|Year : 2021 | Volume
| Issue : 1 | Page : 57-61
Unclassified sudden infant death due to congenital long QT syndrome with TRPM4 mutation
Jasleen Kaur1, Ratna Dua Puri2, Sharmila B Mukherjee1, Bijal Vyas2
1 Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India
2 Institute of Genetics and Genomics, Sir Ganga Ram Hospital and Research Institute, New Delhi, India
|Date of Submission||10-Oct-2020|
|Date of Decision||27-Oct-2020|
|Date of Acceptance||09-Dec-2020|
|Date of Web Publication||27-Feb-2021|
Dr. Sharmila B Mukherjee
Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, Bangla Sahib Marg, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
Background: Congenital long QT syndrome (cLQTS) are heritable disorders due to genetic mutations causing prolonged corrected QT (QTc) interval that may result in fatal arrhythmias. Clinical Description: A well 20-day-old, exclusively breastfed boy had an episode of unresponsiveness with no other symptoms. There was a history of four previous unexplained infantile deaths after similar complaints. General and systemic examination was normal. The differential diagnoses were neonatal apnea, seizures, and inborn errors of metabolism. Management: Sepsis, hypoglycemia, and electrolyte imbalance were ruled out. Electrocardiography (ECG), chest radiograph, and echocardiograph were normal. Ultrasonogram of the cranium ruled out structural abnormality and bleed. Electroencephalogram was normal. First-line metabolic investigations were normal. On day 28 of life, he had a recurrent episode of apnea. ECG evaluation during this episode revealed a prolonged QTc interval. Suspecting cLQTS, Trio Whole Exome Sequencing for mutations in the cLQTS susceptibility genes was performed in the proband and parents. A heterozygous variation, c.290C>T; p.Thr97Met in TRPM4 was identified in the symptomatic neonate and asymptomatic mother, suggesting autosomal dominant inheritance. The baby was started on oral propranolol, but succumbed at 8 weeks. The mother was referred for cardiac management and parents counseled about possible prenatal diagnosis in subsequent pregnancies. Conclusion: cLQTS should be suspected in neonatal apnea, when no other cause is appreciable. A normal ECG does not exclude cLQTS. If there is a strong suspicion, repeat ECGs and appropriate genetic testing should be done. Patients should be managed according to standard guidelines.
Apnea, channelopathy, corrected QT, Schwartz score
|How to cite this article:|
Kaur J, Puri RD, Mukherjee SB, Vyas B. Unclassified sudden infant death due to congenital long QT syndrome with TRPM4 mutation. Indian Pediatr Case Rep 2021;1:57-61
|How to cite this URL:|
Kaur J, Puri RD, Mukherjee SB, Vyas B. Unclassified sudden infant death due to congenital long QT syndrome with TRPM4 mutation. Indian Pediatr Case Rep [serial online] 2021 [cited 2023 Feb 3];1:57-61. Available from: http://www.ipcares.org/text.asp?2021/1/1/57/310236
Congenital long QT syndrome (cLQTS) is a group of heritable disorders with delayed myocardial ventricular repolarization resulting in prolonged corrected QT (QTc) interval; considered as suspicious if >440 ms, and definite when >450 ms (males) or >470 ms (females). These occur due to mutations in 17 LQTS susceptibility genes that encode pore-forming α-subunits and accessory subunits in ion channels. Differences from acquired LQTS include the absence of QTc prolonging structural defects, medical conditions, drugs, or electrolyte imbalances. cLQTS may lead to sudden cardiac arrest or death, primarily due to polymorphic ventricular tachycardia (torsades de pointes) that may get provoked by sudden emotional or physical stress, even sudden noise or exposure to cold.
Sudden unexpected death syndrome (SIDS) is the death of an infant less than a year old, apparently during sleep, that remains unexplained after a thorough investigation (clinical history, complete autopsy, and review of circumstances of death). Unclassified sudden infant death are deaths not meeting SIDS criteria, when natural or unnatural alternative diagnoses are equivocal, and autopsies could not be performed. Around 12% of SIDS are due to cLQTS. Other fatal arrhythmias are Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome.
