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CLINICAL STUDIES

Maternally inherited cardiomyopathy: clinical and molecular characterization of a large kindred harboring the A4300G point mutation in mitochondrial deoxyribonucleic acid

Carlo Casali, MD, PhD^*, Giulia d’Amati, MD, PhD, Paola Bernucci, MD, PhD, Luciano DeBiase, MD, Camillo Autore, MD, Filippo M. Santorelli, MD^*, Domenico Coviello, PhD^|| and Pietro Gallo, MD

^* Istituto di Clinica delle Malattie Nervose e Mentali, Università di Roma–La Sapienza, Rome, Italy
Dipartimento di Medicina Sperimentale e Patologia, Università di Roma–La Sapienza, Rome, Italy
Istituto di Chirurgia del Cuore e dei Grossi Vasi–Cardiologia 2, Università di Roma–La Sapienza, Rome, Italy
Dipartimento di Scienze Cardiovascolari e Respiratorie, Università di Roma–La Sapienza, Rome, Italy
^|| Istituto di Biologia e Genetica, Università di Genova, Genoa, Italy

Reprint requests and correspondence: Carlo Casali, MD, PhD, Istituto di Clinica delle Malattie Nervose e Mentali, Università di Roma–La Sapienza, Viale dell’Università 30, 00186 Rome, Italy
Casali{at}uniroma1.it

OBJECTIVES

The purpose of this study was to describe the clinical and molecular features of a large family with maternally inherited cardiomyopathy (MICM).

BACKGROUND

Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point mutations have been associated with MICM. However, the distinctive clinical and morphologic features of MICM are not fully appreciated. This is partially due to the small size of the reported pedigrees, often lacking detailed clinical and laboratory information.

METHODS

Clinical and genetic analysis of the family was carried out.

RESULTS

Echocardiography showed mostly symmetrical hypertrophic cardiomyopathy in 10 family members. The illness had an unfavorable course. Progressive heart failure occurred in three subjects, who eventually died; one individual underwent heart transplantation. Electrocardiographic or echocardiographic signs of cardiac hypertrophy in the absence of significant clinical complaints were observed in five subjects. Neurologic examination was normal. The mutation was detected in blood from all available subjects. Abundance of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The severity of the disease could not be foreseen by the proportion of mutation in blood.

CONCLUSIONS

This report contributes a better description of the clinical aspects of MICM and provides important clues to distinguish it from hypertrophic cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer ribonucleic acid for isoleucin, should be systematically searched in patients with MICM. The identification of an underlying maternally inherited mitochondrial DNA defect in familial cases of cardiomyopathy may considerably influence the management and genetic counseling of affected patients.

Abbreviations and Acronyms   HCM = hypertrophic cardiomyopathy   MICM = maternally inherited cardiomyopathy   mtDNA = mitochondrial deoxyribonucleic acid   PCR = polymerase chain reaction   tRNAIIe = transfer ribonucleic acid for isoleucin

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