Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years ... Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by Levitas et al., 2010). - Genetic Heterogeneity of Dilated Cardiomyopathy Mutations in many other genes have been found to cause different forms of dilated cardiomyopathy. These include CMD1C (601493), with or without left ventricular noncompaction, caused by mutation in the LDB3 gene (605906) on 10q22-q23; CMD1D (601494), caused by mutation in the TNNT2 gene (191045) on 1q32; CMD1E (601154), caused by mutation in the SCN5A gene (600163) on 3p; CMD1G (604145), caused by mutation in the TTN gene (188840) on 2q31; CMD1I (604765), caused by mutation in the DES gene (125660) on 2q35; CMD1J (605362), caused by mutation in the EYA4 gene (603550) on 6q23-q24; CMD1L (606685), caused by mutation in the SGCD gene (601411) on 5q33; CMD1M (607482), caused by mutation in the CSRP3 gene (600824) on 11p15.1; CMD1N (607487), caused by mutation in the TCAP gene (604488) on 17q12; CMD1O (608569), caused by mutation in the ABCC9 gene (601439) on 12p12.1; CMD1P (609909), caused by mutation in the PLN gene (172405) on 6q22.1; CMD1R (613424), caused by mutation in the ACTC gene (102540) on 15q14; CMD1S (613426), caused by mutation in the MYH7 gene (160760) on 14q12; CMD1T (613740), caused by mutation in the TMPO gene (188380) on chromosome 12q22; CMD1U (613694), caused by mutation in the PSEN1 gene (104311) on 14q24.3; CMD1V (613697), caused by mutation in the PSEN2 gene (600759) on 1q31-q42; CMD1W (611407), caused by mutation in the gene encoding metavinculin (VCL; 193065) on 10q22-q23; CMD1X (611615), caused by mutation in the gene encoding fukutin (FKTN; 607440) on 9q31; CMD1Y (611878), caused by mutation in the TPM1 gene (191010) on 15q22.1; CMD1Z (611879), caused by mutation in the TNNC1 gene (191040) on 3p21.3-p14.3; CMD1AA (612158), caused by mutation in the ACTN2 gene (102573) on 1q42-q43; CMD1BB (612877), caused by mutation in the DSG2 gene (125671) on 18q12.1-q12.2; CMD1CC (613122), caused by mutation in the NEXN gene (613121) on 1p31.1; CMD1DD (613172), caused by mutation in the RBM20 gene (613171) on chromosome 10q25.2; CMD1EE (613252), caused by mutation in the MYH6 gene (160710) on chromosome 14q12; CMD1FF (613286), caused by mutation in the TNNI3 gene (191044) on chromosome 19q13.4; CMD1GG (613642), caused by mutation in the SDHA gene (600857) on chromosome 5p15; and CMD1HH (613881), caused by mutation in the BAG3 gene (603883) on chromosome 10q25.2-q26.2; CMD1II (615184), caused by mutation in the CRYAB gene (123590) on chromosome 6q21; CMD1JJ (615235), caused by mutation in the LAMA4 gene (600133) on chromosome 6q21; CMD1KK (615248), caused by mutation in the MYPN gene (608517) on chromosome 10q21; CMD1LL (615373), caused by mutation in the PRDM16 gene (605557) on chromosome 1p36; and CMD1MM (see 615396), caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11. Several additional loci for familial dilated cardiomyopathy have been mapped: CMD1B (600884) on 9q13; CMD1H (604288) on 2q14-q22; CMD1K (605582) on 6q12-q16; and CMD1Q (609915) on 7q22.3-q31.1. The symbol CMD1F was formerly used for a disorder later found to be the same as desmin-related myopathy (601419). Autosomal recessive forms of dilated cardiomyopathy have been reported, including CMD2A (611880), caused by mutation in the TNNI3 gene, and CMD2B (614672), caused by mutation in the GATAD1 gene (614518).
