Table 1.

Summary of mitochondrial disorders with cardiac phenotypes.

Disease	Incidence Age at Onset/Death	Primary Phenotype	Cardiac Manifestations	Genetic Mutations	Treatments
MELAS	0.18/100,000   <20 years   Rapid progression to death after onset	Stroke-like symptoms Encephalopathy Lactic Acidemia Myopathy	30% of cases: HCM, DCM Conduction abnormalities (WPW)	A324G (80% of cases)	Nitric oxide precursors Citrulline supplementation Ketogenic diet Creatine, CoQ10, lipoic acid therapy
Leigh Syndrome	1/32,000–40,000   <1–2 years   Median age of death 2.4 years	Encephalopathy with cognitive and behavioral dysfunction Seizures Hypotonia/Ataxia Oculomotor dysfunction Respiratory dysfunction	20% of cases: HCM Pericardial effusions Conduction abnormalities	Mutations to SURF1 gene   G13513A (WPW and HCM)	High dose biotin Thiamine for SLC19A3 CoQ10
MERRF	0.9 or <1/100,000   10–20 years   Progression to death within 2–15 years of onset (median 8.4 years)	Myoclonus Lactic acidosis Cerebellar ataxia Muscle weakness Ragged red fibers	DCM HCM Conduction abnormalities (WPW, SVT, RBBB)	A8344G (83–90% of cases and 53% of cases with cardiac involvement)	Treatment of seizures with antiepileptic drugs
MIDD	6/100,000 (~1% of patients with diabetes)   <35 years	Diabetes (type I or II) Bilateral neurosensory hearing loss	LVH (55%) HCM (15–30%) Conduction abnormalities (WPW, SSS, Afib)	A3243G	Treatment of diabetes Cochlear implantation CoQ10
NARP	1/12,000–40,000   3-12 months	Neuropathy Ataxia Retinitis Pigmentosa Deafness Myoclonic epilepsy	DCM HCM Conduction abnormalities (WPW)	Point mutations at 8993 MT-ATP6 gene (most commonly T8993G, then T8993C)	Experimental: mitochondrially targeted obligate heterodimeric zinc finger nucleases to target mitochondrial DNA with the NARP T8993G mutation
GRACILE	1/47,000 (in Finland, may be lower worldwide)   Onset in utero   50% die within first 4 months of life, remainder die by 4 years	Growth restriction Aminoaciduria Cholestasis Iron overload Early death	Prolonged QT Reduced levels of complex III in myocardial tissues post mortem	homozygous point mutation A232G within the BCS1L gene	Symptomatic/palliative care (usually lethal in first months of life).
MNGIE	* Only 100 cases ever reported   Mean age of onset 18 years   Mean age of death 35 years	Chronic intestinal dysmotility Leukoencephalopathy Failure to thrive Ptosis Ophthalmoparesis Peripheral neuropathy	LVH Conduction abnormalities (prolonged QT, SVT, sudden cardiac death)	Loss of function mutations to thymidine phosphorylase (TP) gene, chromosome 22q13.32-qter	Allogeneic hematopoietic stem cell transplantation Platelet transfusion Hemodialysis or peritoneal dialysis Experimental gene therapies aimed to restore thymidine phosphorylase activity
Barth Syndrome	1:300,000–400,000   <1 year   Most die within first 4 years of life	DCM Skeletal myopathy (proximal) Neutropenia Growth retardation	DCM Cardiac abnormalities in utero Endocardial fibroelastosis LV noncompaction Conduction abnormalities (prolonged WT, SVT, WPW, VT)	G4.5 gene (TAZ gene) on Xq28	Treatment of heart failure Cardiac transplantation
LHON	1/31,000–50,000   2–87 years	Acute/subacute painless vision loss Dystonia Peripheral neuropathy	LV hypertrebeculation Prolonged QT WPW	90% caused by G11778A (ND4 gene), G3460A (ND1 gene), and the T14484C (NG6 gene) which all cause dysfunction in complex I	EPI-743: experimental drug targeting glutathione production Idebenone (antioxidant that can slow vision loss)
Pearson Syndrome	1/1,000,000   Presents in infancy   most deaths by 3 years of age	Transfusion-dependent anemia (presenting finding) Severe Infections Liver, Kidney, Pancreas and CNS abnormalities	Increased wall thickness Depolarization abnormalities Prolonged QT	Large deletions ranging from 4.9–14 kb	Treatment of anemia with transfusions, EPO, GCSF Treatment of pancreatic insufficiency with enzyme replacement
Kearns-Sayre Syndrome	1–3/100,000	Progressive external ophthalmoplegia (ptosis, weakness of eye muscles) Retinopathy Ataxia Elevated CSF proteins	Conduction abnormalities (AV block requiring PPM) Cardiac arrest	Large deletions ranging from 1000 to 10,000 base pairs	ECG screening PPM implantation for AV block
CPEO	1–3/100,000	Loss of motor function of the eye and eyelid Spectrum of disorders with PS and KSS	HCM Arrhythmias	Large mtDNA deletions similar to PS or KSS   AD: mutations to nuclear-encoded genes ANT1, C10orf2 and POLG	Symptomatic/supportive care
Freiderich’s Ataxia	1–47:1,000,000   Presents in childhood   Mean life expectancy 40 years	Progressive ataxia/areflexia Progressive and life-threatening cardiomyopathy (2/3 patients die from cardiovascular causes)	HCM DCM	Expansion of DNA triplet intron repeat GAA in the frataxin (FXN) gene	Idebenone (antioxidant), reduces cardiac hypertrophy

Abbreviations: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), Wolff-Parkinson-White syndrome (WPW), supraventricular tachycardia (SVT), right bundle branch block (RBBB), left ventricular hypertrophy (LVH), sick sinus syndrome (SSS), atrial fibrillation (Afib), ventricular tachyarrhythmias, permanent pacemaker (PPM), autosomal dominant (AD).