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Myostatin-Related Muscle Hypertrophy

, MD, PhD and , ScM, CGC.

Author Information
, MD, PhD
Kennedy Krieger Institute
Department of Neurology
Johns Hopkins School of Medicine
Baltimore, Maryland
, ScM, CGC
Kennedy Krieger Institute
Baltimore, Maryland

Initial Posting: ; Last Update: July 3, 2013.

Summary

Disease characteristics. Myostatin-related muscle hypertrophy is characterized by reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength. Both heterozygotes and homozygotes for a mutation in MSTN encoding the protein growth differentiation factor 8 (myostatin) can exhibit muscle hypertrophy. Clinical manifestations depend on the amount of myostatin protein present. An infant homozygous for an MSTN mutation had muscle mass twice that of sex- and age-matched controls; intellect and cardiac function were normal. He displayed stimulus-induced myoclonus that subsided after two months. Heterozygotes may have increased muscle bulk and strength, but to a lesser degree.

Diagnosis/testing. Skeletal muscle size in an individual with myostatin-related muscle hypertrophy is measured by ultrasound examination, DEXA, or MRI. Subcutaneous fat pad thickness is measured by ultrasound or with a caliper. MSTN is the only gene in which mutation is known to cause myostatin-related muscle hypertrophy.

Management. Myostatin-related muscle hypertrophy is not known to cause medical complications.

Genetic counseling. The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner. At conception, the sibs of a child with homozygous myostatin-related muscle hypertrophy have a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one MSTN mutation with or without increased muscle mass, and a 25% chance of having normal muscle mass and no MSTN mutations. Heterozygotes may have increased muscle mass. Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with the MSTN mutation who may have increased muscle mass, or the proband may have the condition as the result of a new gene mutation. The proportion of cases caused by a de novo mutation is unknown. The chance that sibs of a proband with heterozygous myostatin-related muscle hypertrophy will inherit the MSTN mutation is 50% if a parent has increased muscle mass or has an MSTN mutation. Each child of an individual with heterozygous myostatin-related muscle hypertrophy has a 50% chance of inheriting the MSTN mutation.

Diagnosis

Clinical Diagnosis

The diagnosis of myostatin-related muscle hypertrophy is established by clinical findings of reduced subcutaneous fat pad thickness and increased muscle size in individuals with normal or increased muscle strength and an MSTN mutation identified on molecular genetic testing.

Testing

Skeletal muscle size can be measured by ultrasound, DEXA, or MRI. It is expected to be several deviations above normal for age- and sex-matched controls.

Subcutaneous fat pad thickness can be measured by ultrasound or with a caliper at various standard locations for which normal values exist.

Creatine kinase (CK) serum concentration is expected to be normal.

Molecular Genetic Testing

Gene. MSTN, which encodes the protein growth differentiation factor 8 (also known as myostatin) is the only gene in which mutations are known to cause myostatin-related muscle hypertrophy.

Table 1. Summary of Molecular Genetic Testing Used in Myostatin-Related Muscle Hypertrophy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
MSTNSequence analysisSequence variants 4 including c.506+5G>A 5Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. The only MSTN mutation related to myostatin-related muscle hypertrophy that has been reported [Schuelke et al 2004]

Testing Strategy

To confirm/establish the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Clinical manifestations of myostatin-related muscle hypertrophy appear to be dependent on the amount of myostatin protein present. Therefore both heterozygotes and homozygotes can exhibit muscle hypertrophy.

Homozygotes. A homozygous loss-of-function myostatin mutation was identified in a hypermuscular infant with muscle mass approximately twice that of sex- and age-matched controls [Schuelke et al 2004]. At age 4.5 years, he continued to have increased muscle bulk and strength with normal intellect and normal cardiac function by echocardiography and electrocardiography.

He initially displayed stimulus-induced myoclonus that subsided after two months. The relationship between myoclonus and the MSTN mutation is not clear.

Ultrasonography revealed normal muscle echogenicity and cross-sectional diameter of quadriceps muscle 7.2 SD above the mean.

Heterozygotes. Heterozygotes may have increased muscle bulk and strength. The mother of the child identified to be homozygous for this mutation was a former professional athlete with large calf muscles [Schuelke et al 2004]. See also Genotype-Phenotype Correlations.

Genotype-Phenotype Correlations

No information is currently available as only one MSTN mutation associated with this phenotype has been identified.

In a multigenerational family segregating a 3.4-Mb deletion of chromosome 2q32.1q32.3 including MSTN, four of seven individuals with the deletion available for examination were reported to have increased muscle strength and increased size of the gastrocnemius and soleus muscles, whereas the other three individuals with the deletion did not have increased muscle strength or size [Meienberg et al 2010].

Penetrance

Penetrance is unknown.

Anticipation

Anticipation is not known to occur.

Prevalence

Prevalence is unknown.

Differential Diagnosis

This MSTN mutation does not appear to be associated with myopathy or muscle weakness, thus allowing differentiation of myostatin-related muscle hypertrophy from muscular dystrophies with muscle hypertrophy, including:

The MSTN mutation also causes decreased adipose tissue and needs to be distinguished from familial partial lipodystrophy, Dunnigan type (FPLD2), caused by mutations in LMNA, in which increased muscle mass is not seen [Schmidt et al 2001].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Treatment of Manifestations

Myostatin-related muscle hypertrophy is not currently known to cause any medical complications.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner.

Risk to Family Members

Parents of a proband who is homozygous for myostatin-related muscle hypertrophy

  • The parents of a child with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes and therefore have one MSTN mutation.
  • Heterozygotes may have increased muscle mass.