Dilated cardiomyopathy, a disorder characterized by cardiac dilation and reduced systolic function, represents an outcome of a heterogeneous group of inherited and acquired disorders. Olson and Keating (1996) noted that causes include myocarditis, coronary artery disease, systemic diseases, ... Dilated cardiomyopathy, a disorder characterized by cardiac dilation and reduced systolic function, represents an outcome of a heterogeneous group of inherited and acquired disorders. Olson and Keating (1996) noted that causes include myocarditis, coronary artery disease, systemic diseases, and myocardial toxins; idiopathic dilated cardiomyopathy in which these causes are excluded represents approximately one-half of all cases. Idiopathic dilated cardiomyopathy occurs with a prevalence of about 36.5 per 100,000; it accounts for more than 10,000 deaths in the U.S. annually and is the primary indication for cardiac transplantation. Among cases of idiopathic dilated cardiomyopathy, familial occurrence accounts for 20 to 25%, with the exception of rare cases resulting from mutations in dystrophin (e.g., 300377.0021). Familial dilated cardiomyopathy is characterized by an autosomal dominant pattern of inheritance with age-related penetrance. It presents with development of ventricular dilatation and systolic dysfunction usually in the second or third decade of life. Whitfield (1961) described a family in which 10 members were suffering or had died from cardiomyopathy and 6 others were probably affected. Although both males and females were affected, transmission seemingly occurred only through the female. Schrader et al. (1961) described 2 sisters with familial idiopathic cardiomegaly. Almost certainly the mother, who died at age 34, and probably 1 brother, who died at age 16, had the same condition. In the family reported by Battersby and Glenner (1961), affected persons were limited to 1 sibship and deposits of a nonmetachromatic, diastase-resistant, PAS-positive polysaccharide were described in the myocardium. Undoubtedly heterogeneity exists in the group of cardiomyopathies. Boyd et al. (1965) suggested that there may be 3 forms: (1) a form with predominant fibrosis, (2) a form with predominant hypertrophy (see ventricular hypertrophy, hereditary; 192600), and (3) a form with deposits described above. See amyloidosis III (176300.0007) for another familial cardiomyopathy. Kariv et al. (1966) observed 6 affected persons in 3 generations. In 2 of these persons, Adams-Stokes attacks required an artificial pacemaker. The affected males showed significant increase in the serum levels of multiple muscle-derived enzymes. Heterogeneity was suggested by the finding of normal serum enzyme levels in affected members of a second family. Rywlin et al. (1969) favored the view that obstructive and nonobstructive forms of familial cardiopathy are different expressions of a single entity. Classification into 'hypertrophic' and 'congestive' clinical types by Goodwin (1970) implies the same. Sommer et al. (1972) took an opposite view, i.e., that there is a separate nonobstructive familial cardiomyopathy. They described an Amish family with affected persons in 3 generations. Severity varied widely. The most severely affected pursued a rapidly fatal course whereas others manifested mainly conduction defects compatible with long survival. Machida et al. (1971) described a Japanese family with affected persons in 2 and perhaps 3 generations with male-to-male transmission. Emanuel et al. (1971) suggested that both dominant and recessive forms may exist. The possibility of an autosomal recessive form of congestive cardiomyopathy was raised by Yamaguchi et al. (1977), who found an astoundingly high rate of parental consanguinity (about 64%) and a segregation ratio of 0.196 consistent with autosomal recessive inheritance. Moller et al. (1979) described an autosomal dominant form of congestive cardiomyopathy. The earliest sign of the disease was arrhythmia and/or conduction defects. Symptoms of pump failure had their onset in adulthood. Three members of the extensively affected kindred had died suddenly. Septal hypertrophy was found in 2 affected persons. Fragola et al. (1988) studied 44 first-degree relatives of 12 probands with idiopathic dilated cardiomyopathy. Affected relatives were identified in 4 of 12 families. In each case, the affected relatives were sibs. This may be due to a late age of onset for expression of genetic factors involved in the etiology of this condition. O'Connell et al. (1984) used endomyocardial biopsy and gallium-67 scans in patients with dilated cardiomyopathy to demonstrate a subset of patients with myocardial inflammation. Histologic confirmation was found at autopsy. A defect in suppressor lymphocyte function was found in 1 patient, who showed improvement with immunosuppressive therapy. In 1 family, 5 persons in 3 generations were affected; in another, a father and 2 brothers were affected. Battersby and Glenner (1961) reported striking pericardial effusion in a family with cardiomyopathy. Other early reports (e.g., Evans, 1949) have commented on inflammatory changes found at necropsy. Pericardial effusion occurs episodically with the iron-overload cardiomyopathy of multitransfused thalassemia and occurs also in the cardiomyopathy of Friedreich ataxia (229300). Ozick et