Cardio-Genetic Basis of Sudden Infant Death Syndrome occurring in Temporal Association with Vaccination

Sudden and unexpected death of an infant that remains unexplained after a
thorough investigation of the circumstances, family history, a pediatric
examination and a full autopsy is termed sudden infant death syndrome (SIDS).
The etiology of SIDS is thought to be multifactorial and it is a diagnosis of
exclusion. Cardiac sodium channel (SCN5A) mutations or channelopathies have
been unravelled as an important cause of SIDS, underlying at least 10-15% of
SIDS cases. Brugada Syndrome and Congenital Long QT Syndrome type 3, the
classical disease manifestations of SCN5A mutations, can both be lethal
conditions. The alteration of the delicate balance between inward and outward
ionic currents across the cardiac cell membrane caused by these mutations are
responsible for the potentially fatal ventricular arrhythmias in affected
patients, especially during fever. Though uncommon in the pediatric population,
affected children may present with life-threatening events.

Infant immunization is one of the most remarkable achievements of modern day
medicine in terms of eradicating or drastically reducing mortality and
morbidity due to serious childhood infections. However, there have been several
reports of deaths following vaccination in apparently healthy infants, which
were diagnosed as SIDS. Our recent experience of sudden cardiac death in a 3
month old male and the occurrence of ventricular arrhythmias in a 4 month old
female, both within 48 hours of receiving vaccination, and the subsequent
diagnosis of SCN5A mutations in the patients and their siblings has triggered
the idea for this study. We believe that there could be more to sudden deaths
following vaccination than just SIDS, especially in vulnerable infants with
undiagnosed sodium (SCN5A) channel mutations, particularly because fever has
already been established as an arrhythmia-trigger in affected infants and it
also happens to be the commonest side-effect of vaccination. The key to
unravelling this association is by performing genetic testing of SIDS cases to
look specifically for SCN5A mutations in cases where death was temporally
associated with vaccination. In genetically confirmed subjects,
family-screening will be carried out with clinical evaluation of all members
followed by genetic counselling and predictive testing (if warranted) to
identify the affected individuals. Adequate prophylactic measures such as
aggressive antipyretics and hospitalisation and monitoring during vaccinations
and fever episodes will be undertaken to prevent further mortality among
siblings of the sudden death victim. As we strongly believe in the benefits of
immunization to the individual and the community, we are convinced that this
study will not only clarify some myths about vaccine-related deaths in infants
thought to be *healthy* but will also pave the way for parental education and
counselling regarding the underlying genetic condition and the prevention of
sudden death due to vaccination and fever related ventricular arrhythmias

The objective of this study is to determine the frequency of previously
undiagnosed SCN5A mutations leading to sudden death in temporal association
with vaccination in The Netherlands.

The study is designed as a cohort study. Study subjects will be drawn from the
SIDS registry maintained by the Landelijke Werkgroep Wiegendood (LWW) in The
Netherlands. Previously documented data on gender, age at death, occurrence of
acute life-threatening events prior to death and any history of SIDS or sudden
unexplained young deaths among family members will be retrieved. Genetic
testing will be performed for SCN5A mutations using the stored neonatal
heel-prick blood sample/stored DNA/stored tissue of each subject. In the event
that stored material of a subject is unavailable or is unable to be used for
genetic testing, both parents of the subject will be clinically evaluated and
genetically tested for the presence of SCN5A mutations.

The study is estimated to take 3-6 months to complete. The LWW will provide the
requisite data on the study subjects followed by which the genetic testing will
be carried out at the Department of Clinical Genetics in AMC, Amsterdam.

The benefits of the study will be the identification of an underlying genetic
cause for SIDS in the deceased victims or their parents which will enable
subsequent family-screening and thereby prevention of sudden death of surviving
relatives including the parents and siblings. Appropriate genetic counselling
and follow-up care will be provided to the affected families at the Department
of Clinical Genetics in the AMC with an aim to prevent potentially
life-threatening arrhythmias. The benefits of the study far outweigh the risk
of the possible implications on insurance that the results of the study might
have. SIDS cases alone can serve as the study group due to the nature of the
study analysing the frequency of SCN5A mutations in sudden death cases in
temporal association with vaccination.