DNA, which implies that this disease results from a single deletion event occurring early in development.³⁰ Affected patients have the greatest ratios of mutated to normal mitochondrial DNAs in skeletal muscle, followed by heart muscle, kidney, and liver.^{31 32} The distribution of deleted mitochondrial DNAs is thought to be influenced by the time during development at which the deletion occurred and by replicative segregation.³⁰

Kearns-Sayre syndrome is characterized by the clinical triad of progressive external ophthalmoplegia, atypical pigmentary degeneration of the retina, and heart block. Using 5 cases and 30 others from the literature, Berenberg et al³³ reported that clinical manifestations of cardiac disease occur in 57% of patients with Kearns-Sayre syndrome. Symptoms included syncopal attacks, cardiac arrest, and congestive heart failure. Cardiac conduction defects are variable and include prolonged intraventricular conduction time, bundle branch blocks, and complete AV block. Heart block caused death in 20% of the patients. Pacemaker implantation was reported to improve survival.

Pathological studies^{34 35 36} have shown that abnormalities of the conduction system of patients with Kearns-Sayre syndrome typically involve the distal His bundle, bundle branches, and infranodal conductions. Enlarged, abnormally structured, excessively augmented mitochondria and loss of myofibrils have been demonstrated in skeletal and heart muscle cells from patients with Kearns-Sayre syndrome.

The patients studied here are representative of those previously reported. They had heart block below the His bundle. Patient 1 developed complete heart block associated with syncope 2 years after bifascicular block was noted and was treated successfully with a permanent pacemaker. Thus, pacemaker implantation should be considered in patients with Kearns-Sayre syndrome having second- or third-degree AV block or bifascicular block.

A deletion of mitochondrial DNA at the "hot spot"² was seen in all patients with Kearns-Sayre syndrome in this study. This deletion seems to cause cardiac conduction disturbance in patients with Kearns-Sayre syndrome. Recently, we and others demonstrated that the same deletion of mitochondrial DNA present in skeletal muscle is found in myocardial tissues.^{28 31 32 37} The proportion of deleted genome in the heart muscle from patients with Kearns-Sayre syndrome was reported to be between 15% and 40%.^{31 32} But no data are available on the proportion of mutant genome in the cardiac conduction system, which is thought to be predominantly impaired heart tissue in patients with this syndrome.

Cardiac involvement is not a general feature of ocular myopathy. McComish et al³⁸ reported that hypertrophy of the myocyte and accumulation of normal mitochondria were observed in the biopsy specimen from a patient with ocular myopathy. In our study, two of six patients had ECG or functional cardiac abnormalities. Another two patients showed a deletion at the hot spot, but they did not show abnormality on ECG. We suggest that there is a lower percentage of deleted mitochondrial DNA in the hearts of these patients.

The literature contains only brief descriptions of ECG and echocardiographic findings of individuals with MERRF,^{3 6 39} including one patient with "mild cardiomyopathy"⁶ and one with dilated cardiomyopathy.³⁹ In our study, two patients with MERRF showed asymmetrical septal hypertrophy with wall motion abnormality. One developed a dilated left ventricular cavity with nonthickened left ventricular wall 2 years later. We suggest that cardiac involvement in the MERRF syndrome is not rare and can include hypertrophic cardiomyopathy and dilated cardiomyopathy. Progression from thickened left ventricular wall to cavity enlargement with nonthickened wall can occur in patients with MERRF. Abnormal mitochondrial function or decreased contractile element resulting from accumulation of mitochondria may be a possible cause of the progressive cardiac change in this patient.

An A-to-G mutation at nucleotide position 8344 was seen in all three patients with MERRF. Therefore, this mutation seems to cause ventricular hypertrophy, including asymmetrical septal hypertrophy, and wall motion abnormality, which may develop into a dilated left ventricular cavity. In patients with MERRF, a variable percentage of mutant mitochondrial DNA in different tissues of the same patient has been reported.³⁹ In cardiac tissue, one report has identified 79% mutant mitochondrial DNA in a patient with MERRF.⁴⁰

Hypertrophic cardiomyopathy and left ventricular hypertrophy^{41 42 43 44 45 46 47} have been recognized in patients with the MELAS syndrome. Ito et al⁴¹ reviewed 21 patients with MELAS and reported that 8 patients showed left ventricular hypertrophy. Nishizawa et al⁴³ described a 16-year-old girl with MELAS and hypertrophic cardiomyopathy who died of congestive heart failure. Ultrastructure of the heart muscle showed markedly increased mitochondria. Yoneda et al⁴⁴ described a 14-year-old boy with MELAS, hypertrophic cardiomyopathy, and WPW syndrome. He died of progressive renal failure; autopsy revealed marked concentric hypertrophy of the left ventricular wall. Kobayashi et al⁴⁵ described a 14-year-old boy who had MELAS and developed episodes of chest pain. His ECG showed ST-T depression after exercise. Echocardiography revealed both hypertrophy of the left ventricular wall and dilation of the left ventricle. Nemoto et al⁴⁶ reported cardiac involvement in four patients with MELAS based on ECG and myocardial perfusion imaging abnormalities. Two patients, 10 and 13 years old, showed hypertrophy of the left ventricular wall on echocardiography. The ST-T change on ECG and ²⁰¹Tl myocardial perfusion imaging indicated myocardial ischemic changes in three patients.