al. (1984) reported identical twin sisters with congestive cardiomyopathy and autoimmune thyroid disease. Both had antithyroid microsomal antibodies and cytolytic antiheart myolemmal antibodies. The postpartum state may have been a factor in one of the twins; both cardiomyopathy and autoimmune thyroid disease may become clinically apparent in the postpartum period. Gardner et al. (1985) evaluated a kindred in which 12 persons had cardiomegaly with poor ventricular function and/or dysrhythmia. The disorder was evident by echocardiogram in a 6-month-old infant. Skeletal muscle biopsies showed subtle myopathic alterations. The pedigree, spanning 5 generations, was consistent with autosomal dominant inheritance. Gardner et al. (1987) described a family in which multiple members in 3 and probably 4 generations had dilated cardiomyopathy with overt clinical onset between the fourth and seventh decades. Dysrhythmia was frequent. They concluded that there might be an associated skeletal myopathy manifested by very mild proximal weakness or detectable only on biopsy. MacLennan et al. (1987) described 8 affected individuals, 4 of whom were males in 3 generations. Average age at presentation was 39.5 years. Average time to death from onset of symptoms suggestive of cardiomyopathy in 6 affected members was 16 months. One member died suddenly after being asymptomatic. The myocardium showed variation in muscle fiber size and interstitial fibrosis. Graber et al. (1986) described a large kindred with an autosomal dominant form of disease of the cardiac conduction system and of the myocardium. Stage I occurred in the second and third decades and was characterized by absence of symptoms, normal heart size, sinus bradycardia, and premature atrial contractions. Stage II was marked by first-degree AV block in the third and fourth decades. Stage III occurred in the fourth and fifth decades and was accompanied by chest pain, fatigue, lightheadedness, and advanced AV block, followed by the development of atrial fibrillation or flutter. Stage IV, in the fifth and sixth decades of life, was characterized by congestive heart failure and recurrent ventricular arrhythmias. Right ventricular endomyocardial biopsy specimens showed progressive changes. At autopsy in the proband, the atrial changes were more severe than the ventricular ones. This suggested that the disorder discussed in entry 108770 is the same as this condition. While there was a range in the phenotypic expression of the inherited gene defect in this kindred, the dilated cardiomyopathy was less impressive than the dysrhythmia. Arrhythmias were the earliest manifestation of the disease (in the second to third decade). Schmidt et al. (1988) studied familial dilated cardiomyopathy in 6 families. The familial nature of the disorder was not readily apparent in 3 of these families until thorough family investigations were performed. The authors suggested that the family history should be reviewed in all patients with dilated cardiomyopathy and that further investigation of relatives should be performed if there are cases of unexplained heart disease, sudden unexpected death, or syncopal episodes. Echocardiography is a convenient noninvasive tool for these investigations. Early diagnosis is indicated for 2 reasons: treatment of significant arrhythmias may prevent sudden unexpected death, and genetic counseling can be provided. In studies of the first-degree relatives of 59 index cases with idiopathic dilated cardiomyopathy, Michels et al. (1992) found that 18 relatives from 12 families had dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3%) had familial disease. No differences in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features were detected between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2%) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8%) who were studied separately. In a case-control study of idiopathic dilated cardiomyopathy in Baltimore, a roughly 3-fold increase in risk was observed among blacks after adjustment for potential confounding variables (Coughlin et al., 1990). The increased frequency of dilated cardiomyopathy in black males was the basis in the past of the designation 'Osler-2 myocarditis'; Osler-2 was the black male ward at The Johns Hopkins Hospital. Michels et al. (1993) performed PCR-based assays and Southern blot analysis of the dystrophin gene (DMD; 300377) in 27 males with idiopathic dilated cardiomyopathy. Five families had familial disease, without male-to-male transmission in 4 families. In the fifth family, there was no evidence of male-to-male transmission when the family was entered into the study, but on follow-up the index patient's son was found to have developed the disease. None of the patients had clinical evidence of skeletal muscle disease or any systemic illness that could cause heart disease. The mean age of the patients was 50.2 years; the range of age was 5 to 72 years. No dystrophin gene defects were found. Csanady et al. (1995) compared 31 familial and 209 nonfamilial cases of dilated cardiomyopathy. They concluded that the familial form is more malignant: it occurs at an earlier age and progresses more rapidly than the nonfamilial form. For a review of the genetic and clinical heterogeneity of familial dilated cardiomyopathy, see Seidman and Seidman (2001).
