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Catecholaminergic Polymorphic Ventricular Tachycardia Due to Ryanodine Receptor (RYR2) Gene Mutation

Presenting as Recurrent Apparent Life-Threatening Event Followed by Sudden Death

Nathanya Baez Hernandez, MD; Chetan Sharma, MD; Uzoma Okorie, MD; Elizabeth McPherson, MD


While the majority of infants with an apparent life-threatening event (ALTE) recover uneventfully, some may have underlying causes that place them at increased risk for recurrent events and sudden death.[1] Recurrent ALTEs warrant deeper evaluation with high suspicion for cardiac arrhythmias. We present a two month old infant with recurrent ALTE followed by sudden cardiac death that had essentially normal evaluation including electrocardiogram during admission for an ALTE, but postmortem genetic testing showed a rare pathogenic mutation in the RYR2 gene leading to a retrospective diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). To our knowledge, this is the first case of CPVT presenting as recurrent ALTEs at this young age.

Case Presentation

The patient presented here is a female infant born at 38 weeks to a healthy gravida 3, para 2, mother. Delivery was by Caesarean-section for intrauterine growth retardation. Birth weight was 2470 g (<10%). Apgar scores were 9/9. Family history was notable for sudden death of a sibling at 2 months, which had been attributed to pneumonia despite a normal physical examination just 24 hours prior to his death. Both parents were healthy, but a maternal half aunt had also died suddenly during infancy.

At 7 weeks of age during a minor respiratory infection, our patient presented with an episode of rapid shallow breathing followed by apnea requiring 2 minutes of home cardiopulmonary resuscitation (CPR). On admission, her examination was normal except for mild nasal congestion. Initial work up, including complete blood count, C-reactive protein, comprehensive metabolic panel, chest x-ray, EKG and urinalysis, was unremarkable. Electrocardiogram showed normal sinus rhythm and normal corrected QT interval (QTc) at 449 milliseconds. She was discharged home after 48 hours of observation, but presented again within 10 hours after discharge with a recurrence of apnea and unresponsiveness requiring brief CPR. During her second admission, she had a normal video electroencephalogram monitoring, ammonia, amino acids, and organic acids with mildly elevated lactate. Patient was discharged home with a home Apnea-Bradycardia monitor. Three days after hospital discharge, she had a third apneic episode, for which resuscitation was unsuccessful. Post-mortem genetic testing showed a pathogenic mutation Pro466Ala in the RYR2 gene.


An ALTE describes an acute, unexpected change in an infant’s breathing, appearance, or behavior that is frightening to the parent or caretaker. It is not a specific diagnosis, but rather a “chief complaint” that brings an infant to medical attention. The incidence is estimated to be 0.05 – 1% in population-based studies.[1,2]

ALTEs should not be considered a precursor to Sudden Infant Death Syndrome (SIDS) because the risk factors differ and only 7.4% of infants dying from SIDS had a previous ALTE.[3] Nevertheless, infants with a history of an ALTE are at increased risk for mortality ranging from 0.2% to 1.1%.[4,5] One study reported sudden unexpected death in 2% of ALTE survivors who had required CPR during their initial episode.[6]

There is no consensus regarding evaluation of infants following an ALTE. While the most frequently observed causes include gastroesophageal reflux, infection, and seizures, many of these diagnoses are apparent clinically and the yield for specific investigations such as esophageal pH probe, brain imaging (except when child abuse is suspected), and video electroencephalogram is low.[7] Cardiovascular disease may be a risk factor for subsequent death, but less than 50% of infants with ALTE undergo cardiac evaluation.[8] In those that do undergo cardiac evaluation, less than 5% have a cardiac disease identified, most commonly small atrial or ventricular septal defects; and only 1% has clinically significant arrhythmias that may explain the ALTE.[9,10]

In our index patient, the ALTE recurrence as well as the family history of sudden infant death in an apparently healthy sibling and maternal half aunt suggested the possibility of an underlying hereditary disorder predisposing to cardiac arrhythmia. At the time of death blood was obtained for the GeneDx Sudden Cardiac Arrest Arrhythmia Panel, which includes the following genes: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNJ2, CAV3, RYR2, and CASQ2. No abnormality was found in any of the long QT-associated genes, but a pathogenic mutation, Pro466Ala, was found in RYR2. The RYR2 gene is associated with CPVT as well as arryhthmogenic right ventricular dysplasia. The specific amino acid change Pro466Ala was previously reported in one individual with aborted cardiac arrest and a family history of multiple people with sudden cardiac death.[11]

To read the full article, please go to the July 2016 Issue of CCT.

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