Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13-21.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The objectives of this study were to characterize the clinical features of the disease in a Bedouin tribe from Israel and to map the disease gene.


RESULTS
In this Bedouin tribe, 9 children (age, 7+/-4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6+/-3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins). Segregation analysis suggested autosomal recessive inheritance. All 12 symptomatic patients and 1 asymptomatic sibling (mean age, 13+/-7 years) were found to have a relative resting bradycardia (64+/-13 bpm, versus 93+/-12 bpm in the unaffected siblings), as well as PVT induced by treadmill or isoproterenol infusion and appearing at a mean sinus rate of 110+/-10 bpm. Patients responded favorably to treatment with beta-blockers. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 16-megabase interval on chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at theta=0.00. Sequencing of KCND3, a gene that encodes an I(tO) potassium channel transporter, did not reveal any significant sequence alterations.


CONCLUSIONS
This unique form of autosomal recessive PVT affects young children and may be lethal if left untreated. Linkage analysis maps this disorder to chromosome 1p13-21.
Lahat
H
H
Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel (affiliated with the Sackler School of Medicine, Tel Aviv University, Israel).
Eldar
M
M
Levy-Nissenbaum
E
E
Bahan
T
T
Friedman
E
E
Khoury
A
A
Lorber
A
A
Kastner
D L
DL
Goldman
B
B
Pras
E
E
D000293:Adolescent; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D018912:Arabs / Q000235:genetics*; D001919:Bradycardia / Q000175:diagnosis / Q000453:epidemiology; D002395:Catecholamines / Q000378:metabolism*; D002648:Child; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D015897:Comorbidity; D003241:Consanguinity; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D004562:Electrocardiography; D005080:Exercise Test; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D007545:Isoproterenol; D007557:Israel / Q000453:epidemiology; D008126:Lod Score; D005082:Physical Exertion; D012640:Seizures / Q000453:epidemiology; D013575:Syncope / Q000453:epidemiology; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000208:ethnology* / Q000503:physiopathology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D005819:Genetic Markers; D007545:Isoproterenol