In 5 of 11 families with autosomal dominant dilated cardiomyopathy and conduction system defects, Fatkin et al. (1999) identified 5 heterozygous missense mutations in the LMNA gene (150330.0005-150330.0009). Each mutation caused heritable, progressive conduction system disease (sinus bradycardia, ... In 5 of 11 families with autosomal dominant dilated cardiomyopathy and conduction system defects, Fatkin et al. (1999) identified 5 heterozygous missense mutations in the LMNA gene (150330.0005-150330.0009). Each mutation caused heritable, progressive conduction system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Furthermore, serum creatine kinase levels were normal in family members with mutations in the lamin rod domain, but mildly elevated in some family members with a defect in the tail domain of lamin C. The findings indicated that the lamin A/C intermediate filament protein plays an important role in cardiac conduction and contractility. In an editorial accompanying the report of Fatkin et al. (1999), Graham and Owens (1999) tabulated the chromosomal locations of the known loci responsible for inherited forms of dilated cardiomyopathy. Brodsky et al. (2000) presented a large family with a severe autosomal dominant dilated cardiomyopathy with an atrioventricular conduction defect in some affected members. In addition, some affected individuals had skeletal muscle symptoms varying from minimal weakness to a mild limb-girdle muscular dystrophy. One individual had a pattern of skeletal muscle involvement that the authors considered consistent with mild Emery-Dreifuss muscular dystrophy. Affected individuals were heterozygous for a single nucleotide deletion in the lamin A/C gene (150330.0013). The authors highlighted the wide range in phenotype arising from this mutation. In 2 families with dilated cardiomyopathy with conduction defects, Sebillon et al. (2003) identified 2 different mutations in the LMNA gene (150330.0028, 150330.0029). In 1 family, the phenotype was characterized by early-onset atrial fibrillation preceding or coexisting with dilated cardiomyopathy. Taylor et al. (2003) screened the LMNA gene in 40 families with familial CMD and 9 patients with sporadic CMD and identified mutations in 3 families (see, e.g., 150330.0017) and 1 sporadic patient (S573L; 150330.0041). There was significant phenotypic variability in the patients studied, but the presence of skeletal muscle involvement, supraventricular arrhythmia, conduction defects, and 'mildly' dilated cardiomyopathy were predictors of LMNA mutations. The LMNA mutation carriers had a significantly poorer cumulative survival compared with noncarrier CMD patients, with an event-free survival at age 45 years of 31% versus 75%, respectively. In affected members of a French family with dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias and skeletal muscular dystrophy of the quadriceps muscles, Charniot et al. (2003) identified an arg377-to-his mutation in the LMNA gene (R377H; 150330.0017). The same mutation had been reported in patients with limb-girdle muscular dystrophy type-1B (159001), a slowly progressive muscular dystrophy with age-related atrioventricular cardiac conduction disturbances and the absence of early contractures. Charniot et al. (2003) suggested that factors other than the R377H mutation may have influenced the phenotypic expression in this family. Kimura (2011) reviewed the contribution of genetics in the pathogenesis of dilated cardiomyopathy and discussed functional aspects of sarcolemmal, contractile element, Z disc element, sarcoplasmic element, and nuclear lamina mutations. The author noted that there was no major disease gene for Japanese CMD patients reported to date. - Associations Pending Confirmation Mutation in the ILK gene (see 602366.0001) is a possible cause of CMD.
The diagnosis of LMNA-related dilated cardiomyopathy (DCM) is established in individuals with the following:...
DiagnosisClinical DiagnosisThe diagnosis of LMNA-related dilated cardiomyopathy (DCM) is established in individuals with the following:A clinical diagnosis of DCM, usually in the setting of conduction system disease and/or supraventricular or ventricular arrhythmiasAn identified mutation in LMNAThe diagnosis of DCM is based on the principal findings of left ventricular enlargement and reduced systolic function in which other causes have been excluded:Reduced systolic function is usually described as a reduction in left ventricular ejection fraction, which can be measured by two-dimensional echocardiography, angiography, or nuclear left ventricular functional studies. An ejection fraction of less than 50% or a fractional shortening of less than 25%-30% is considered systolic dysfunction.Left ventricular enlargement is most commonly identified with two-dimensional echocardiography. Other testing modalities include cardiac computed tomography (CT), MRI, and left ventricular angiography or nuclear studies.Other causes to be excluded are, most importantly, coronary artery disease, structural heart disease (valvular heart disease, congenital heart disease, and others), thyroid disorders, and acute myocarditis.Note: LMNA-related DCM is almost always associated with conduction system disease and/or arrhythmias that commonly occur prior to the development of heart failure symptoms. Clinicians should also be aware that in some cases the conduction system disease precedes any evidence of DCM (see Clinical Description).Molecular Genetic TestingGene. LMNA is the only gene associated with LMNA-associated DCM.Clinical testingSequence analysis/ mutation scanning. For individuals known to have LMNA-related DCM, sequence analysis approaches a sensitivity of 100%, as almost all mutations