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Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is characterized by episodes of syncope, seizures or sudden death, in response to physical activity or emotional stress, and affects mainly young children with morphologically normal hearts. We have recently described an autosomal recessive form of the disorder in seven families from a Bedouin tribe in the north of Israel, and mapped the disease-causing gene to chromosome 1p13-1p21. Direct sequencing of the calsequestrin 2 (CASQ2), a candidate gene from within the linkage interval, revealed a negatively charged aspartic acid change to a positively charged histidine at position 307 of the protein. CASQ2 serves as the major calcium reservoir within cardiac myocytes. This mutation occurs in a highly conserved residue of the protein. The implication of the calcium release cascade in this disease, may lead to a better understanding of the pathophysiologic events underlying ventricular tachycardia, and to the use of drugs directly involved in intracellular calcium control for the treatment of the CPVT patients.

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., Methods and 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.

Monoamine oxidase (MAO) is an important enzyme in the catabolism of brain biogenic amines. Platelet MAO has been reported to be moderately reduced in manic-depressive patients and markedly reduced in schizophrenic patients. This enzyme's activity has been shown to be under a large degree of genetic control and has been proposed as a 'genetic marker' in schizophrenia. A transcultural replication of the finding of low platelet MAO in schizophrenia and manic-depressive illness was carried out at the Jerusalem Mental Health Centre. Manic-depressive patients were found to have higher platelet MAO activity than schizophrenic patients, as reported previously, but control individuals were as low as the schizophrenic patients. It is unlikely that platelet MAO activity is a transculturally-valid marker for schizophrenia.