We present a neonate presenting with apnea and significant history of infantile sibling deaths. His initial electrocardiography (ECG) was normal and prolonged QTc was detected only after a second episode recurred.
| Clinical Description|| |
A 20-day-old male neonate presented with the first episode of brief unresponsiveness, as described by the mother. There was no history of preceding bluish discoloration, pallor, seizures, lethargy, or refusal to feed. He had been afebrile and accepting exclusive breastfeeds well. He had been born at term in a hospital by vaginal delivery to a 30-year-old mother, with uneventful antenatal history. He had cried immediately after birth, weighed 2.6 kg, and was discharged within 24 h. The baby was the fifth born of a nonconsanguineous couple with four unaccounted for infantile deaths [Figure 1]. There was no history of any acute cardiac event or sudden death in other family members. At admission, he was hemodynamically stable with normal pulse rate, rhythm, and volume. Examination revealed normal weight, length and head circumference, anterior fontanelle, and absence of dysmorphic facies or gross congenital anomalies. The respiratory, cardiovascular, and abdominal systems were unremarkable. Activity and neonatal reflexes were normal and symmetrical.
Since the history was suggestive of a seizure or apnea, in view of the unexplained infantile deaths and inconclusive examination, the differential diagnoses of neonatal apnea, neonatal seizures, and neonatal-onset inborn errors of metabolism were kept.
Management and Outcome
Baseline investigations ruled out sepsis, hypoglycemia, and dyselectrolytemia; hemoglobin 15.5 g/dL, total leukocyte count 8.5 × 103/L, platelet count 200 × 109/L, C-reactive protein 2 mg/L, blood sugar 107 mg/dL, Na + 135 mEq/L, K + 4.1 mEq/L, Ca2 + 4.2 mg/dL, and Mg2 + 1.8 mEq/L. The liver function and renal function tests were normal. No cardiac abnormalities were detected on standard ECG, X-ray chest, and echocardiography. The electroencephalogram and ultrasound of the cranium were unremarkable. First-line metabolic investigations revealed normal pH, lactate and ammonia levels, absence of urinary ketones, and negative neonatal metabolic screen. The baby remained well, with weight gain and no recurrence of the event.
However, on day 28 of life, he had a recurrent episode of apnea. ECG evaluation during this episode revealed a QTc of 520 ms [Figure 2] and [Figure 3]. Despite the nonapplicability of certain parameters (syncope, poststress test recovery), the Schwartz score [Table 1] was 3.5, highly suggestive of cLQTS. After a cardiology consultation, the baby was started on oral propranolol (1 mg/kg/day in 3 divided doses) which was gradually increased to10 mg/kg/day. The cardiac evaluation of both parents was normal. A genetic opinion was sought. After pretest counseling, Trio Whole Exome Sequencing was performed to evaluate genes for LQTS and other arrhythmogenic disorders. The baby was discharged on oral propranolol after 2 weeks of hospital stay, after being explained about danger signs and asked to come for follow-up every week. Despite being on beta-blockers, the infant had a sudden unexplained death at 8 weeks of age. The baby had not been ill and had not been prescribed any other medication.
|Table 1: 2011 Modified Schwartz score for clinical diagnosis of Long QT Syndrome|
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The mutation study subsequently revealed a novel heterozygous variation, c.290C>T; p.Thr97Met in TRPM4 (Transient Receptor Potential Cation Channel subfamily M or Melastatin 4 gene) in the symptomatic proband, the asymptomatic mother, but not the asymptomatic father.
The American College of Medical Genetics and Genomics criteria that define the significance of variants identified on next-generation sequencing identified this as a variant of uncertain significance (VUS). It was not reported previously in the literature and had an extremely low frequency in the genome aggregation database (gnomad). There was conflicting evidence by the insilico mutation prediction software tools; sorting intolerant from tolerant and protein variation effect analyzer reported it to be likely pathogenic, whereas Functional Analysis Through Hidden Markov Models and the Meta-analytic support Vector machine reported it as benign. Posttest counseling was done as per protocol, and the mother was referred for cardiac management.
| Discussion|| |
Congenital LQTS is the first described, and one of the most studied channelopathies. Clinical manifestations vary from no symptoms to recurrent syncope, seizures, apnea, palpitations (rarely), and lethal arrhythmias. Its prevalence is 1 in 2000 births in symptomatic individuals, and 1 in 1000 when asymptomatic affected family members are included. This case highlighted the importance of getting an ECG done immediately after an apnea, despite documenting a normal QTc earlier. The high index of suspicion was kept due to other common causes of apnea being ruled out, and the strong history of recurrent unclassified sudden infant deaths.