identified to date have been missense, nonsense, or splice-site mutations. Duplication/deletion testing. Duplication/deletion testing may increase testing sensitivity, as two reports have identified LMNA-related DCM resulting from deletions [van Tintelen et al 2007, Gupta et al 2010]. Table 1. Summary of Molecular Genetic Testing Used in LMNA-Related Dilated CardiomyopathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityLMNASequence analysis/ mutation scanning 2Sequence variants 3>99%Clinical Duplication/ deletion testing 4Exon(s) or whole-gene deletions/duplicationUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis of LMNA-related DCM in a proband. Molecular genetic testing for LMNA-related cardiomyopathy:Is indicated for all persons with DCM of unknown cause in the setting of prominent conduction system disease with or without supraventricular or ventricular arrhythmias;Should be considered for any person with DCM of unknown cause;May be appropriate in individuals with significant conduction system disease, which can precede evidence or accompany early evidence of DCM in some individuals.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMutations in LMNA cause several disorders of striated muscle, nerve, adipose, and vascular tissue, collectively referred to as the laminopathies. Laminopathies result primarily from missense mutations, with occasional nonsense and splice-site mutations and short insertions or deletions. A remarkable exception is the synonymous mutation (a nucleotide change that does not alter the amino acid) in LMNA codon 608 (GGC changed to GGT that does not change the Gly608 residue) causing Hutchinson-Gilford progeria. Synonymous mutations have also been suggested for limb-girdle muscular dystrophy type 1B [Todorova et al 2003]. Muscular dystrophyAutosomal dominant Emery-Dreifuss muscular dystrophy; a humero-peroneal muscular dystrophy, usually with adult onset. Cardiac conduction system disease is commonly observed.Limb-girdle muscular dystrophy type 1B; dystrophy of the limb musculature, predominantly proximally. Cardiac conduction system disease is also commonly observed (see Limb-Girdle Muscular Dystrophy Overview).Neuropathy. Autosomal recessive Charcot-Marie-Tooth disease type 2B1 (CMT2B1; see Charcot-Marie-Tooth Neuropathy Type 2)Lipodystrophy. Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD2), in which adipocytes degenerate during puberty, followed by abnormal fat deposition, glucose intolerance, and late-onset diabetes mellitus [Cao & Hegele 2000, Hegele et al 2000, Speckman et al 2000]. Most LMNA mutations causing FPLD2 involve arginine at amino acid residue 482.Hutchinson-Gilford Progeria syndrome. Synonymous autosomal dominant mutations in codon 608 cause an aberrant splicing of the terminal 50 amino acids of exon 11 [De Sandre-Giovannoli et al 2003, Eriksson et al 2003, Capell & Collins 2006].Other related disorders. See Emery-Dreifuss Muscular Dystrophy, Genetically Related Disorders.
LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and reduced systolic function frequently accompanied by significant conduction system disease. LMNA-related DCM usually presents in adulthood either with conduction system disease commonly accompanied by arrhythmias or with symptomatic DCM, including heart failure or embolus from a left ventricular mural thrombus. However, LMNA-related DCM may be discovered in an asymptomatic person during a medical evaluation conducted for another reason (e.g., a routine preoperative ECG) or clinical screening of at-risk relatives....
Natural HistoryLMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and reduced systolic function frequently accompanied by significant conduction system disease. LMNA-related DCM usually presents in adulthood either with conduction system disease commonly accompanied by arrhythmias or with symptomatic DCM, including heart failure or embolus from a left ventricular mural thrombus. However, LMNA-related DCM may be discovered in an asymptomatic person during a medical evaluation conducted for another reason (e.g., a routine preoperative ECG) or clinical screening of at-risk relatives.Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. Conduction system involvement usually starts with disease of the sinus node and/or atrioventricular node that can manifest as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block (commonly first-degree heart block that progresses to second- and third-degree block).The following are also common:Symptomatic bradyarrhythmias requiring cardiac pacemakersSupraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome)Ventricular arrhythmias including frequent premature ventricular contractions (PVCs), ventricular tachycardia, and ventricular fibrillationSudden cardiac death may occur with progressive disease. Although more malignant, life-threatening arrhythmias may occur with longstanding and usually previously symptomatic DCM; sudden cardiac death can also be the presenting manifestation of LMNA-related DCM. Furthermore, only mild to moderate left ventricular dilatation despite progressive disease has been noted by some investigators. Occasionally, individuals with LMNA-related cardiomyopathy also manifest signs or symptoms of skeletal myopathy, which may be associated with elevated serum creatine kinase (CK) concentration.Large prospective longitudinal studies to define the range of natural history of individuals with LMNA mutations have not yet been published. Selected Reports Highlighting the Clinical Cardiovascular Manifestations of LMNA-Related DCMThe initial report of LMNA-related DCM by Fatkin et al [1999] included five families with conduction system disease characterized by sinus bradycardia, atrioventricular