Cardiomyopathy, Dilated, 1u

A number sign (#) is used with this entry because dilated cardiomyopathy-1U is caused by heterozygous mutation in the PSEN1 gene (104311) on chromosome 14q24.3.

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Li et al. (2006) described an African American family with dilated cardiomyopathy segregating with mutation in the PSEN1 gene (CMD1U). Affected members were identified in 3 generations. Onset of dilated cardiomyopathy and heart failure ranged from age 24 to 69 years. Mortality from progressive heart failure usually followed within a few years of diagnosis. The index patient presented with symptomatic heart failure due to idiopathic dilated cardiomyopathy at age 52 years. Another family member, who presented with idiopathic dilated cardiomyopathy and heart failure at the age of 51 years, required cardiac transplantation at age 62 years. Extensive hospital records showed that the affected member in the first generation received the diagnoses of heart failure and nonischemic dilated cardiomyopathy at age 69 years and of dementia at the age of 71 years. Both the cardiomyopathy and dementia progressed and resulted in repeated hospitalizations until the patient's death at age 78 years, in advanced heart failure.

While familial Alzheimer disease (see 607822) can be caused by presenilin mutations, these genes are also expressed in the heart and are critical to cardiac development. Li et al. (2006) hypothesized that mutations in presenilin may also be associated with dilated cardiomyopathy (DCM; see 115200) and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. They evaluated a total of 315 index patients with DCM for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. Li et al. (2006) identified a novel heterozygous PSEN1 missense mutation (D333G; 104311.0034) in 1 family and a single heterozygous PSEN2 missense mutation (600759.0008) in 2 other families. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers.