Sudden unexpected nocturnal death among patients with diabetes occurs approximately ten times more commonly than in the general population. Malignant ventricular arrhythmia due to Brugada syndrome has been postulated as a cause, since a glucose-insulin bolus can unmask the Brugada electrocardiographic signature in genetically predisposed individuals. In this report we present a 16-year-old male with insulin-dependent diabetes who died suddenly at night. His diabetes had been well controlled, without significant hypoglycaemia. At autopsy, he had a full stomach and a glucose level of 7 mmol/L in vitreous humor, excluding hypoglycaemia. Genetic analysis of autopsy DNA revealed a missense mutation, c.370A>G (p.Ile124Val), in the
Sudden unexpected nocturnal death among patients with diabetes is greatly feared and poorly understood, occurring approximately ten times more commonly than in the general population [
We report the postmortem molecular genetic investigation of a 16-year-old boy with type 1 diabetes who died in his sleep. His blood glucose had been well-controlled; he had a full stomach at autopsy and a glucose level in vitreous humor of 7 mmol/L. These features argue strongly against hypoglycaemia. Molecular genetic investigation revealed a missense mutation (p.Ile124Val) in the
The boy was diagnosed as having type 1 diabetes at the age of 15 years (nine months prior to his death) presenting with mild diabetic ketoacidosis following a nine-month history of polydipsia and polyuria. He was managed with insulin and at the time of his death was receiving four injections per day: insulin aspart three times daily (approximately 12 units at meals, varied by carbohydrate load and prevailing blood sugar level) and insulin glargine 30 units at bed time. Three months prior to his death, his HbA1c level was 7.3% (56 mmol/mL). He was fully compliant with therapy and home glucose monitoring, and he remained physically active and fit. Review of his monitoring book and history revealed no episodes of severe hypoglycaemia or obvious nocturnal hypoglycaemia. On the evening prior to his death he had been completely well, had a normal full meal, had his insulin, and went to bed as usual at approximately 9:30 p.m. He was found dead the following morning lying face down on his bed and could not be resuscitated. He had no previous history of syncope or seizure and never had cause to have any cardiac tests during his life.
At autopsy, there were no pathological findings to indicate a cause of death. Cardiac and cerebral examinations were normal. Significantly, however, he had a full stomach, suggesting that he died soon after his meal. A standard toxicology screen was negative. The glucose level in his vitreous humor excluded hypoglycaemia at 7 mmol/L (126 mg/dL) [
The coding regions for those genes linked to Long QT syndrome types 1, 2, 3, 5, 6, and 7 were amplified and subjected to capillary-based sequencing, as described earlier [
Sequence analysis of proband. Sequence electropherograms show the presence of the c.370A>G, p.Ile124Val (p.I124V), mutation in exon 4 of the
There was no known history of sudden death in the family. Both parents and his only sibling were investigated. 12 lead ECGs were normal in the mother and sibling. Exercise testing and cardiac magnetic resonance imaging were normal in the mother. The father’s ECG showed subtly abnormal repolarisation with a marginally prolonged QT interval; the heart-rate corrected QT interval (QTc) was 0.46 seconds (on no medication) (Figure
12-lead electrocardiagram of the deceased’s father. The ST-T segment is unusual and very flat in lead II, such that determining the end of the T wave is difficult. In lead I, R-R is 690 ms, QT is 396 ms, and QTc is 477 ms. In lead V5, R-R is 711 ms, QT s 391 ms, and QTc is 464 ms; the T wave is of low amplitude with a slight double bump morphology.
After genetic counselling, DNA was obtained from the father, mother and sister and these were tested for the presence of the mutation c.370A>G, p.Ile124Val, in the
This case suggests a cause of death in a patient with diabetes who died in bed with a negative autopsy. It demonstrates a possible link between dead-in-bed syndrome and Brugada syndrome, thereby supporting earlier work [
Cardiac ion channelopathies explain 20 to 40% of autopsy negative sudden death in 1–40-year-olds [
Death during sleep, most commonly in young males, is typical in Brugada syndrome and Long QT type 3, both of which are caused by dysfunction of the cardiac sodium ion channel Nav1.5 [
In Brugada syndrome a diagnostic cardiac depolarization abnormality is seen on the 12-lead ECG with right-bundle branch block appearance in V1 and V2 associated with ST elevation [
There is some conflicting evidence regarding the pathogenicity of the mutation reported here. I124V was initially discovered in a 5-week-old infant who died suddenly and had a negative postmortem examination [
Protein prediction programmes | Splice site prediction programmes | ||||||||
---|---|---|---|---|---|---|---|---|---|
PolyPhen-2a,** | Mutation |
Mutation |
I-MUTANT 3.0d | MutPrede | SNPs and GOf | SIFTg | SNAPh | ASSPi |
HSFl |
Benign |
Disease-causing |
Neutral | Neutral |
Deleterious |
Neutral |
Tolerated |
Neutral |
No effect | SRp55 site created |
It is interesting that the father, who carries the same mutation, had a negative ajmaline challenge. Ajmaline is a cardiac sodium channel blocker, and 75–80% of Brugada syndrome mutation carriers can be unmasked by it [
Supportive evidence for a link between the diabetic dead-in-bed syndrome and cardiac sodium channel dysfunction comes from a recent report from an adult male with diabetes [
A large meal also unmasks the Brugada sign in genetically predisposed individuals. Ikeda et al. [
Another group has looked for genetic abnormalities in patients with diabetes who have died suddenly. Tu et al. [
The death of this 16-year-old boy presumably occurred due to a malignant ventricular arrhythmia caused by the combination of a genetic predisposition to occult cardiac Brugada syndrome and an electrolyte disturbance brought about by a full stomach and a high level of insulin. This case raises the possibility that some other young people with diabetes who have died unexpectedly at night will have done so due to a coexistent inherited arrhythmic predisposition. This might include long QT syndrome, for example, since hypoglycaemia is known to be potentially proarrhythmic in diabetes through QT interval prolongation and intracellular calcium overload [
Prevention of deaths in inherited arrhythmic syndromes is possible, but a diagnosis has first to be made. Given the proarrhythmic events explained above, which occur in patients with diabetes, an argument presents itself for obtaining a family history for young sudden death or arrhythmic syndromes, and a 12 lead ECG in every case. We suggest that good quality DNA should be retained following sudden death of a young person with diabetes, as should be standard practice for any sudden unexplained natural death in the young [
Gene encoding for connective tissue growth factor
Gene encoding for glucose-6-phosphatase
Gene glycerol-3-phosphate dehydrogenase 1-like protein
Gene encoding for paired mesoderm homeobox protein 2b
Gene encoding for sodium channel protein type 5 subunit alpha, isoform a
Sodium ion channel protein, voltage-gated, type V, alpha subunit.
All authors have no conflict of interests to disclose.
The authors are most grateful for the family’s support and permission to report this tragic case. The authors thank Dr. Tim Koelmeyer forensic pathologist (now retired) for his foresight in referring the case for investigation. A part of the genetic testing costs and Dr. Skinner’s salary were funded by Cure Kids. The sponsorship is in the form of a nondirective grant; Cure Kids had no role in study design or any other aspect of this report.