Table 1.
Genetic and Clinical Findings in Individuals with PPA2 Variants
| ID | Sex (M/F) | PPA2 Variants: cDNA (NM_176869.2), Protein (NP_789845.1) | OXPHOS Activities (Normal Ranges in Brackets) |
Clinical Features |
Other Findings | ||
|---|---|---|---|---|---|---|---|
| AO | Age at Death | Cardiac Phenotype | |||||
| F1, II:1, P1 | M | c.[514G>A];[683C>T], p.[Glu172Lys];[Pro228Leu] | ND | 4 years | 15 years | autopsy: slight dilation of both ventricles; small pale area in the epicardium of the left ventricle, evidence of focal inflammation with neutrophils, lymphocytes, and eosinophils | sensitive to small amounts of alcohol |
| F1, II:2, P2 | M | c.[514G>A];[683C>T], p.[Glu172Lys];[Pro228Leu] | ND | 14 years | alive at 38 years | cardiac MRI: myocardial fibrosis; received implantable defibrillator | sensitive to small amounts of alcohol |
| F1, II:3, P3 | M | c.[514G>A];[683C>T], p.[Glu172Lys];[Pro228Leu] | ND | 10 years | 20 years | autopsy: dilation of the left ventricle, circumferential lamina of scarring in midmyocardium with focal subendocardial involvement; very widespread mostly mature scarring of midmyocardium in all sectors | sensitive to small amounts of alcohol |
| F1, II:4, P4 | F | c.[514G>A];[683C>T], p.[Glu172Lys];[Pro228Leu] | normal in skeletal muscle | 9 years | alive at 33 years | cardiac MRI: myocardial fibrosis; received implantable defibrillator. | sensitive to small amounts of alcohol; immunohistochemical studies of skeletal muscle showed changes suggestive of a mild chronic myopathy |
| F2, II:, P5 | M | c.[500C>T];[500C>T], p.[Pro167Leu];[Pro167Leu] | ND | 10 days | 11 days | autopsy: herds of fresh necrosis mainly of the right heart and interstitial lymphocyte infiltration; electron microscopy: myocard showed mitochondria with degeneration of cristae | elevated plasma lactate levels; tachypnoea and tachycardia; tonic-clonic seizures; death after severe bradycardia |
| F2, II:2, P6 | F | c.[500C>T];[500C>T], p.[Pro167Leu];[Pro167Leu] | normal in skeletal muscle and fibroblasts | 14 days | 14 days | autopsy: acute and subacute necrosis more pronounced in the right heart more severe than in the left heart; electron microscopy: myocardium showed mitochondria with degeneration of cristae like in P5 | metabolic acidosis with elevated plasma lactate levels; tachypneoa; vomiting, generalized seizure; cardio-respiratory decompensation; death 6.5 hr after onset of symptoms; multiple subacute necroses in the semioval center of both cerebral hemispheres |
| F2, II:3, P7 | M | c.[500C>T];[500C>T], p.[Pro167Leu];[Pro167Leu] | normal in skeletal muscle and fibroblasts; heart muscle: LV: CI 4.1 (5.5–51.5) and CIV 64 (73.2–516.6) decreased, RV: CI not detectable, CII 9.0 (25.8–40.7), CIV 42 (73.2-516.6) | 3 days | 32 days | cardiac tachyarrhythmia; ECG showed hypodynamic right ventricle; autopsy: myocardium without necrosis and inflammatory infiltrations; myocytes with reduced amount of myofibrils; region of fibrosis, partially fat tissue in the right heart | elevated plasma lactate, transaminases, lactate dehydrogenase, creatine kinase (CK), CK-MB, and troponin levels |
| F3, II:1, P8 | F | c.[500C>T];[500C>T], p.[Pro167Leu];[Pro167Leu] | ND | 5.5 months | 5.5 months | autopsy: evidence for long-standing myocyte loss, increased interstitial myocyte loss, increased interstitial collagen, focal myocyte fiber disarray in the left ventricle and interventricular septum | 24 hr history of vomiting and diarrhea, 1× seizures; multiple cardiac arrests; hypoxic injury of the brain; the liver showed mild fatty change |
| F3, II:3, P9 | F | c.[500C>T];[500C>T], p.[Pro167Leu];[Pro167Leu] | normal in skeletal muscle | 8 months | 11 months | autopsy: extensive fibrosis of the heart muscle | plasma lactate elevated, diarrhea, vomiting; focal seizure then generalized seizure; cardiac arrest |
| F4, II:1, P10 | M | c.[380G>T];[514G>A], p.[Arg127Leu];[Glu172Lys] | normal in skeletal muscle; CI decreased heart muscle 0.026 (0.125 ± 0.048) | 10 months | 2 years | echocardiography: ejection fraction of 74%, mild left ventricular hypertrophy; autopsy: extensive transmural fibrosis of the left ventricle, acute myocardial ischemia | seizures, urinary organic acids: increased 3-hydroxybutyrate, acetoacetate, and C14:1, C14, C16:1 acylcarnitine elevation in blood. |
Abbreviations are as follows: AO, age at onset; F, female; M, male; ND, not determined.