Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease

Limongelli, Giuseppe; Esteban, Maria Teresa Tome; Dejthevaporn, Charungthai; Rahman, Shamima; Hanna, Michael G.; Elliott, Perry

doi:10.1093/eurjhf/hfp186

Cited by 120 publications

(83 citation statements)

References 27 publications

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“…OXPHOS dysfunction was first identified in neuromuscular disorders but symptoms can potentially affect any organ, with any age of onset and any mode of inheritance (2). The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3,4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5,6).…”

mentioning

confidence: 99%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6 gt/gt mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6 gt/gt mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6 gt/gt mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6 gt/gt hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6 gt/gt mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6 gt/gt isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches. mouse model | mitochondrial diseases M itochondria generate the majority of energy required for cellular function and survival. Defects in mitochondrial oxidative phosphorylation (OXPHOS) cause a wide range of diseases, collectively affecting ∼1/5,000 births (1). OXPHOS dysfunction was first identified in neuromuscular disorders but symptoms can potentially affect any organ, with any age of onset and any mode of inheritance (2). The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3, 4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5, 6). As identified by Cochrane review, "there is currently no clear evidence supporting the use of any intervention in OXPHOS disorders" (7). Thus, there is an urgent need for suitable animal models to study pathogenic mechanisms and novel therapeutic approaches. Such models can also shed light on the wide range of common, complex diseases to which mitochondrial dysfunction contributes (8).Despite the high prevalence of OXPHOS disorders, relatively few genetic models have been...

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mentioning

confidence: 99%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…1 We read their letter with great interest. We agree that in patients with respiratory chain disease (RCD), exercise limitation represents a complex interaction of cardiovascular, respiratory, and neuromuscular mechanisms.…”

Section: Josef Finsterermentioning

confidence: 98%

Cardiac manifestations of mitochondrial disorders

Finsterer

Stöllberger

2010

European J of Heart Fail

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“…Although none had DCM initially, progression to impaired systolic function was seen during the follow-up period. 81 Mutations in the nuclear protein SCO2 are the most commonly described cause of mitochondrial cardiomyopathy in infants.…”

Section: Mitochondrial Diseasementioning

confidence: 99%

Genetic Cardiomyopathies Causing Heart Failure

Cahill

Ashrafian

Watkins

2013

Circulation Research

152

117

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Despite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high. There is increasing evidence that the risk and course of HF depend on genetic predisposition; however, the genetic contribution to HF is heterogeneous and complex. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation. (Circ Res. 2013;113:660-675.)

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Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease

Cited by 120 publications

References 27 publications

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Cardiac manifestations of mitochondrial disorders

Genetic Cardiomyopathies Causing Heart Failure

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