 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
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. Molecular genetic testing for MSTN, the only gene known to be associated with myostatin-related muscle hypertrophy, is available on a research basis.
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 a MSTN mutation. Each child of an individual with heterozygous myostatin-related muscle hypertrophy has a 50% chance of inheriting the MSTN mutation.
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 a MSTN mutation identified on molecular genetic 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. MSTN, which encodes the protein growth differentiation factor 8 (also known as myostatin) is the only gene known to be associated with myostatin-related muscle hypertrophy.
Research testing. Testing for MSTN mutations is available on a research basis only.
| Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|
| Direct DNA 1 | c.506+5G>A in MSTN | Unknown | Research only |
1. Direct DNA methods may include mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with myostatin-related muscle hypertrophy.
No other phenotypes are associated with mutation in MSTN.
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].
No information is currently available as only one MSTN mutation associated with this phenotype has been identified.
Penetrance is unknown.
Anticipation is not known to occur.
Prevalence is unknown.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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:
Duchenne and Becker muscular dystrophy (see Dystrophinopathies)
Limb-girdle muscular dystrophy 1C (caveolinopathy) (see also Limb-Girdle Muscular Dystrophy Overview)
Limb-girdle muscular dystrophies 2C, 2D, 2E (sarcoglycanopthies) (see Limb-Girdle Muscular Dystrophy Overview)
Channelopathies such as myotonia congenita, a chloride channelopathy resulting from mutations in CLCN1
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].
Myostatin-related muscle hypertrophy is not currently known to cause any medical complications.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
The phenotypes associated with myostatin-related muscle hypertrophy are inherited in an incomplete autosomal dominant manner.
This section is written from the perspective that molecular genetic testing for this condition is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
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 the MSTN gene 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 a 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 upon the status of the proband's parents. If a parent is found to have increased muscle mass, his or her family members may be affected.
DNA banking. 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. DNA banking is particularly relevant when molecular genetic testing is available on a research basis only. See
for a list of laboratories offering DNA banking.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| MSTN | 2q32.2 | Growth/differentiation factor 8 | Leiden Muscular Dystrophy pages (MSTN) | MSTN |
| 601788 | MYOSTATIN; MSTN |
| Class of Variant Allele | DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequences |
|---|---|---|---|
| Normal | c.163G>A | p.Ala55Thr | NM_005259.2 NP_005250.1 |
| c.458A>G | p.Lys153Arg | ||
| Pathologic | c.506+5G>A (IVS1+5G>A) | -- |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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 ß 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 a 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].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
No specific resources exist for Myostatin-Related Muscle Hypertrophy.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
Nicole Johnson, ScM, CGC, Johns Hopkins School of Medicine (2005-2009)
Kathryn R Wagner, MD, PhD (2005-present)
30 April 2009 (me) Comprehensive update posted live
4 October 2005 (me) Review posted to live Web site
14 February 2005 (kw) Original submission
