Alternative titles; symbols
ORPHA: 1344; DO: 0080662;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.2 | Atrial standstill, digenic (GJA5/SCN5A) | 108770 | Autosomal dominant | 3 | GJA5 | 121013 |
A number sign (#) is used with this entry because of evidence that atrial standstill-1 (ATRST1) is caused by coinheritance of a variant in the SCN5A gene (600163) in combination with a rare connexin-40 (GJA5; 121013) genotype.
Atrial standstill associated with massive atrial dilation (ATRST2; 615745) is caused by mutation in the NPPA gene (108780) on chromosome 1p36.
Atrial standstill (AS) is a rare condition characterized by the absence of electrical and mechanical activity in the atria. On surface ECG, AS is distinguished by bradycardia, junctional (usually narrow complex) escape rhythm, and absence of the P wave. Nearly 50% of patients with AS experience syncope. AS can be persistent or transient, and diffuse or partial (summary by Fazelifar et al., 2005).
In a discussion of atrial standstill, Harrison and Derrick (1969) described Latin-American sibs with possible cardiac amyloidosis. Both parents and sister had died suddenly. Allensworth et al. (1969) described 3 sibs, aged 38, 34 and 33, with bradycardia, cardiac enlargement, and congestive heart failure. The electrocardiogram (ECG) showed absent P waves with normal QRS configuration and duration. Stimulation of the atrium with a cardiac catheter or a pacemaker did not induce atrial depolarization.
In 3 of 5 sibs and in the son of 1 of the 3 sibs (a male), Williams et al. (1972) found first-degree heart block and ectopic supraventricular rhythms progressing to persistent standstill with complete loss of response to direct atrial stimulation. The extensively affected kindred reported by Amat-y-Leon et al. (1974) may have had the same condition. Familial atrial standstill is characteristic of amyloidosis type III (176300.0007), also known as the Danish or cardiac form. Shah et al. (1992) reported the cases of adult sisters with total atrial standstill.
Makita et al. (2005) studied a Japanese boy who at 3 years of age presented with severe bradycardia and was diagnosed with sick sinus syndrome (see SSS1, 608567) with paroxysmal atrial fibrillation based on Holter ECG recordings. At 5 years of age, histologic examination of a right ventricular endocardial specimen was reported as normal. By age 10 years, the patient had atrial standstill with a maximum RR interval of 6.65 seconds. Examination at 11 years of age showed absence of P waves and a 40-bpm junctional rhythm with ventricular escape beats, with normal QRS duration and QTc interval. Holter ECG exhibited junctional rhythm with a maximum RR interval of 5.42 seconds, and intracardiac recordings showed a junctional rhythm with ventricular escape beats, absence of atrial activity, and a slightly prolonged 56-ms His-ventricular interval. Family history revealed that 2 of the paternal grandfather's sibs died suddenly in the first decade of life; however, other family members were asymptomatic, and there was no history of cardiac pacemaker implantation or cardiac surgery.
The transmission pattern of ATRST1 in the family reported by Groenewegen et al. (2003) was consistent with autosomal dominant inheritance.
Groenewegen et al. (2003) reported a family in which 1 deceased and 3 living members had atrial standstill. They identified a heterozygous asp1275-to-asn (D1275N; 600163.0034) in the SCN5A gene in all 3 affected living members and in 5 unaffected members; the deceased member was an obligate carrier. Eight family members were found to be homozygous for 2 closely linked polymorphisms within regulatory regions of the gene for the atrial-specific gap junction protein connexin-40 (121013): a G-to-A substitution at nucleotide -44 and an A-to-G transition at nucleotide 71. Only the 3 affected living members coinherited the SCN5A mutation and the 2 rare GJA5 polymorphisms. Groenewegen et al. (2003) proposed that atrial standstill in this family resulted from the coinheritance of the SCN5A mutation and the rare GJA5 polymorphisms.
In a Japanese family in which an 11-year-old boy had sick sinus syndrome that progressed to atrial standstill, Makita et al. (2005) analyzed 3 cardiac ion channel genes previously associated with atrial standstill, atrial fibrillation, or sick sinus syndrome: SCN5A, HCN4 (605206), and GJA5. No mutations were found in HCN4, but the proband and his asymptomatic father were heterozygous for a missense mutation in SCN5A (L212P; 600163.0048). In addition, the proband and his unaffected mother and maternal grandmother were all heterozygous for the same 2 rare GJA5 polymorphisms identified by Groenewegen et al. (2003) in atrial standstill patients, -44A/+71G. The proband's asymptomatic father had normal sinus rhythm with nonspecific ST depression in the inferior leads on ECG, whereas his unaffected mother and maternal grandmother had normal ECGs. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. Makita et al. (2005) suggested that defects in SCN5A underlie atrial standstill, and that coinheritance of GJA5 polymorphisms represents a possible genetic modifier of the clinical manifestations.
Allensworth, D. C., Rice, G. J., Lowe, G. W. Persistent atrial standstill in a family with myocardial disease. Am. J. Med. 47: 775-784, 1969. [PubMed: 4981961] [Full Text: https://doi.org/10.1016/0002-9343(69)90170-3]
Amat-y-Leon, F., Racki, A. J., Denes, P., Ten Eick, R. E., Singer, D. H., Baharati, S., Lev, M., Rosen, K. M. Familial atrial dysrhythmia with A-V block: intracellular microelectrode, clinical electrophysiologic, and morphologic observations. Circulation 50: 1097-1104, 1974. [PubMed: 4430108] [Full Text: https://doi.org/10.1161/01.cir.50.6.1097]
Fazelifar, A. F., Arya, A., Haghjoo, M., Sadr-Ameli, M. A. Familial atrial standstill in association with dilated cardiomyopathy. Pacing Clin. Electrophysiol. 28: 1005-1008, 2005. [PubMed: 16176547] [Full Text: https://doi.org/10.1111/j.1540-8159.2005.00198.x]
Groenewegen, W. A., Firouzi, M., Bezzina, C. R., Vliex, S., van Langen, I. M., Sandkuijl, L., Smits, J. P., Hulsbeek, M., Rook, M. B., Jongsma, H. J., Wilde, A. A. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ. Res. 92: 14-22, 2003. [PubMed: 12522116] [Full Text: https://doi.org/10.1161/01.res.0000050585.07097.d7]
Harrison, W. H., Jr., Derrick, J. R. Atrial standstill: a review, and presentation of two new cases of familial and unusual nature with reference to epicardial pacing in one. Angiology 20: 610-617, 1969. [PubMed: 5347950] [Full Text: https://doi.org/10.1177/000331976902001007]
Makita, N., Sasaki, K., Groenewegen, W. A., Yokota, T., Yokoshiki, H., Murakami, T., Tsutsui, H. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Heart Rhythm 2: 1128-1134, 2005. [PubMed: 16188595] [Full Text: https://doi.org/10.1016/j.hrthm.2005.06.032]
Shah, M. K., Subramanyan, R., Tharakan, J., Venkitachalam, C. G., Balakrishnan, K. G. Familial total atrial standstill. Am. Heart J. 123: 1379-1382, 1992. [PubMed: 1575158] [Full Text: https://doi.org/10.1016/0002-8703(92)91048-6]
Williams, D. O., Jones, E. L., Nagle, B., Smith, S. Familial atrial cardiomyopathy with heart block. Quart. J. Med. 41: 491-508, 1972. [PubMed: 4636548]