Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.

BACKGROUND: Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. OBJECTIVE: The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old. METHODS: Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years. RESULTS: Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%). CONCLUSION: Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.

Acute fatal acetaminophen overdose without liver necrosis.

Two unusual cases of suicidal overdose of acetaminophen (paracetamol) without the usual extensive centrilobular necrosis of the liver are reported. Both cases were subjected to comprehensive drug screening by immunoassay, and a combination of gas chromatography with mass spectrometry, nitrogen detection, and electron capture detection. Acetaminophen was detected in both cases. No other drugs were detected in case #1, and only a small amount of olanzapine (<0.1 mg/L) was detected in case #2. No anatomical cause of death was identified in either case. If untreated, the normal outcome of a large acetaminophen overdose would be massive hepatic necrosis with delayed death and low blood and tissue acetaminophen concentrations. In contrast, particularly high postmortem acetaminophen concentrations were measured in both our cases with little hepatic tissue damage. For case #1, femoral blood acetaminophen 1280 mg/L, vitreous 878 mg/L, and liver 729 mg/kg; in case #2, cardiac blood 1220 mg/L, vitreous 779 mg/L, liver 3260 mg/kg, and gastric 11,500 mg/500 g. Acetaminophen was measured using high performance liquid chromatography with UV detection (254 nm) using 3-hydroxyacetanilide as the internal standard. The very high concentrations of acetaminophen is these cases but relatively little hepatic damage suggests an alternative, possibly cardiac, mechanism of death.