Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

Abstract

Background— Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. Methods and Results— We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A , we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Conclusions— Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

Atrial Fibrillation and Mechanisms of Stroke

“…Even though AF is absent, this disorder leads to atrial dilatation, progressive loss of atrial activity with eventual atrial standstill, and thromboembolism. 45 …”

Atrial fibrillation and NPPA gene p.S64R mutation

“…The NPPA gene was tested by direct sequencing of the coding and flanking regions according to methods previously described. 3 The rs10033464 and rs2200733 SNPs 4 were tested in p.(Ser64Arg) carriers. In case of episodes of atrial fibrillation, we performed in-depth diagnostics by multislice computed tomography and electroanatomic mapping 6,7 (see online supplement methods, http:// links.lww.com/JCM/A60).…”

“…2 At the same locus, we mapped the autosomal recessive atrial dilated cardiomyopathy (MIM#615745) in six families from a geographic isolate in the northeast of Italy; all affected members were carriers of the homozygous NPPA gene mutation (p. Arg150Gln). 3 In a large genome-wide association study, two common single nucleotide polymorphisms (SNPs), rs10033464 and rs2200733 at the 4q25 locus, have been independently associated with increased risk of AF 4 and later proposed as possible modifiers of the effects of p.(Ser64Arg) mutation. 5 The prevalence of NPPA mutations in the general population and the impact of mutations in this gene on lone atrial fibrillation are unknown.…”

Atrial Cardiomyopathy An Orphan Disease or Common Disorder?

“…The findings of Disertori et al 7 clearly highlight the importance of elucidating the genetic basis of inherited diseases and have public health implications. The remarkable longitudinal observations indicate that atrial dilatation and electric abnormalities in homozygous Arg150Gln carriers are progressive, indicating a need for early genotyping of family members, as well as regular follow-up, thromboembolic prophylaxis, aggressive intervention to avoid hypertension, drugs and other acquired factors that might exacerbate aspects of the phenotype, and prepregnancy genetic counseling.…”