Diagnosing the Heart of the Problem
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© 1993 Nature Publishing Group http://www.nature.com/naturegenetics • editorial nature volume 4 no. 3 july 1993 Diagnosing the heart of the problem In the glamorous world of professionaJ sports, into the spotlight. Last year, the teenage son of few athletes are lucky enough to escape physicaJ Terry Yorath, a former Welsh international soccer injury at some time or other. Debilitating ailments player and the current team manager, suddenly such as torn anteriorcruciate ligaments and rotator collapsed and died while playing soccer at home. cuffs are seemingly as commonplace in the sports And just three months ago, on April 29, Reggie pages as the anatomy textbooks. There is a growing Lewis, the 27-year-old captain of the Boston awareness, however, that the strenuous physical Celtics, collapsed onto the parquet floor of the exertion of competitive athletes carries its own Boston Garden during a crucial basketball playoff potentially life-threatening risks. In the United game. Initial tests by the team physician failed to States, heart failure, not physicaJ injury, is the discern a serious problem, but when Lewis most common form ofsudden death among young returned to the game he complained of further athletes: more than 100 athletes have died of dizzy spells. Later in hospital, the team doctor sudden heart failure during the past 10 years, assembled what he called a 'Dream Team' of 12 whereas only half that figure succumbed to severe eminent cardiologists who proclaimed that Lewis physicaJ trauma. suffered from hypertrophic cardiomyopathy, A relatively well-known cause of sudden death invoking instant memories of Gathers. Not among athletes is Marfan syndrome, which claimed surprisingly, the front page of The Boston Globe the life of volleyball player Flo Hyman. Marfan declared: "Lewis' career called probably over". syndrome is characterized by excessive growth of But the saga then took a bizarre twist, illustrating limb bones (an obvious advantage for some sports) the severe difficulty of clinical diagnosis for this but also by a weakened aorta which is prone to problem. Reportedly upset by the lack of direct rupture'. But perhaps the best known sports fatality consultation with his cardiologists, Lewis in the United States was Hank Gathers, a talented transferred to the Brigham and Women's Hospital 23-year-old college basketball player who collapsed for a second opinion. After extensive tests, it was from heart failure during a game on March 3, announced that Lewis actuaJly had a much more 1990, and died hours later. Gathers suffered from benign, neurological condition, neurocardiogenic hypertrophic cardiomyopathy, which affects l in syncope (sudden loss of consciousness brought 5,000 people and is characterized by increased about by abnormal signals from the vagus nerve thickening ofthe heart muscle and a life-threatening to the heart), which can easily be managed with~ arrhythmia. Gathers had fainted on court three blockers. This left some highly distinguished months earlier, but his subsequent medication cardiologists bickering in public about the accuracy (inderaJ) left him feeling lethargic, and he had of Lewis' diagnosis, with one member of the taken a reduced dose the night he died. original group ofphysicians openly sceptical about Lately, two widely reported events have thrust the milder diagnosis2• the problem ofhypertrophic cardiomyopathy back Lewis' plight has prompted officials in Boston nature genetics volume 4 july 1993 211 © 1993 Nature Publishing Group http://www.nature.com/naturegenetics editorial • and other US cities to advocate screening programs dozen families with FHC did not show linkage to for young athletes to pinpoint potential cases at chromosome 1, suggesting even greater genetic risk of sudden cardiac failure. (Some universities heterogeneity. In this issue8, Ketty Schwartz and do screen their student athletes for Marfan coworkers describe a third FHC locus on chromo syndrome.) In the United Kingdom, a pilot study some 11,havingfirstruledoutanumberofcandidate is underway to detect warning signs in teenage genes. Other loci for FHC may still be found. athletes using echocardiography, but there are Progress is also being made in another congenital doubts that screening will be either feasible or heart disorder associated with ventricular