Pediatric mitochondrial diseases and the heart

Abstract

Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development.

Cardiac and mitochondrial function in HIV-uninfected fetuses exposed to antiretroviral treatment

“…HIV itself is known to cause mitochondrial DNA (mtDNA) depletion as well as mitochondrial respiratory chain (MRC) disturbances in HIV patients who have never received cART [13]. Moreover, mitochondrial toxicity derived from cART has been widely described in adults, especially as it relates to nucleoside reverse transcriptase inhibitors (NRTIs), which are known to inhibit mtDNA polymerase gamma [14] promoting mitochondrial dysfunction [15] responsible for a wide range of clinical manifestations including myocardiopathy in children and adults [16,17]. During pregnancy, the mitochondrial effects of HIV infection and NRTI exposure have been scarcely assessed with conflicting results [18–20] reporting decreased [21] or increased mtDNA content [20] in HEU children with in utero cART exposure and neonatal zidovudine prophylaxis [21–25].…”

Mitochondrial disease in children

“…Barth and Sengers syndromes are described above but other causes of mitochondrial cardiomyopathy presenting in infancy are increasingly recognized, either as an isolated finding or as part of a complex multisystem disorder. These include disorders of mitochondrial translation and defects of coenzyme Q 10 biosynthesis [79]. Cardiomyopathy may be seen in some children and adults with the m.3243A>G mutation and may be a cause of sudden death in these individuals [47,80].…”

“…Nuclear gene defects appear to be a more frequent cause of mitochondrial cardiomyopathy, particularly in infancy, as recently reviewed in Ref. [79]. Cardiac conduction defects have been reported frequently in children and adults with KSS, and complete heart block may be a life‐threatening event in these individuals, indicating a need for regular screening ECGs [81].…”

Aspects of paediatric cardiovascular pathology

“…In children mutations occurring in nuclear genes involved in mitochondrial DNA replication account for over 80% of cases of mitochondrial cardiomyopathy. 10 Isolated Complex I deficiency accounts for 30% of mitochondrial disease in children. The majority of the mutations causing mitochondrial cardiomyopathy in adults are mutations in the mitochondrial DNA and are thus maternally inherited.…”