Often seen but rarely recognised: cardiac complications of lamin A/C mutations

Jop H van Berloa, Denis Dubocb and Yigal M Pintoa,*

a Department of Cardiology, University Hospital Maastricht and Experimental and Molecular Cardiology, Maastricht, Netherlands
b Service de Cardiologie, GH Cochin, Paris, France

* Correspondence to: Yigal M. Pinto, Department of Cardiology, University Hospital Maastricht and Experimental and Molecular Cardiology, CARIM, P. Debyelaan 25, Postbus 5800, 6202 AZ, Maastricht, Netherlands. Tel.: +31-433877097; fax: +31-433875104
E-mail address: Y.pinto{at}cardio.azm.nl

This editorial refers to "A novel mutation, Ser143Pro, in the lamin A/C gene is common in Finnish patients with familial dilated cardiomyopathy"1 by S. Kärkkäinen on page 885.

Most cardiologists are quite alarmed when they learn that a patient carries a mutation in the SCN5a gene responsible for "Brugada" syndrome. In contrast, when confronted with a family carrying a lamin A/C mutation, they are often less aroused. In this issue of the Journal, a founder mutation in the lamin A/C gene that causes cardiomyopathy with a particularly grave prognosis is reported.1 This finding underscores the fact that mutations in the lamin A/C gene very often affect the heart, often with devastating consequences. However, in contrast with SCN5a and other genes known to cause sudden death, the role of lamin mutations in heart failure as well as sudden death is only now beginning to be appreciated. The paper in this issue by Kärkkäinen et al. underscores the need to increase our awareness and understanding of cardiac pathologies caused by lamin mutations.

Pathophysiology of lamin A/C mutations

The lamin A/C gene codes, by alternative splicing, for the nuclear envelope proteins lamin A and lamin C. Mutations in lamin A/C have been related to different diseases, such as Emery–Dreifuss muscular dystrophy, Dunnigan's type familial partial lipodystrophy a distinct generalized lipoatrophy syndrome, limb-girdle muscular dystrophy, mandibuloacral dysplasia, axonal neuropathy CMT2B1, and dilated cardiomyopathy (DCM). Recently, interest in this protein has been further heightened by the finding that lamin A/C mutations also cause some forms of progeria, characterised by premature aging and death in the second decade of life.

Although the broad range of diseases caused by lamin A/C mutations suggests that this protein plays a vital role in diverse biological systems, the precise pathophysiology of lamin A/C mutations remains enigmatic.

Some light has been shed by the recent development of lamin knockout models. Mice lacking lamin A/C also develop cardiomyopathy, thus providing an animal model to study the cardiac effects of lamin dysfunction.2 One current hypothesis on how lamin A/C dysfunction may affect cellular and cardiac biology states that disturbed lamin function impairs nuclear stability. In turn, this may hinder nuclear functions, as has been recently suggested.3 A second hypothesis, not necessarily incompatible with the first one, states that lamins A and C are necessary to direct the proper function of transcription factors, so lamin dysfunction could impair the regulation of gene expression.4 Finally, it has been proposed that vital cytoskeletal proteins adhere to lamins, and that the loss of lamin function interferes with cytoskeletal functions. Despite these insights, there is still no clear concept explaining how these functions of lamins explain the cardiac pathology seen in carriers of lamin A/C mutations.

Prevalence of lamin A/C mutations

Nevertheless, the idea that lamin A/C must be important for the heart is irrefutably demonstrated by the finding that mutations in the lamin A/C gene can cause cardiomyopathy. In the last few years more than 14 different genes have been found to cause dilated cardiomyopathy when mutated.5 When all studies reporting one of these causative genes for hereditary dilated cardiomyopathy are examined together, lamin A/C mutations emerge as the most frequently reported by far, with more than half of all published reports involving patients with a mutation in the lamin A/C gene.6 Part of the high discovery rate of lamin A/C gene mutations could be due to the specific phenotype of the DCM caused by mutations in this gene, but this does not seem to fully explain the high frequency of reports compared to other genes. Within the group of hereditary cardiomyopathies, lamin A/C mutations seem to comprise a highly prevalent, if not the most prevalent group.

Assuming that 10% of heart failure cases are familial, and that half may be caused by mutations in the lamin A/C gene, as has been suggested, then 2.5–5% of the heart failure population harbour a mutation in the lamin A/C gene. This prevalence is probably excessive, but decreasing estimates by a factor of 10 still leaves ~0.5% of all patients with heart failure carrying a mutation in the lamin A/C gene. This means that in the Netherlands, which has 200,000 heart failure patients, 1000 of them may carry a mutation in the lamin A/C gene. Consistent with this idea, since 2001, 150 carriers of a mutation in this gene have been identified in the Netherlands alone. The relative ease with which we encounter these mutations again underscores the notion that lamin A/C mutations are probably more prevalent than currently appreciated.