conduction block, and atrial fibrillation or flutter. Fifty-four percent of affected individuals required pacemaker implantation. Disease onset ranged from age 19 to 53 years (mean age 38 years). Symptoms of skeletal myopathy were not observed, although three members of one family with a p.Arg571Ser mutation in the lamin C isoform had elevated serum CK concentrations.Brodsky et al [2000] reported one family with a deletion in exon 6 (c.959delT) and severe DCM, conduction system disease, and variable skeletal muscle involvement. In five affected family members, three had Emery-Dreifuss muscular dystrophy-like and limb-girdle muscular dystrophy-like skeletal muscle myopathy; two had atrioventricular block, one had atrial arrhythmia, and one developed DCM. Two individuals progressed to heart failure; no family members required pacemaker implantation.Becane et al [2000] reported findings in 17 affected individuals and two asymptomatic relatives from a family with the nonsense mutation p.Gln6*. Eight other family members had died suddenly: in two, sudden death was the sole and presenting symptom; in six (3 of whom had prior pacemaker implantation), sudden death was preceded by arrhythmias and left ventricular dysfunction. Mean age of disease onset was 34.6 years (range 15-56 years). In total, 6/17 required pacemaker intervention, 7/17 had DCM, 7/17 had atrial arrhythmias, and 11/17 had atrioventricular block. Five of 17 also had skeletal muscle involvement manifest as contractures involving the Achilles’ tendon, neck, and elbow.Jakobs et al [2001] reported two families with conduction system disease characterized by progressive atrioventricular block and atrial arrhythmias. Onset was earlier in individuals with the p.Arg225* nonsense mutation (range 20-50 years) than in those with the p.Glu203Lys missense mutation (range 30-69 years). In both families DCM and heart failure occurred in the fifth and sixth decades and pacemaker implantation was common.Hershberger et al [2002] reported findings in eight members of a family with a highly penetrant missense mutation (p.Leu215Pro). Presentation was similar and included DCM preceded by atrioventricular block and atrial arrhythmia. Seven of eight required pacemaker intervention, although only two of the eight reported had progression to DCM.Sebillon et al [2003] identified three families with LMNA mutations from a cohort of 66 probands (47 with familial DCM and 19 simplex cases of DCM). LMNA mutations were identified only in families with conduction system disease. In one family, early-onset atrial fibrillation was observed, followed by DCM.Taylor et al [2003] identified LMNA mutations in four of 49 probands (40 familial cases, 9 simplex cases) with DCM. Of the four probands with LMNA mutations, three had a positive family history and one was a simplex case. Prognosis was worse for the 12 individuals with an LMNA mutation, with an event-free survival at age 45 years of 31% versus 75% for those with DCM who did not have LMNA mutations.In the largest series to date, Parks et al [2008] analyzed 324 unrelated probands with DCM of whom 187 had familial disease. Nineteen individuals (5.9% of all cases) had LMNA sequence variants, including 7.5% of probands with familial DCM and 3.6% of simplex cases. Conduction system disease and DCM were common in those who had LMNA variants:The average age of onset of conduction system disease in 56 persons was 40.8±9.6 years (median age 40 years).The average age of onset of DCM for 37 persons was 42.8±8.7 years (median age 42 years).An unusual finding in this study was that in six of the 19 kindreds (32%) with a protein-altering LMNA variant, at least one family member documented to have DCM did not have the LMNA variant. The authors suggest that this finding (termed “incomplete segregation”) indicates the existence of other causative factors (e.g., another causative mutation in a gene other than LMNA), challenging the assumption that a single-gene mutation explains all cardiac disease in a family with familial dilated cardiomyopathy.Pasotti et al [2008] described the findings in 60 of 94 individuals with a LMNA mutation from 27 families who had disease manifestations: 40 had DCM with atrioventricular block; 12 had DCM with ventricular tachycardia/ventricular fibrillation; six had DCM with atrioventricular block and EDMD-2; and two had atrioventricular block and EDMD-2. Fifteen underwent heart transplantation; 15 had sudden cardiac death events; and 12 appropriate ICD interventions were reported. Penetrance was 68% by age 39 years, 86% by age 59 years, and 100% in those older than age 60 years.
The differential diagnosis of LMNA-related dilated cardiomyopathy (DCM) relates to the general phenotype of DCM of unknown cause. Current evidence indicates that IDC (i.e., DCM of unknown cause) may be familial (and therefore possibly genetic) in 20%-50% of cases....
Differential DiagnosisThe differential diagnosis of LMNA-related dilated cardiomyopathy (DCM) relates to the general phenotype of DCM of unknown cause. Current evidence indicates that IDC (i.e., DCM of unknown cause) may be familial (and therefore possibly genetic) in 20%-50% of cases.With a clear pattern of familial disease, a genetic cause of DCM is likely (see Dilated Cardiomyopathy Overview).Compared to other genetic disorders, LMNA-related cardiomyopathy may be the most common cause of familial DCM with prominent conduction system disease (see Prevalence).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Following the diagnosis of LMNA-related dilated cardiomyopathy (DCM), if not previously completed, a three- to four-generation family history should be obtained, and the following evaluations performed:...
