Cardiomyopathy, Dilated, 2a
A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-2A (CMD2A) is caused by homozygous mutation in the gene encoding cardiac troponin I (TNNI3; 191044) on chromosome 19q13. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.
Clinical FeaturesGoldblatt et al. (1987) described 3 members of a Madeira Portuguese family with dilated cardiomyopathy. The first patient presented at age 11 years with dyspnea and congestive heart failure and died 10 weeks later. A cousin was discovered to have cardiac abnormality on routine employment examination at age 20 years and died 14 months later in congestive heart failure. His sister presented at the age of 21 years with gradually diminishing effort tolerance. The brother and sister were the offspring of first-cousin parents.
Seliem et al. (2000) described the natural history of dilated cardiomyopathy among infants of Arab descent from the Eastern Province of Saudi Arabia. They evaluated 55 consecutive cases of dilated cardiomyopathy in patients less than 10 years of age seen during a 5-year interval. Echocardiography was the primary diagnostic modality. The 55 cases represented 20% of the offspring of 41 families of Arab descent. In 19 families (46%), parents were first cousins; there was no obvious consanguinity in 22 families (54%). Age at presentation was less than 30 months (95%) (range, 1 to 100 months); males accounted for 38% of the patients. Forty-six percent of patients died, while 27% of patients either improved or recovered. The left ventricular shortening fraction at diagnosis ranged from 5 to 28% and was not correlated with outcome.
Murphy et al. (2004) studied a family in which the proband presented at 27 years of age with a history of progressive cardiac failure. Echocardiography showed a dilated left ventricle with poor function and he underwent cardiac transplantation at age 28, at which time his left ventricle end-diastolic volume (LVEDV) was 7.1 cm and fractional shortening was 4%. Histologic examination of the explanted heart showed myofibrillar loss, hyperchromatic nuclei, and myocyte hypertrophy, but no myofibril or myocyte disarray. His sister presented with heart failure at 29 years of age, with an LVEDV of 5.1 cm and fractional shortening of 19%. His parents and another sib were healthy, with normal electrocardiograms and echocardiograms. No family member showed evidence of cardiac conduction disease or skeletal myopathy.
InheritanceGoldblatt et al. (1987) found 6 reports of families with congestive cardiomyopathy with a pedigree pattern consistent with autosomal recessive inheritance. These included the families of Battersby and Glenner (1961) and Kariv et al. (1964)--see 115200. An elevated rate of parental consanguinity and a horizontal pedigree pattern suggested autosomal recessive inheritance of dilated cardiomyopathy in Japanese families (Yamaguchi and Toshima, 1980).
Seliem et al. (2000) evaluated the mode of inheritance of dilated cardiomyopathy among infants of Arab descent from the Eastern Province of Saudi Arabia. They evaluated 55 consecutive cases of dilated cardiomyopathy in patients less than 10 years of age seen during a 5-year interval. Complex segregation analysis of the family data, using the mixed model of inheritance, showed that a model of recessive inheritance best fit the data.
Molecular GeneticsIn 2 affected members of a family with dilated cardiomyopathy-2A, Murphy et al. (2004) identified homozygosity for a missense mutation (A2V; 191044.0009) in the TNNI3 gene. The unaffected parents and an unaffected sister were heterozygous for the mutation. The parents were unaware of any familial relationship, but haplotype analysis indicated remote consanguinity.
Carballo et al. (2009) cast doubt on the pathogenicity of the A2V mutation, stating that their analysis of the effect of A2V on ATPase regulation indicated that troponin function was not significantly altered.