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This basically cross-sectional study from the Harvard Medical School explores genetic links between childhood-onset left ventricular (LV) hypertrophies and adult-onset hypertrophic cardiomyopathy (HCM). The investigators recruited 84 unrelated children (75% boys) who received a diagnosis of idiopathic LV hypertrophy when ≤15 years of age (mean, 7±6 years; range 2 days to 15 years).
They searched for mutations known to cause adult cardiomyopathies (in 8 genes encoding sarcomere proteins: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2, ACTC) or early-onset LV hypertrophy (2 genes encoding metabolic proteins: PRKAG2, LAMP2). Mutations were found in about half (25/51) the patients with no apparent family history of HCM and two-thirds (21/33) of those classified as having familial cardiomyopathy (49% [95%CI, 36%–62%] vs 64% [95%CI, 45%–80%]; n.s.).
The study addresses an issue of particular relevance to clinicians and biologists: namely, the genetic basis of HCM in children. Despite scanty information on patient recruitment and exclusion of systemic diseases (as well as some rather vague outcome considerations), the central conclusion from this indepth molecular study that many a genetic cause can be attributed to many cases of childhood idiopathic HCM appears fundamentally sound.
An HCM echocardiographic phenotype in pediatric age is a particularly challenging finding. The spectrum of the possible causes is much wider in children than in adult patients. The recent ESC position paper (1) lists 34 possible determinants of a hypertrophic phenotype, 30 of which are genetic. In adults most of these causes are theoretical, since many of the possible underlying conditions would have led either to a much earlier symptom-based diagnosis or to death before adulthood.
By contrast, in children all these entities are real possibilities which need to be considered in a differential diagnosis based on a wide variety of considerations, including clinical traits, type of inheritance, enzymatic dosages, biopsy study of skeletal muscle tissue or myocardium, and mitochondrial DNA analysis. Two recent registry studies of children with HCM echocardiographic phenotype give some idea of the ratio between “idiopathic” and non-idiopathic forms. In the Australian national registry (2), 69% of the 80 children with HCM had idiopathic disease, and the remaining 31% were considered to have secondary forms (most often Noonan syndrome).
Remarkably, familiarity was apparent only in 21% of all the children under study. More recently, the U.S.A. Pediatric Cardiomyopathy Registry (3) were able to report data on 855 HCM patients under 18 years of age. While 74% were classified as having idiopathic disease, 9% had inborn metabolic errors, 9% had malformation syndromes and 8% had neuromuscular disorders.
In clinical practice, even after exclusion of cardiomyopathies related to in-born metabolic defects, neuromuscular diseases and syndromic forms, the genetic basis of childhood HCM is a largely uncharted terrain.
Several questions need to be addressed:
The study reported by Morita et al is provides the first available attempt to address such
questions based on a large series of patients. The investigators consider 84 children with unexplained LV hypertrophy in whom secondary forms of HCM appear to have been reasonably excluded.
In about half (54%) the patients, it was possible to identify a genetic cause by examining 10 genes known to determine HCM in adults. Remarkably, no significant frequency difference was apparent between sporadic and familiar forms of HCM. In all but one of the children the implicated mutations occurred in sarcomeric genes. The authors rightly remark that despite the major clinical differences between childhood LV hypertrophy and adult HCM, an etiological relationship is apparent between the two conditions.
Notably, 11 of the 25 gene mutations identified in the study had not previously been reported in adults (or children). As many as 17 of the mutations occurred in the MYBPC3 gene, and the vast majority (n=13) were missense (rather than truncation) mutations. The authors note that this high frequency may signify that missense mutations lead to greater functional impairment than truncation mutations.
Clinicians will be interested in knowing whether cases of childhood HCM with an identifiable genetic aetiology are phenotypically different from the other cases. No evidence of any morphological or functional difference emerged from this study (without a well defined population) which was not designed to address such questions.
Some of the investigators’ observations are also of relevance to adult HCM. In as many as twothirds of the cases of presumptive sporadic HCM available for familial study, the investigators were able to identify a mutation (mainly MYBPC3) in a parent with no current expression of HCM phenotype.
Considered in its entirety, this work (despite obvious limitations) highlights the interest and relevance of studying genetic determinants of childhood HCM and should encourage more research in this particularly fertile field.
1. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kühl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2008;29:270-6.
2. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115:773-81.
3. Pedra SR, Smallhorn JF, Ryan G, Chitayat D, Taylor GP, Khan R, Abdolell M, Hornberger LK. Fetal cardiomyopathies: pathogenic mechanisms, hemodynamic findings, and clinical outcome. Circulation. 2002;106:585-91.
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