ManagementEvaluations Following Initial Diagnosis Following the diagnosis of LMNA-related dilated cardiomyopathy (DCM), if not previously completed, a three- to four-generation family history should be obtained, and the following evaluations performed:Comprehensive cardiovascular evaluationEvaluation for conduction system disease and arrhythmia:Personal and family history of presyncope, syncope, resuscitated sudden cardiac death, palpitations, and other symptoms of arrhythmiaElectrocardiography: Follow-up of abnormalities with additional testing as indicated (e.g., 24-hour monitoring or event monitors) Referral to a cardiologist or electrophysiologist for any indication of symptomatic disease Indicated in some patients: invasive electrophysiologic evaluation for conduction system disease Evaluation for left ventricular dysfunction and DCM:Family history for cardiomyopathy of any type, personal history of shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, chest pain Assessment of left ventricular function, most commonly by two-dimensional echocardiography to determine left ventricular dimensions and function. Alternatively, MRI provides similar data, and radionuclide ventriculography provides a measure of the ejection fraction.If there is evidence of DCM, referral to a cardiovascular specialist for comprehensive cardiovascular evaluation for evidence of other causes of DCM (e.g., coronary artery disease)Measurement of serum CK concentration to evaluate for skeletal myopathyHistory and physical examination for signs and symptoms of skeletal myopathy. If there is evidence of myopathy, referral to a neuromuscular disease specialist for evaluationTreatment of ManifestationsFor the general approach to managing DCM, see Dilated Cardiomyopathy Overview, Management.The Pasotti et al [2008] report (see Natural History) provides the most longitudinal data on LMNA-related DCM: 94 individuals with a LMNA mutation were followed for a median of 57 months (36-107 months). Additional reports of large prospective longitudinal natural history studies of LMNA-related DCM are not yet available.In 2008 the Heart Failure Society of America commissioned a guideline document for the management of genetic cardiomyopathies that included specific mention of LMNA-related DCM [Hershberger et al 2009 (see ; registration or institutional access required)]. Elements of the guidelines include the following: Because of the complexity of treatment interventions in LMNA-related DCM in symptomatic and asymptomatic individuals, referral to centers with special expertise in cardiovascular genetic medicine should be considered. For evaluation of a person with newly diagnosed DCM, see Evaluations Following Initial Diagnosis.Consider genetic testing and genetic counseling. Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia).With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this guideline was developed in large part because of the risk of lethal arrhythmias in persons with a LMNA mutation who have systolic function well above a left ventricular ejection fraction of 35%, the usual measure of systolic dysfunction below which ICDs are indicated in most US guidelines.Evaluate first-degree relatives, including extended family history, medical history, physical examination, echocardiogram, ECG. The management of LMNA-related DCM is focused on treatment of conduction system disease, arrhythmia, and DCM. Cardiac conduction system disease and arrhythmiasChronic atrial fibrillation unresponsive to cardioversion is treated with anticoagulants and agents for ventricular rate control.Other symptomatic supraventricular arrhythmias are treated with pharmacologic agents, and at times are augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations).Symptomatic bradyarrhythmias or asymptomatic but significant heart block is treated with an implantable electronic pacemaker. When a device is to be implanted, use of an implantable cardiac defibrillator (ICD) rather than an electronic pacemaker has been advocated and should be strongly considered, as the risk of mortality from sudden cardiac death usually accompanies supraventricular arrhythmias and conduction system disease. Sudden cardiac death presumably results from lethal tachyarrhythmias despite the presence of a pacemaker to treat bradyarrhythmias [van Berlo et al 2005, Meune et al 2006], and for this reason use of an ICD has been advocated for LMNA-related cardiomyopathy with significant conduction system disease and/or arrhythmia regardless of left ventricular ejection fraction [Hershberger et al 2009].Symptomatic ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, and resuscitated sudden cardiac death are treated with an ICD.When DCM is present and the left ventricular ejection fraction is less than 35%, an ICD should be implanted following the usual guidelines [Hunt 2005].LMNA-related DCMTreatment of symptomatic DCM, including heart failure, is pharmacologic with ACE inhibitors and beta blockers, as summarized in guideline documents [Hunt et al 2005].With progressive deterioration in left ventricular function (left ventricular ejection fraction <30%), some experts recommend full anticoagulation to prevent the development of left ventricular mural thrombus and embolic events including stroke.Cardiac