Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects.
BACKGROUND
Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study.


OBJECTIVE
To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects.


RESULTS
Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and alphaB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative.


CONCLUSIONS
A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.
Arbustini
Eloisa
E
Molecular Diagnostic Laboratory, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy. e.arbustini@smatteo.pv.it
Pasotti
Michele
M
Pilotto
Andrea
A
Pellegrini
Carlo
C
Grasso
Maurizia
M
Previtali
Stefano
S
Repetto
Alessandra
A
Bellini
Ornella
O
Azan
Gaetano
G
Scaffino
Manuela
M
Campana
Carlo
C
Piccolo
Giovanni
G
Viganò
Mario
M
Tavazzi
Luigi
L
D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000378:metabolism; D001706:Biopsy; D002313:Cardiomyopathy, Restrictive / Q000097:blood / Q000235:genetics*; D004252:DNA Mutational Analysis; D003893:Desmin / Q000097:blood / Q000235:genetics* / Q000276:immunology; D004699:Endocardium / Q000473:pathology; D005260:Female; D006327:Heart Block / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017421:Sequence Analysis; D038203:alpha-Crystallin B Chain / Q000235:genetics
D000906:Antibodies; C059215:CRYAB protein, human; D003893:Desmin; D038203:alpha-Crystallin B Chain