Correspondence

Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child

N Engl J Med 2004; 351:1030-1031September 2, 2004

Article

To the Editor:

Schuelke et al. (June 24 issue)1 describe a child with muscle hypertrophy in association with a mutation in the myostatin gene. Another possible case of a myostatin mutation in an exceptionally strong child was described more than 2500 years ago in Greek mythology, in the story about Hercules. As an infant, Hercules strangled a snake in each hand when the goddess Hera tried to kill him. His legendary strength was obvious from the time of his birth, and it was not the result of any exercise program.

Branimir Čatipović, M.D.
Department of Veteran Affairs, Mason City, IA 50401
bcatipovic@hotmail.com

1 References

1. 1

   Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682-2688
   Full Text | Web of Science | Medline

To the Editor:

Schuelke et al. report a case of muscle hypertrophy associated with a mutation in the myostatin gene. The patient was homozygous for a guanine-to-adenine transition at nucleotide g.IVS1+5 — a mutation that may lead to missplicing. The mother was heterozygous for this mutation, and the father was unavailable. The authors hypothesize that the muscular hypertrophy was due to lack of myostatin. Although this hypothesis is attractive, another possibility was not addressed.

The myostatin gene (GDF8) maps to chromosome 2q32.1 in humans. Maternal isodisomy of chromosome 2 could explain the homozygosity of the described mutation. All or part of chromosome 2 may be subject to maternal imprinting.1,2 Abnormal imprinting can lead to growth abnormalities and tissue hypertrophy.3 For example, patients with the Beckwith–Wiedemann syndrome, a paternal imprinting disorder, may have macroglossia, hemihypertrophy (including muscle hemihypertrophy), and organomegaly; embryonal rhabdomyosarcoma has also been observed.4 Abnormal maternal imprinting usually, but not always, causes growth suppression.3 In the case reported by Schuelke et al., maternal isodisomy of chromosome 2 should be ruled out as a possible cause of the muscle hypertrophy.

Marc S. Williams, M.D.
Gundersen Lutheran Medical Center, La Crosse, WI 54601
mswillia@gundluth.org

4 References

1. 1

   University of Chicago. Human imprinting map. (Accessed August 13, 2004, at http://www.genes.uchicago.edu/upd/upd.html.)
   

2. 2

   Webb AL, Sturgiss S, Warwicker P, Robson SC, Goodship JA, Wolstenholme J. Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation. Prenat Diagn 1996;16:958-962
   CrossRef | Web of Science | Medline

3. 3

   Butler MG. Imprinting disorders: non-Mendelian mechanisms affecting growth. J Pediatr Endocrinol Metab 2002;15:Suppl 5:1279-1288
   Web of Science | Medline

4. 4

   OMIM, Online Mendelian Inheritance in Man. Baltimore: Johns Hopkins University. (Accessed August 13, 2004, at http://www.ncbi.nlm.nih.gov/omim/.)
   

Author/Editor Response

Williams raises the question of whether the increased muscle mass in the child we describe might be due to an imprinting disorder and suggests that maternal isodisomy should be ruled out. Here we provide data to rule out uniparental isodisomy of chromosome 2 on the basis of microsatellite-marker analysis of specimens from the patient and his mother. We detected a founder haplotype for which the patient was homozygous in a 20-cM segment around the myostatin gene (Figure 1Figure 1Results of Haplotype Analysis.). Thus, the mode of inheritance in this child seems most likely to have been autosomal recessive, as it is in myostatin knockout mice1 and double-muscled cattle.2 There is additional evidence against an imprinting disorder: the effect of the myostatin splice-site mutation could be demonstrated in vitro after a genomic myostatin construct was transfected into mammalian cells. In this system, myostatin transcription is regulated by a cytomegalovirus promoter in which imprinting does not play a role.1 Most children with imprinting disorders have multiple-organ involvement and dysmorphic features,3,4 which was not the case with our patient.

Birgit Uhlenberg, M.D.
Barbara Lucke
Markus Schuelke, M.D.
Charité University Medical Center, 13353 Berlin, Germany
markus.schuelke@charite.de

4 References

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   McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90
   CrossRef | Web of Science | Medline

2. 2

   Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 1997;17:71-74
   CrossRef | Web of Science | Medline

3. 3

   Buntinx IM, Hennekam RC, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56:176-183
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   Engstrom W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr 1988;147:450-457
   CrossRef | Web of Science | Medline

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