By comparison, 108 patients with the Brugada syndrome were reported in 1998, 6–9 years after the initial publication.7 The first mutation in the lamin A/C gene was reported in 1999 by Bonne et al. In the 5 years since that report appeared, over 300 patients with a lamin A/C gene mutation causing heart failure have been reported. By comparison, recent estimates of the incidence of Brugada syndrome range from 5 to 66 per 10,000. However, this estimate is based on populations in parts of Southeast Asia and a small region in Japan and is probably an overestimation for the rest of the world.8 Therefore, although there are fewer clinical clues to arouse suspicions of lamin A/C mutations, their prevalence seems to have caught up with that of the Brugada syndrome.

Clinical characteristics of lamin A/C mutations

Clinically distinguishing characteristics of the cardiac effects of lamin A/C mutations have not been clearly defined. Only a few clinical clues suggestive of the presence of a lamin A/C mutation have been described. Previous retrospective reports have shown that heart failure caused by lamin A/C gene mutations carries a worse prognosis than other forms of dilated cardiomyopathy.9 In this issue of the Journal, a Finnish founder mutation in the lamin A/C gene is presented that caused dilated cardiomyopathy in five unrelated Finnish families.1

When one pools the available clinical data on published patients and carriers of lamin A/C mutations, it is clear that the cardiac effects of the disease usually start before the age of 30 with rather mild conduction system disease (first-degree atrioventricular block) or atrial arrhythmias. The conduction system disease gradually worsens until half of the patients are in need of a pacemaker. Only 15–20 years later, most patients begin to develop heart failure. However, almost half of the patients die suddenly before they reach the stage of overt heart failure. Out of all the published cases, sudden death has been responsible for up to 50% of total mortality due to lamin A/C mutations.6 The events leading to death in these patients have not, however, been fully established, and it is not clear if an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden death would benefit these patients. Nevertheless, it is known that sudden death can occur despite pacemaker therapy and that spontaneous or induced ventricular dysrhythmias have been found in patients with lamin A/C gene mutations. While there is no debate regarding the need for ICD therapy in secondary prevention, the efficacy of ICD therapy as primary prevention needs to be addressed in a prospective study.

In line with these notions, in the same Finnish population described in this issue, the survival of mutation carriers was poor, adding yet another lamin A/C mutation to the grim list of deadly cardiomyopathies caused by these mutations. It is of interest that the prognosis of these patients is also clearly unfavourable even compared to other dilated cardiomyopathies (see Fig. 3a in the paper by Kärkkäinen et al.).

In conclusion, lamin A/C mutations are frequently reported as a cause of cardiomyopathy, often causing sudden death at a young age, even before patients reach clinically overt heart failure. Still, lamin A/C mutations are not regularly screened for and there are no clinical guidelines to aid in the diagnosis and treatment of this syndrome.

This calls for a pro-active strategy for identifying these patients and evaluating the proper mode of treatment.

Acknowledgments

JHvB is supported by NHS Grant 2002T016.

Footnotes

1 10.1016/j.ehj.2004.01.020 Back

References

  1. Kärkkäinen S, Heliö T, Miettinen R et al. A novel mutation, Ser143Pro, in the lamin A/C gene is common in Finnish patients with familial dilated cardiomyopathy. Eur. Heart J. 2004;25:885–893.[Abstract/Free Full Text]
  2. Nikolova V, Leimena C, McMahon AC et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 2004;113(3):357–369.[Abstract/Free Full Text]
  3. Lammerding J, Schulze PC, Takahashi T et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 2004;113(3):370–378.[Abstract/Free Full Text]
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  6. Van Berlo JH, de Voogt WG, van der Kooi AJ et al. Sudden death cannot be prevented by pacemaker therapy in patients with lamin A/C mutations. Circulation. 2002;106(19):ll-645.
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  9. Arbustini E, Pilotto A, Repetto A et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J. Am. Coll. Cardiol. 2002;39(6):981–990.[CrossRef][Medline]

Related articles in EHJ:

A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy
Satu Kärkkäinen, Tiina Heliö, Raija Miettinen, Petri Tuomainen, Paula Peltola, Juha Rummukainen, Kari Ylitalo, Maija Kaartinen, Johanna Kuusisto, Lauri Toivonen, Markku S Nieminen, Markku Laakso, and Keijo Peuhkurinen
EHJ 2004 25: 885-893. [Abstract] [Full Text]  




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