title: Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features.
abstract: Isolated hypertrophic cardiomyopathy may represent the sole clinical feature of a mitochondrial disorder in adult patients. The clinical outcome is characterized by a rapid progression to dilation and failure. A mitochondrial etiology in these cases is not obvious at clinical investigation and may represent an unexpected finding at autopsy or after cardiac transplant. We describe the morphologic, biochemical, and molecular features of hearts from 3 transplanted patients with isolated mitochondrial cardiomyopathy caused by homoplasmic mutations in the MTTI gene, coding for mitochondrial isoleucine tRNA (mt-tRNA(Ile)). On gross examination, the 3 hearts showed a symmetric pattern of hypertrophy. At histology, cardiomyocytes were hypertrophic and showed sarcoplasmic vacuoles filled with granules that stain with antimitochondrial antibodies. On frozen sections, the combined cytochrome c oxidase (COX)/succinate dehydrogenase stain showed a large prevalence of COX-deficient cardiomyocytes. Mitochondrially encoded COX subunit I was almost absent on immunohistochemistry, whereas the nuclear-encoded COX subunit IV was normally expressed. Ultrastructural analysis confirmed the marked mitochondrial proliferation. Biochemical studies of cardiac homogenates revealed a combined respiratory chain defect. Quantitative restriction fragment length polymorphism analysis of DNA from cardiac homogenate confirmed that the mt-tRNA mutations were also detected in the patient's blood. High-resolution Northern blot analysis showed a marked decrease in the steady-state level of mt-tRNA(Ile), confirming pathogenicity. In conclusion, pathologists play a major role in unraveling the mitochondrial etiology of isolated hypertrophic cardiomyopathies, provided that a detailed diagnostic flowchart is followed. Once the mitochondrial etiology is clearly defined, molecular analyses on the heart are an invaluable tool to assign mutation pathogenicity.
authors: Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
authors: Carla
authors: C
authors: Giordano
authors: Elena
authors: E
authors: Perli
authors: Maurizia
authors: M
authors: Orlandi
authors: Annalinda
authors: A
authors: Pisano
authors: Helen A
authors: HA
authors: Tuppen
authors: Langping
authors: L
authors: He
authors: Rocco
authors: R
authors: Ierinò
authors: Luciano
authors: L
authors: Petruzziello
authors: Amedeo
authors: A
authors: Terzi
authors: Camillo
authors: C
authors: Autore
authors: Vincenzo
authors: V
authors: Petrozza
authors: Pietro
authors: P
authors: Gallo
authors: Robert W
authors: RW
authors: Taylor
authors: Giulia
authors: G
authors: d'Amati
mesh_terms: D000293:Adolescent; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002648:Child; D016027:Heart Transplantation / Q000473:pathology; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D012313:RNA; D000077278:RNA, Mitochondrial; D012355:RNA, Transfer, Ile / Q000235:genetics*; D014617:Vacuoles / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D000077278:RNA, Mitochondrial; D012355:RNA, Transfer, Ile; D012313:RNA