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Stanford BIO 230 - Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

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brief report The new england journal of medicine n engl j med 350;26 www.nejm.org june 24, 2004 2682 Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child Markus Schuelke, M.D., Kathryn R. Wagner, M.D., Ph.D., Leslie E. Stolz, Ph.D., Christoph Hübner, M.D., Thomas Riebel, M.D., Wolfgang Kömen, M.D., Thomas Braun, M.D., Ph.D., James F. Tobin, Ph.D., and Se-Jin Lee, M.D., Ph.D. From the Departments of Neuropediatrics(M.S., C.H.), Pediatric Radiology (T.R.), andNeonatology (W.K.), Charité, UniversityMedical Center Berlin, Berlin; the Depart-ments of Neurology (K.R.W.) and MolecularBiology and Genetics (S.-J.L.), Johns Hop-kins University School of Medicine, Balti-more; the Department of Cardiovascularand Metabolic Diseases, Wyeth Research,Cambridge, Mass. (L.E.S., J.F.T.); and theInstitute of Physiological Chemistry, Mar-tin Luther University, Halle-Wittenberg, Ger-many (T.B.). Address reprint requests toDr. Schuelke at the Department of Neuro-pediatrics, Charité, University Medical Cen-ter Berlin, Augustenburger Platz 1, D-13353Berlin, Germany, or at [email protected] Engl J Med 2004;350:2682-8. Copyright © 2004 Massachusetts Medical Society. uscle wasting and weakness are among the most common in- herited and acquired disorders and include the muscular dystrophies,cachexia, and age-related wasting. Since there is no generally acceptedtreatment to improve muscle bulk and strength, these conditions pose a substantialburden to patients as well as to public health. Consequently, there has been consider-able interest in a recently described inhibitor of muscle growth, myostatin, or growth/differentiation factor 8 (GDF-8), which belongs to the transforming growth factor b superfamily of secreted proteins that control the growth and differentiation of tissuesthroughout the body. The myostatin gene is expressed almost exclusively in cells ofskeletal-muscle lineage throughout embryonic development as well as in adult ani-mals and functions as a negative regulator of muscle growth. 1,2 Targeted disruption ofthe myostatin gene in mice doubles skeletal-muscle mass. 1 Conversely, systemic over-expression of the myostatin gene leads to a wasting syndrome characterized by ex-tensive muscle loss. 3 In adult animals, myostatin appears to inhibit the activation ofsatellite cells, which are stem cells resident in skeletal muscle. 4,5 The potential relevance of myostatin to the treatment of disease in humans has beensuggested by studies involving mdx mice, which carry a mutation in the dystrophin geneand therefore serve as a genetic model of Duchenne’s and Becker’s muscular dystro-phy. 6 For example , mdx mice that lacked myostatin were found not only to be strongerand more muscular than their mdx counterparts with normal myostatin, but also to havereduced fibrosis and fatty remodeling, suggesting improved regeneration of mus-cle. 7 Furthermore, injection of neutralizing monoclonal antibodies directed againstmyostatin into either wild-type or mdx mice increases muscle mass and specific force,suggesting that myostatin plays an important role in regulating muscle growth in adultanimals. 8,9 The function of myostatin appears to be conserved across species, since mutationsin the myostatin gene have been shown to be responsible for the “double-muscling”phenotype in cattle. 10-13 The phenotypes of mice and cattle lacking myostatin and thehigh degree of sequence conservation of the predicted myostatin protein in many mam-malian species have raised the possibility that myostatin may help regulate musclegrowth in humans. We report the identification of a myostatin mutation in a child withmuscle hypertrophy, thereby providing strong evidence that myostatin does play an im-portant role in regulating muscle mass in humans.A healthy woman who was a former professional athlete gave birth to a son after a nor-mal pregnancy. The identity of the child’s father was not revealed. The child’s birthweight was in the 75th percentile. Stimulus-induced myoclonus developed severalmcase reportDownloaded from www.nejm.org at Stanford University on September 22, 2004.Copyright © 2004 Massachusetts Medical Society. All rights reserved.n engl j med 350;26 www.nejm.org june 24, 2004 brief report 2683 hours after birth, and the infant was admitted tothe neonatal ward for assessment. He appeared ex-traordinarily muscular, with protruding musclesin his thighs (Fig. 1A) and upper arms. With theexception of increased tendon reflexes, the physi-cal examination was normal. Hypoglycemia andincreased levels of testosterone and insulin-likegrowth factor I were excluded. Muscular hypertro-phy was verified by ultrasonography when the in-fant was six days of age (Fig. 1B and 1C). Dopplerechocardiography and electrocardiography per-formed soon after birth and every six months there-after were consistently normal. At 4.3 years of age(body-surface area, 0.78 m 2 ), the child had a pulserate of 95 beats per minute, a left ventricular ejectionfraction of 70 percent, fractional shortening at themidwall of 56 percent, and a cardiac output of 2.81liters per minute, with a left ventricular measure-ment of 3.42 cm during diastole (50th percentile)and 1.99 cm (25th percentile) during systole andrespective septal measurements of 0.59 cm (75thpercentile) and 0.81 cm (75th percentile).The stimulus-induced myoclonus gradually sub-sided after two months. The child’s motor andmental development has been normal. Now, at 4.5years of age, he continues to have increased musclebulk and strength, and he is able to hold two 3-kgdumbbells in horizontal suspension with his armsextended.Several family members (Fig. 1D) have been re-ported to be unusually strong. Family member II-3was a construction worker who was able to unloadcurbstones by hand. The 24-year-old mother of thechild (III-5) appeared muscular, though not to theextent observed in her son; she did not report anyhealth problems. No family members aside fromthe mother were available to provide samples forgenetic analysis.31 421 2Index patient312971 82 6543IIIIIIIVABCDNeonatePatient7 MonthsControlΣ=3.1 cm2 Σ=6.7 cm22.02.41.70.61.30.80.70.31.0 cmVLVMVIFRFVLVMVIFRF Figure 1. Photographs of the Child at the Ages of Six Days and Seven Months (Panel A), Ultrasonograms (Panel B) and Morphometric Analysis (Panel C) of the Muscles of the Patient and a Control Infant, and the Patient’s Pedigree (Panel D). The arrowheads in Panel A indicate the


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Stanford BIO 230 - Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

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