Sibs of a proband

  • At conception, each sib of a child with homozygous myostatin-related muscle hypertrophy has a 25% chance of having homozygous myostatin-related muscle hypertrophy, a 50% chance of having one MSTN mutation with or without increased muscle mass, and a 25% chance of having normal muscle mass and no MSTN mutations.
  • Heterozygotes may have increased muscle mass.

Offspring of a proband. The offspring of an individual with homozygous myostatin-related muscle hypertrophy are obligate heterozygotes for a mutation in MSTN and may have increased muscle mass.

Other family members of a proband. Each sib of the proband's parents has a 50% chance of having one MSTN mutation and may have increased muscle mass.

Parents of a proband who is heterozygous for myostatin-related muscle hypertrophy

  • Individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with an MSTN mutation who may have increased muscle mass or may have the condition as the result of a de novo gene mutation. The proportion of cases caused by a de novo mutation is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation for evidence of muscle hypertrophy.

Note: Although individuals diagnosed with heterozygous myostatin-related muscle hypertrophy may have a parent with increased muscle mass, the family history may appear to be negative because of incomplete penetrance or failure to recognize the condition in family members.

Sibs of a proband

  • The chance that the sibs of the proband will inherit the MSTN mutation depends on the genetic status of the proband's parents.
  • If a parent of the proband has increased muscle mass, the chance that the sibs will inherit the MSTN mutation is 50%.

Offspring of a proband. Each child of an individual with heterozygous myostatin-related muscle hypertrophy has a 50% chance of inheriting the MSTN mutation.

Other family members of a proband. The chance that other family members will be affected depends on the status of the proband's parents. If a parent has increased muscle mass, his or her family members may be affected.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Myostatin-Related Muscle Hypertrophy have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Myostatin-Related Muscle Hypertrophy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Myostatin-Related Muscle Hypertrophy (View All in OMIM)

601788MYOSTATIN; MSTN

Normal allelic variants. Five missense substitutions in conserved amino acid residues have been identified [Ferrell et al 1999]. Two of these, p.Ala55Thr in exon 1 and p.Lys153Arg in exon 2, are polymorphic normal benign variants in the general population (see Table 2).

Pathologic allelic variants. Only one MSTN mutation related to muscle hypertrophy has been reported to date; c.506+5G>A results in misspliced mRNA [Schuelke et al 2004] (see Table 2; for more information, see Table A). In a multiplex family, a heterozygous contiguous gene deletion including the entire MSTN gene was reported. Some of the individuals in this family who had the heterozygous contiguous gene deletion had increased muscle strength and size [Meienberg et al 2010].

Table 2. Selected MSTN Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalc.163G>Ap.Ala55ThrNM_005259​.2
NP_005250​.1
c.458A>Gp.Lys153Arg
Pathologicc.506+5G>A
(IVS1+5G>A)
--

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Myostatin, composed of 375 amino acids, is also known as growth differentiation factor 8 and belongs to the transforming growth factor β superfamily. Myostatin is a negative regulator of muscle growth expressed almost exclusively in developing and adult skeletal muscle [McPherron et al 1997].

Abnormal gene product. The only known mutation results in no detectable myostatin production. Loss or inhibition of myostatin is associated with increased skeletal muscle growth by muscle fiber hyperplasia and hypertrophy [McPherron et al 1997].

  • Mice heterozygous for an Mstn mutation have muscle mass intermediate between homozygous myostatin null mice and wildtype mice.
  • "Double-muscled" cattle previously linked to the muscular hypertrophy (mh) locus on chromosome 2 have also been found to have mutations in the gene for myostatin [Grobet et al 1997, Kambadur et al 1997].

References

Literature Cited

  1. Ferrell RE, Conte V, Lawrence EC, Roth SM, Hagberg JM, Hurley BF. Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes. Genomics. 1999;62:203–7. [PubMed: 10610713]
  2. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Ménissier F, Massabanda J, Fries R, Hanset R, Georges M. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17:71–4. [PubMed: 9288100]
  3. Kambadur R, Sharma M, Smith TP, Bass JJ. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 1997;7:910–6. [PubMed: 9314496]
  4. 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. [PubMed: 9139826]
  5. Meienberg J, Rohrbach M, Neuenschwander S, Spanaus K, Giunta C, Alonso S, Arnold E, Henggeler C, Regenass S, Patrignani A, Azzarello-Burri S, Steiner B, Nygren AO, Carrel T, Steinmann B, Mátyás G. Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency. Eur J Hum Genet. 2010;18:1315–21. [PMC free article: PMC3002852] [PubMed: 20648054]
  6. Schmidt HH, Genschel J, Baier P, Schmidt M, Ockenga J, Tietge UJ, Pröpsting M, Büttner C, Manns MP, Lochs H, Brabant G. Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene. J Clin Endocrinol Metab. 2001;86:2289–95. [PubMed: 11344241]
  7. Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, Tobin JF, Lee SJ. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350:2682–8. [PubMed: 15215484]

Suggested Reading

  1. Lee SJ. Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol. 2004;20:61–86. [PubMed: 15473835]

Chapter Notes

Author History

Julie S Cohen, ScM, CGC (2013-present)
Nicole Johnson, ScM, CGC, Johns Hopkins School of Medicine (2005-2009)
Kathryn R Wagner, MD, PhD (2005-present)

Revision History

  • 3 July 2013 (me) Comprehensive update posted live
  • 30 April 2009 (me) Comprehensive update posted live
  • 4 October 2005 (me) Review posted to live Web site
  • 14 February 2005 (kw) Original submission
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