Establishing diagnosis by the modified 2011 Schwartz's score was often challenging, despite sensitivity and specificity of 89% and 82%, respectively. These included reasons such as heterogeneity of symptoms, inconsistent ECG abnormalities (as in our case), presence of normal QTc in a proportion of genetically proven patients (10% LQT3 and 36% LQT1), and as mentioned earlier, two parameters being not applicable in young infants. The neonatal onset of symptoms is not uncommon. An American pediatric electrophysiological society conducted a multicentric study in which 287 individuals with LQTS under the age of 21 years were enrolled. Twenty percent of them were neonates. In 2013, the Heart Rhythm Association and Asia Pacific Heart Rhythm Society Expert Consensus Statement added another diagnostic criterion, unequivocally pathogenic mutation in LQTS genes.
A few clinical phenotypes of cLQTS have been recognized. Our case would be considered Romano–Ward syndrome (autosomal dominant with isolated cardiac involvement) based on clinical findings. Although hearing assessment had not been done, Jervell-Lange-Nielsen syndrome (autosomal recessive with cardiac involvement and deafness) was excluded by the family history. Andersen–Tawil syndrome (hypokalemic periodic paralysis, facial and skeletal dysmorphism) and Timothy syndrome (syndactyly, structural cardiac anomalies, and developmental delay) were excluded due to lack of other systemic involvement.
Almost 80% of cLQTS are due to mutations in three major LQTS-susceptibility genes; KCNQ1 (LQT1) and KCNH2 (LQT2), or SCN5A (LQT3). Five percent are due to mutations in 14 minor genes including calmodulin, triadin, and membrane adaptor protein gene (ANKB). No mutations are identified in 15%, despite clinical phenotype. In these situations, testing for exon deletions and duplications should be considered, due to their identification in 5%–15% of such individuals. The overall disease penetrance of cLQTS is low, varying from 10% to 25%. However, it is highly penetrant early in life in Jervell and Lange-Nielsen syndrome, multiple LQTS-causative mutations without deafness, infantile malignant calmodulinopathies, and homozygous/compound heterozygous mutations in TRDN encoding triadin. Digenic/biallelic inheritance or two pathogenic variations are found in 4%–10% LQTS and associated with a severe phenotype.
The protein encoded by the TRPM4 gene is a calcium-activated nonselective ion channel found in various organs such as the heart, kidneys, and brain. It mediates the transport of monovalent cations (Na+, K+, Cs +, and Li+) across membranes, resulting in depolarization. The novel TRPM4 mutation identified in this case was a VUS, as outlined earlier. Variants in this autosomal dominant gene have been reported in both life-threatening arrhythmias and asymptomatic carriers. The results of in silico mutational analyses, computer models that can predict the functionality of the encoded protein, were inconclusive. The biggest barrier to ascertaining status by specific variant testing was the lack of stored DNA from the previous siblings.
According to standard guidelines, all patients with cLQTS must receive long-acting β-blockers, irrespective of symptoms or age, with up titrating to the highest tolerated dose. Rigorous physical activity and QTc prolonging medications should be avoided. Indications for implantable cardioverter defibrillators (ICD) include patients with resuscitated cardiac arrest, recurrent syncope despite β blockers, contraindications for β blockers, QTc ≥0.5 s, and family history of sudden deaths. A risk analysis must be done regarding the risk of a sudden cardiac event versus the potential complications of ICD. Although there are case reports of young infants with ICDs, it was not a feasible option for this baby. Left cardiac sympathetic denervation is warranted when β blockers and ICD fail.
The primary aim of clinicians is to suspect and identify cLQTS in all ages and clinically relevant circumstances. Patients should be referred to cardiologists and geneticists for appropriate management and counseling. Although we could not prevent the death of the proband despite medication, two significant outcomes were initiation of maternal therapy and counseling the family regarding the possibility of prenatal diagnosis in future pregnancies.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]