transplantation or other advanced therapies should be considered with progressive DCM, advancing heart failure, and otherwise refractory disease in persons receiving comprehensive cardiovascular care from experts in the field [Hunt 2005].SurveillanceScreening and identification of DCM before the onset of symptoms enables the initiation of medical therapy that may delay disease progression. At-risk but clinically unaffected first-degree relatives are advised to undergo cardiovascular screening tests (medical history, physical examination, echocardiogram, and ECG) every two to five years and/or whenever new symptoms present [Burkett & Hershberger 2005, Hershberger et al 2009].Asymptomatic relatives who have the family-specific LMNA mutation are advised to undergo cardiovascular screening tests (medical history, physical examination, echocardiogram, and ECG) every one to two years and/or whenever new symptoms present [Burkett & Hershberger 2005, Hershberger et al 2009].Evaluation of Relatives at RiskWhen the disease-causing LMNA mutation has been identified in a family, molecular genetic testing can be offered to relatives at risk in order to facilitate prompt diagnosis, surveillance, and treatment in those in whom the disease-causing LMNA mutation has been detected.If molecular genetic testing is not available, the first-degree relatives of a proband with LMNA-related DCM should be evaluated by medical history, physical examination, echocardiogram, and ECG to determine if any have detectable DCM and/or conduction system disease. Note: Because the age of onset is variable and penetrance is reduced, a normal baseline echocardiogram and ECG in a first-degree relative who has not undergone molecular genetic testing does not rule out LMNA-related DCM in that individual, and the recommendations set forth in Surveillance should be followed.Any abnormal cardiovascular test results in a relative of a proband should be followed up with a full cardiovascular assessment to evaluate for any acquired causes of disease (e.g., coronary artery disease). Results on screening tests that do not meet criteria for DCM but do show some abnormality (e.g., left ventricular enlargement but normal function; decreased ejection fraction but normal-sized left ventricle) may reflect variable expression of LMNA-related DCM in that relative. Close surveillance (e.g., cardiovascular testing every 1-2 years) for progression of cardiovascular disease is recommended for such individuals.Note: Because most LMNA-related DCM is adult onset, clinical screening is usually not recommended for children or adolescents unless onset of disease in the proband was in these age groups, or unless cardiovascular symptoms are present.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. LMNA-Related Dilated Cardiomyopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLMNA1q22Prelamin-A/CHuman Intermediate Filament Database LMNA (lamin C1) Human Intermediate Filament Database LMNA (lamin A) Human Intermediate Filament Database LMNA (lamin C2) IPN Mutations, LMNA LMNA homepage - Leiden Muscular Dystrophy pagesLMNAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for LMNA-Related Dilated Cardiomyopathy (View All in OMIM) View in own window 115200CARDIOMYOPATHY, DILATED, 1A; CMD1A 150330LAMIN A/C; LMNANormal allelic variants. LMNA comprises twelve exons. Alternative splicing of exon 10 produces two proteins, lamin A and lamin C (see Normal gene product).Pathologic allelic variants. See Table 2. More than 200 sequence variants in LMNA have been reported (see Leiden Muscular Dystrophy site). LMNA-related dilated cardiomyopathy (DCM) results from missense mutations, with occasional nonsense or splice-site mutations and short insertions or deletions of LMNA.Table 2. Selected LMNA Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1711C>Ap.Arg571SerNM_005572.3 1NP_005563.1c.16C>Tp.Gln6*NM_170707.2 2NP_733821.1c.607G>Ap.Glu203Lysc.644T>Cp.Leu215Proc.673C>Tp.Arg225*c.959delTp.Arg321Glufs*159See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1.This transcript variant uses an alternate splice site in the 3' coding region, compared to variant NM_170707.2, resulting in a shorter isoform (also known as lamin C) with a C terminus distinct from that in the lamin A isoform.2. This transcript variant encodes isoform 1, also known as lamin A.Normal gene product. Alternative splicing of exon 10 produces two proteins: lamin C, with 572 amino acids (NM_005572.3; NP_005563.1) and lamin A (NM_170707.2; NP_733821.1), which is identical to lamin C for the first 566 amino acids, but has an additional 98 terminal amino acids (total of 664).Both lamins A and C are structural proteins of the inner nuclear membrane and are found in many different tissues [Capell & Collins 2006].Abnormal gene product. The mechanism of cellular injury that causes LMNA-related DCM remains incompletely understood. Because lamin A/C is a structural protein of the nuclear membrane, it has been suggested that fragility of the nuclear membrane in the setting of repetitive contraction of skeletal or cardiac muscle may predispose to nuclear injury and cellular apoptosis. An alternative hypothesis suggests that an abnormal lamin A/C protein may disrupt the chromatin/lamin-associated protein complex, thereby disturbing gene expression.