effective3, in part because healthy athletes hypertrophy and sudden death (and which was frequently have hypertrophic hearts anyway. raised at one time in connection with Lewis' Back to the bench: With time, an accurate molecular condition) - Long QT syndrome (LQT)9. The diagnosis of hypertrophic cardiomyopathy may discovery two years ago by Mark Keating's group become practical, but there are considerable hurdles that the locus for this form ofventricular arrhythmia to overcome, not least ofwhich is the heterogeneity was tightly linked to the Harvey ras-1 gene on of the condition. However, there have been some chromosome 11 p prompted speculation that the encouraging advances in unravelling the molecular defective gene was an oncogene (ras can act as a basis of hypertrophic cardiomyopathy of late, regulator of cardiac ion channels). However, this allowing the field to recover from an ignominious intriguing notion has since been dismissed and beginning. More than 50% of hypertrophic researchers are down to a few hundred kilobases of cardiomyopathy cases are known to be familial, DNA in their search for the gene. New data indicate inherited as an autosomal dominant trait, and most that there is also a second locus for LQT10, as some of the others are likely to be sporadic forms. In families do not show linkage to chromosome 11. 1979, John Darsee and colleagues reported that There is one curious difference, however: deaths in familial hypertrophic cardiomyopathy (FHC) was these non-linked families are reported to occur in linked to the HLA locus, only to retract that paper subjects at rest, rather than during periods ofintense (among many others) four years later after admitt exercise or excitement. ing the data had been fabricated. It was not until Eventually, the molecular insights into the multiple 1989 that the principal FHC locus was mapped to congenital causes of heart disease will facilitate the chromosome 14. Studies from the group of J.G. diagnosis ofthese conditions. But the complexity of and Christine Seidman at the Harvard Medical the ~-MHC gene, which contains 40 exons, does not School have elegantly demonstrated that the make screening of the sole known cause of FHC common form of FHC is caused by a number of straightforward, even though such tests are being mutational mechanisms involving the ~-cardiac offered for families at risk in Britain and elsewhere. myosin heavy chain gene4·6, which encodes one of The effectiveness of treatment of the disease with the major contractile proteins of the cardiac drugs such as amiodarone is also uncertain3, myocyte. These mutations include unequal crossing although Reggie Lewis can take heart (no pun over (with the adjacent a-heavy chain gene), gene intended) that at least one professional basketball deletions and a host ofmissense mutations clustered player with cardiomyopathy has played for ten in the globular head of the myosin polypeptide. years while taking medication. Nevertheless, Celtics Unequal crossing-over initially provided an fans will be hoping that the 'Dream Team's' attractive explanation for the abundance of bleak prognosis will suffer the same fate as that of sporadic hypertrophic cardiomyopathy cases, but their former franchise player, Larry Bird-an early the original family presenting with the hybrid retirement. D myosin gene has subsequently been found to 6 References contain a deleterious missense mutation • 1. McKusick, V. Nature 352, 279-281 (1993). There are at least two other loci for FHC that have 2. Johnson, W.O. Sports 11/ustr. May 24, 36-41 (1993). in Nature Genetics. In 3. Clark, A.L. & Coats, A.J.S. Br. med. J. 306, 409-410 been identified, as reported (1993). the first linkage study7, a new locus for what seems 4. Tanigawa, G. et a/. Ce// 62, 991-998 (1990). to be a severe form of FHC was assigned by the 5. Geisterfer-Lowrance, A.A .T. et al. Cell 62, 999-1006 (1990). Harvard group to chromosome lq. A cluster of 6. Watkins, H. et al. New Engl. J. Med. 326, 1108-1114 (1992). candidate genes fall within this region, including 7. Watkins, H. et al. Nature Genet. 3, 333-337 (1993). 8. Carrier, L. et al. Nature Genet. 4, 311-313 (1993). tropomyosin, troponin I and actin, but the exact 9. Keating, M. et al. Science 252, 704-706 (1991). gene remains a mystery for now. At least half-a- 10. Curran, M. et al. J. clin. Invest. (in the press). lume 4 1993 212 nature genencs vo july .