Abstract
BACKGROUND: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy. METHODS: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap. RESULTS: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events. CONCLUSION: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e002419 |
| Journal | Circulation. Genomic and precision medicine |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2019 |
Fingerprint
Keywords
- genetics
- human
- long QT syndrome
- pediatrics
- phenotype
Cite this
International Triadin Knockout Syndrome Registry. / Clemens, Daniel J.; Tester, David J.; Giudicessi, John R.; Bos, J. Martijn; Rohatgi, Ram K.; Abrams, Dominic J.; Balaji, Seshadri; Crotti, Lia; Faure, Julien; Napolitano, Carlo; Priori, Silvia G.; Probst, Vincent; Rooryck-Thambo, Caroline; Roux-Buisson, Nathalie; Sacher, Frederic; Schwartz, Peter J.; Silka, Michael J.; Walsh, Mark A.; Ackerman, Michael John.
In: Circulation. Genomic and precision medicine, Vol. 12, No. 2, 01.02.2019, p. e002419.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - International Triadin Knockout Syndrome Registry
AU - Clemens, Daniel J.
AU - Tester, David J.
AU - Giudicessi, John R.
AU - Bos, J. Martijn
AU - Rohatgi, Ram K.
AU - Abrams, Dominic J.
AU - Balaji, Seshadri
AU - Crotti, Lia
AU - Faure, Julien
AU - Napolitano, Carlo
AU - Priori, Silvia G.
AU - Probst, Vincent
AU - Rooryck-Thambo, Caroline
AU - Roux-Buisson, Nathalie
AU - Sacher, Frederic
AU - Schwartz, Peter J.
AU - Silka, Michael J.
AU - Walsh, Mark A.
AU - Ackerman, Michael John
PY - 2019/2/1
Y1 - 2019/2/1
N2 - BACKGROUND: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy. METHODS: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap. RESULTS: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events. CONCLUSION: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.
AB - BACKGROUND: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy. METHODS: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap. RESULTS: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events. CONCLUSION: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.
KW - genetics
KW - human
KW - long QT syndrome
KW - pediatrics
KW - phenotype
UR - http://www.scopus.com/inward/record.url?scp=85061859306&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061859306&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.118.002419
DO - 10.1161/CIRCGEN.118.002419
M3 - Article
C2 - 30649896
AN - SCOPUS:85061859306
VL - 12
SP - e002419
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
SN - 1942-325X
IS - 2
ER -