Atrial Standstill 2

A number sign (#) is used with this entry because of evidence that atrial standstill-2 (ATRST2) is caused by homozygous mutation in the NPPA (108780) gene on chromosome 1p36.

For a discussion of genetic heterogeneity of atrial standstill (AS), see ATRST1 (108770).

Description

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).

Clinical Features

Disertori et al. (1983) reported 8 patients from 3 Italian families in a small mountain community with complete or partial persistent atrial standstill. Three patients presented with palpitations, 2 with congestive heart failure, and 1 with cerebral embolism; in the remaining 2 patients, bradycardia was observed during evaluation for an unrelated problem. Diagnostic criteria for complete AS included absence of P wave in any lead of electrocardiogram (ECG), no electrical activity of atria on endocavitary recordings, lack of atrial excitability, absence of atrial wall movement on fluoroscopy, and no mitral A wave on echocardiogram. The 5 patients with complete AS also exhibited marked cardiac enlargement, primarily due to atrial enlargement, with impaired functional class. Some had bradycardia for many years, but none had syncope; all underwent placement of a permanent pacemaker to correct the bradycardia, with subsequent significant improvement in myocardial function at a mean follow-up of 41 months. Four of the patients showed signs of ventriculoatrial regurgitation, and 2 of the patients had cerebral embolism. The remaining 3 patients were diagnosed with partial AS, characterized by absence of P waves in any lead of the ECG and endocavitary recording of electrical activity limited to a localized region of the atrium; these patients also had atrial enlargement but to a lesser degree than those with complete atrial standstill, and 1 had cerebral embolism. At mean follow-up of 48 months, no case of partial AS had developed into complete AS. Analysis of family history showed a high incidence of unexplained sudden death in young or middle-aged members, with 9 cases in the last 2 generations.

Disertori et al. (2013) provided follow-up on the 8 patients originally studied by Disertori et al. (1983) and described 5 more patients from the same community in northeastern Italy with atrial dilation and standstill, 1 from 1 of the original families and 4 from 3 new families. The 13 patients were 31 to 58 years of age at the time of diagnosis. Diagnosis at onset was idiopathic atrial dilation, associated with AS in 7 and bradycardia-tachycardia syndrome in 6; the latter group developed AS during follow-up. Cerebral embolism occurred in 7 of 13 patients, with peripheral embolism in 1. Of the original 8 patients, 5 died 8 to 25 years after diagnosis, 4 with out-of-hospital sudden death, 1 due to stroke, and 1 after months of posttraumatic tetraplegia. Follow-up in the 13 patients documented progressive biatrial enlargement, with atria classified as 'giant' in the 4 patients with the longest follow-up and 'severely enlarged' in the remaining 9 patients. Electrophysiologic studies over time showed progressive lowering of atrial voltages and bradycardia-tachycardia syndrome evolving to AS.

Mapping

Disertori et al. (2013) performed a genome scan in 'family 1' of Disertori et al. (1983) with atrial standstill and found a single region of interest, on chromosome 1p36.32-p36.13. Two-point linkage analysis yielded a maximum lod score of 2.23 at marker D1S2667 (theta = 0); multipoint linkage analysis of the 3 original Italian families with AS yielded a maximum lod score of 2.75. Multipoint linkage analysis of all 6 families with AS studied by Disertori et al. (2013) resulted in a maximum lod score of 3.38 at D1S2740 (p = 0.002). Multipoint nonparametric analysis yielded a lod score of 3.05 at the same marker, confirming the autosomal recessive model of inheritance. Recombination events narrowed the candidate locus to a 41.11-cM interval on 1p36, between D1S468 and D1S199.

Molecular Genetics

In affected individuals with atrial dilation and standstill mapping to chromosome 1p36 from 6 families within a small community in northeastern Italy, 3 of which were originally reported by Disertori et al. (1983), Disertori et al. (2013) sequenced 4 candidate genes and identified homozygosity for a missense mutation in the NPPA gene (R150Q; 108780.0003) that segregated with disease in each family. The mutation was present in heterozygosity in 16 of 192 controls from the same geographic area, but was not found in 200 randomly selected Italian controls. The 40 family members heterozygous for the mutation all had normal ECGs and none showed the arrhythmias observed in early and late phases of the disease in homozygous patients; only 1 had paroxysmal lone atrial fibrillation (see 612201). Follow-up of heterozygous family members ranged from 1 to 9 years, without evidence of an evolving phenotype.