Hypertrophic cardiomyopathy—the clinical challenge of managing a hereditary heart condition

Jens Mogensen*, Ajay Bahl and William J McKenna

Department of Cardiological Sciences, St. George's Hospital Medical School, Cranmer Terrace, Tooting, SW17 0RE, London, UK

* Corresponding author. Tel.: +44-20-8725-2002; fax: +44-20-8682-0944
E-mail address: jmogense{at}sghms.ac.uk

See doi:10.1016/S1095-668X(00)00522-5for the article to which this editorial refers.

Within this issue of the European Heart Journal van Lange and coworkers investigated current genetic knowledge and practice of Dutch cardiologists regarding counselling and DNA-testing of familial hypertrophic cardiomyopathy (HCM). The study revealed that Dutch cardiologists regarded their genetic knowledge as insufficient and demonstrated that a substantial proportion of HCM patients did not receive adequate information about the hereditary nature of their disease. In addition clinical investigations of relatives at risk of having inherited the disease and genetic analysis to identify disease-causing mutations in affected families were seldom initiated. The authors concluded that the current genetic care for HCM patients is poor and that knowledge needs to be enhanced by improved education of medical students and cardiologists and development of specialised clinics.

HCM is the most common inherited cardiac condition with a prevalence in young adults of at least 1:500. The condition is diagnosed by demonstration of unexplained thickening of the left ventricle. Disease manifestations typically develop during adolescence although clinical presentation may occur at any age.1 The clinical expression is heterogeneous and varies even between related individuals carrying identical mutations.2 The major clinical problems are reduced exercise capacity, risk of arrhythmia, thrombo-embolic events, and sudden death. Patients at high risk of sudden death can be identified by non-invasive evaluation and treatment with ICD with or without anti-arrhythmic drugs is effective.3,4

HCM is inherited in an autosomal dominant mode and disease carriers will have a 50% risk of passing the disease gene on to each of their children. Molecular genetic studies over the past decade have defined HCM as a disease of the cardiac sarcomere with the identification of disease-causing mutations in eight different contractile protein genes.5 With advances in diagnostic molecular genetic techniques it is now feasible to perform mutation analysis for use in clinical practice. Genetic investigation of the eight recognised disease-causing HCM genes is practical within a reasonable timeframe and will result in a genetic diagnosis in about 50–60% of unselected HCM probands. The fact that comprehensive mutation analysis fails to identify gene abnormalities in a significant proportion indicates that more disease genes have yet to be identified. In addition, other diseases mimicking the phenotypic expression of HCM such as left ventricle non-compaction, cardiac variant of Fabry's disease, glycogen storage diseases, the recently reported AMP activated protein kinase disease (PRKAG2) associated with Wolff–Parkinson–White (WPW)-syndrome and conduction abnormalities, Friedreich's ataxia, mitochondrial diseases, and incomplete expression of syndromes like Noonan and LEOPARD may account for a proportion of patients diagnosed as HCM.6–10

It is recommended clinical practice that cardiologists should inform their patients that HCM is familial and that cardiological evaluation of relatives ‘at risk’ is warranted to ensure early diagnosis and treatment to avoid severe complications and sudden death in otherwise undiagnosed individuals.11 However, the logistics of offering and performing family evaluation are not inconsiderable within the context of a routine cardiology clinic and ideally should involve a joint clinic with clinical geneticists. It is desirable to hand out written information about the disease to index patients at their first clinical visit including an offer of clinical investigation addressed to relatives at risk of having inherited the disease. In accordance with established ethical guidelines index patients should distribute the information and relatives return a reply slip to the department, which subsequently arrange clinical investigation if wanted. Relatives do often have questions following receipt of written information and it is important to have a contact person available who has knowledge of the disease. A specially trained and experienced nurse may serve as coordinator of the investigations and as contact person for the family. Following clinical investigations, healthy children without signs and symptoms of disease are typically recommended follow-up every 2–3 years until early puberty. During adolescence when most individuals develop signs or symptoms of disease, follow-up is most frequently performed on a yearly basis. The follow-up scheme for healthy adults is individualised and depends on the age of the person, the family history with respect to age of onset of disease, and severity of disease expression including the number of sudden deaths. For instance, termination of follow-up could be considered in adult healthy individuals with a benign family history although discharged individuals should be informed that HCM caused by one of the disease genes, in particular myosin binding protein C, may have a late onset and if cardiac related symptoms develop they should be seen by a cardiologist.

Clinical features of HCM may be subtle even in individuals who develop severe disease related complications. Current clinical methods for cardiac evaluation including, 12 lead ECG, echocardiography, and MRI may not identify all such individuals. The most definitive way to reveal individuals at risk of developing HCM is the identification of a disease-causing mutation by genetic investigation of recognised HCM genes. Establishment of a genetic diagnosis enables the physician to discharge non-carriers of the mutation since they are not at risk of developing the disease and to focus clinical resources on mutation carriers. The knowledgeof an individual's carrier status help the physician to interpret symptoms and to choose appropriate investigations such as long-term monitoring for arrhythmia. In addition to the clinical advantages of genetic diagnosis HCM families often find it relieving to obtain an accurate answer to whether they do or do not carry a mutation. They are usually aware of the hereditary nature of the disease from other relatives and prefer clarification to the uncertainty of not knowing their carrier status.

It remains to be clarified if the costs of genetic investigations outweigh the savings of the health care system by termination of clinical screening of non-carriers. However, the fact that genetic investigations have become cheaper and less labour intensive within recent years make it likely that genetic diagnosis will ultimately be cost-effective for the health care system. Besides equipment for genetic analysis staff with specific knowledge of the molecular aspects of HCM is needed to interpret results of the investigations and ensure that genetic changes identified in patients are truly disease causing and not just rare but normal variants within the human genome. Experienced physicians with knowledge of both genetic and clinical aspects of the disease should inform patients about the results and implication of the genetic investigations in close collaboration with clinical geneticists to ensure adequate counselling of patients.

There is no doubt that the number of diseases in which genetic diagnosis will have clinical consequences for patients will continue to increase and as pointed out by van Lange et al. training of physicians in the aspects of genetics and counselling is important. The implementation of genetic diagnosis into clinical practice is challenging but once in place it has the potential to benefit clinical diagnosis and management.

References

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Related articles in EHJ:

Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era?
I.M van Langen, E Birnie, N.J Leschot, G.J Bonsel, and A.A.M Wilde
EHJ 2003 24: 560-566. [Abstract] [Full Text]  




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