Genetic analyses of mitochondrial DNA were not performed in these patients. Our study confirms the results of others, suggests that cardiac involvement frequently occurs in patients with MELAS, and extends these by identification of mitochondrial DNA mutations. An A-to-G mutation at nucleotide position 3243 was seen in all five patients with MELAS. Two patients showed symmetrical hypertrophy of the left ventricle; one also had wall motion abnormalities. Left ventricular hypertrophy is a characteristic clinical feature in the heart of patients with MELAS.

In patients with MELAS, it was reported that the percentage of mutant genomes was similar in both clinically affected and unaffected tissues. The percentage of mutant genomes in the heart was reported to be 83% in a patient with MELAS who showed severe concentric hypertrophy of the left ventricle and died of heart failure. The different threshold of vulnerability to quantitatively similar impairments of oxidative phosphorylation may explain the differential organ involvement in this disorder.⁴⁸ The variable vascular involvement in MELAS may further influence organ dysfunction.⁴⁹

We conclude that a deletion of mitochondrial DNA may produce cardiac conduction disturbances, while substitutions (the A-to-G mutation at nucleotide positions 8344 and 3243) seem to cause left ventricular hypertrophy and wall motion abnormalities.

Clinical Implications and Limitations of the Study
Mitochondrial diseases are generally called mitochondrial myopathies. Clinically, neurologists usually identify them. When neurologists see patients with mitochondrial diseases, cardiac pathologies should be considered in the evaluation of symptoms. Patients with Kearns-Sayre syndrome should be evaluated for AV conduction disturbances that may cause syncope, Adams-Stokes syndrome, and sudden death. Patients having ophthalmoplegia and retinitis should be followed carefully for heart block because heart block develops after the ophthalmoplegic abnormalities. Patients with MERRF and MELAS should be followed for symptoms associated with cardiac hypertrophy and dilated cardiomyopathy. Cardiac involvement may cause death in patients with MELAS because two patients died of congestive heart failure at the ages of 14 and 16. Patients with MERRF may develop dilated cardiomyopathy, as our patient 11 did.

On the other hand, a cardiologist seeing a patient for conduction abnormality, left ventricular hypertrophy, or a dilated cardiomyopathy should evaluate the patient for clinical and laboratory findings of Kearns-Sayre syndrome, MERRF, or MELAS. The presenting symptoms of patients with Kearns-Sayre syndrome include ptosis or ophthalmoplegia, pigmentary degeneration of the retina, cardiac conduction defects, short stature, cerebellar signs, hearing loss, mental retardation, vestibular system dysfunction, and delayed puberty. Patients with MERRF may have myoclonus, generalized convulsion, cerebellar ataxia, muscular atrophy, abnormal electroencephalogram, elevated blood lactate and pyruvate, and ragged-red fibers. Patients with MELAS may show ragged-red fibers, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. The symptoms begin between 3 years of age and adulthood.

In the present study, only one clinically affected mother was found in the family histories of patients examined. This is surprising, given that mitochondrial disorders are maternally transmitted. There are two possible explanations for our findings.^{50 51} First, the deletion or point mutations of mitochondrial DNA may be new mutations that occurred during fetal development. Alternatively, the mothers of affected patients may carry a number of defective mitochondria below the threshold number required for phenotypic expression. In fact, the mothers of two patients with MERRF showed mutant mitochondrial DNA without clinical symptoms.

Conclusions
We conclude that the clinical features of cardiac involvement vary according to the different subgroups of mitochondrial diseases. AV conduction disturbance is characteristic of and frequently seen in Kearns-Sayre syndrome. Cardiac involvement is atypical in ocular myopathy. Asymmetrical septal hypertrophy associated with wall motion abnormalities seems to be characteristic of MERRF. Progression from asymmetrical septal hypertrophy to dilated cardiomyopathy may also occur in this disorder. Symmetrical left ventricular hypertrophy with or without abnormal wall motion seems to be characteristic of MELAS. Particular abnormality in mitochondrial DNA may cause characteristic cardiac change in mitochondrial diseases.

	Acknowledgments

 
This study was supported in part by a Research Grant for Intractable Diseases from the Ministry of Health and Welfare in Japan. We are indebted to Christine E. Seidman, MD, Brigham and Women's Hospital and Harvard Medical School, for the critical review of this manuscript. We thank Shoko Taniguchi for technical assistance.

Received April 6, 1994; revision received August 8, 1994; accepted August 31, 1994.

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