City of New York
New York, NY
A 26yo Hispanic woman with a history of an "unknown cardiac problem" according to the family collapsed dead at home with no antecedent symtoms or complaints.
The sudden death of an apparently healthy young person is an unfortunately common and challenging
problem for the autopsy pathologist. This is even more challenging when the gross and microsopic
findings at autopsy are unremarkable. In this situation, molecular genetic testing is required to rule
out a group of diseases which have no findings at autopsy, the cardiac channelopathies.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
A complete autopsy revealed no overt injuries or natural disease either grossly or microscopically.
Mulitiple sections or myocradium were examined and were without pathological change. Toxicology was
positive for cocaine and ethanol.
The cause of death was signed out as acute intoxication due to the combined effects of cocaine and
alcohol. However, a year later, it was brought to our attention that the patient had had an abnormal EKG
with a prolonged QT interval. She died before she could be further worked up. Her two young children
were now being seen by a cardiologist. We performed genetic testing for long QT syndrome. It showed a
deleterious mutation KCNQ1 S277L (830 C>T), heterozygote. The cardiologist confirmed the same
disease-causing variant in the two children, both of whom are now under close clinical monitoring.
The cause of death remained acute intoxication due to the combined effects of cocaine and alcohol.
Long QT syndrome was added as a contributory factor.
This case addresses the appropriate workup of a sudden death without anatomic cause after complete
autopsy and scene investigation. Toxicology is also part of the routine workup of such a case in a
forensic seeting and here offered the initial answer. However, in this case or if the toxicology were
completely negative,further workup was warranted. In our office we do routine genetic testing for
mutations in 6 genes that cause cardiac channelopathies. This revealed a deleterious mutation in the
decedent. The second point illustarted by this case is that medical examiners routinely see cases of
sudden unexplained deaths in otherwise healthy individuals in whom cocaine use has been confirmed. These
deaths are typically ascribed to acute cocaine intoxication, although blood levels of cocaine are a
notoriously unreliable indicator of toxicity - i.e. some individuals with relatively high blood cocaine
levels survive, while other with significantly lower levels succumb. Recent advances in molecular
genetics have begun to shed light on the biological mechanisms that underlie these differences.
Mutations in several genes that maintain normal heart rhythm have been shown to be particularly
susceptible to the effects of cocaine which can function as a specific trigger interrupting normal ion
currents in the heart. The case described here, an apparent cocaine overdose subsequently determined to
be an individual with an underlying genetic mutation has led us to reconsider how such cases should be
evaluated in determining cause of death. Our routine genetic testing of cases of sudden unexplained
deaths in which there is no cocaine use reveals that approximately twenty percent of decedents have an
underlying genetic mutation in one or more cardiac ion channel genes. This is also true for sudden
infant deaths. As cocaine is a known trigger for altering cardiac function , testing sudden unexplained
deaths in otherwise healthy individuals with acute cocaine intoxication might be expected to yield
Review of the Literature/Treatment Options (if applicable):
Inherited ion channel disease sometimes explain the sudden death of a person in apparent good health.
Examples of these diseases are long QT syndrome, short QT syndrome, Brugada syndrome amd
catecholaminergic polymorphic ventricular tachycardia (CPVT). These diseases share the fact that there
are abnormalities in the proteins of the sodium and potassium ion channels of the heart or of the
receptors controlling intracellular calcium release. Long QT syndrome is characterized by a prolongation
of the QT interval (>480ms)on EKG. Several different genes have been implicated. Short QT syndrome
is characterized by a short QT interval (<340ms) and has so far been associated with potassium channel
mutations. Brugada syndrome also has characteristic changes on EKG and is caused by SCN5A mutations in
about 25% of cases. CPVT displays polymorphic tachycardias with increased heart rate. The ryanodine
receptor 2 gene and calsequestrin gene have been implicated. When such a disease is suspected at
autopsy, tissue should be saved for possible genetic testing. Tissue samples (preserved in RNAlater) and
blood cards (samples of blood that have been spotted and dried on blotting paper) can be used.
Genetic testing for the channleopathies offers important information for determination of cause of
death in cases that otherwise would be unexplained sudden deaths. It also provides valuable genetic
information for surviving family memebers. Detecting genetic susceptabilities to cocaine induced
arrythmias is also of public health importance to help dispel any notion that "recreational" cocaine use
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