Myostatin-related muscle hypertrophy (MRMH) is a rare genetic disorder with an incomplete autosomal dominant mode of inheritance. It is caused by deletions in the intron of the MSTN gene located on chromosome 2q32.2.
Causative mutations lead to a loss of myostatin function which results in significant skeletal muscle growth accompanied by loss of subcutaneous fat tissue. Characteristic MRMH symptoms are evident at birth. Increased muscle mass in MRMH does not necessarily entail augmented physical strength.
Diagnosis is based on clinical findings and supported by genetic tests. Genetic counseling is advisable due to the familial nature of MRMH.
Myostatin-related muscle hypertrophy (MRMH) develops because of pathological mutations in the MSTN gene on the long arm of chromosome 2  . MRMH has a strong familial component but can also occur sporadically . Heterozygotic carriers of MRMH-associated mutations present with a milder MRMH phenotype than homozygotes, suggesting an incomplete autosomal dominant mode of inheritance .
Myostatin - also called growth/differentiation factor 8 (GDF-8) - downregulates muscle growth in mammals. Loss of myostatin function leads to MRMH, while myostatin overexpression is associated with muscle wasting syndromes  . Skeletal muscle overgrowth in MRMH can lead to an effective doubling of muscle tissue volume with a concomitant loss of subcutaneous fat  . Additionally, infant MRMH patients can also show increased tendon reflexes and congenital stimulus-induced myoclonus, which should resolve spontaneously after a few months .
The effect MRMH-associated muscle growth is still under dispute. While MRMH cases in humans seem to suggest increased physical strength in children , detailed histopathological investigations of myostatin-deficient skeletal muscles have revealed a strong predominance of type IIb muscle fibers with tubular aggregates together with a loss of oxidative capacity due to mitochondrial depletion .
Mutations: Most nonsense, splice, or frameshift; Loss of gene function BSCL2 allelic disorders Caveolin-1: Homozygous nonsense (Glu38X) Frequency: AGPAT2 & BSCL2 in 95% Clinical features Generalized lipodystrophy: Subcutaneous & Visceral GI: Hepatomegaly; splenomegaly [neuromuscular.wustl.edu]
Entire Body System
Atrophy: Limbs Lipodystrophy: P anniculitis-Induced Most prominent early: Face; Arms; Thorax Progression: Abdomen; Lower extremities CNS: Variable; Seizures, Basal ganglia calcification Skin: Erythematous lesions Hepatosplenomegaly Laboratory Microcytic Anemia [neuromuscular.wustl.edu]
[…] isolated sensorineural hearing loss with susceptibility to aminoglycoside exposure Mitochondrial membrane protein-associated neurodegeneration Mitochondrial membrane transport disorder Mitochondrial myopathy Mitochondrial myopathy and sideroblastic anemia [orpha.net]
- Precocious Puberty
puberty Cryptorchidism Laboratory Muscle biopsy EMG: Denervation, chronic 2 Action potentials: Long polyphasic Lipodystrophy: Hereditary Insulin-resistant diabetes mellitus with acanthosis nigricans (Flier's syndrome ) ● Insulin receptor (INSR) ; Chromosome [neuromuscular.wustl.edu]
puberty Male sterility due to chromosome Y deletion Malformation of the cerebellar hemispheres Malformation of the cerebellar vermis Malformation of the neurenteric canal, spinal cord and column Malformation syndrome Malformation syndrome with hamartosis [orpha.net]
Macrostomia Macrostomia-preauricular tags-external ophthalmoplegia syndrome Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome Macrothrombocytopenia with mitral valve insufficiency MAC spectrum MACS syndrome Macular amyloidosis [orpha.net]
[…] splice, or frameshift; Loss of gene function BSCL2 allelic disorders Caveolin-1: Homozygous nonsense (Glu38X) Frequency: AGPAT2 & BSCL2 in 95% Clinical features Generalized lipodystrophy: Subcutaneous & Visceral GI: Hepatomegaly; splenomegaly; Portal hypertension [neuromuscular.wustl.edu]
Liver, Gall & Pancreas
[…] fat loss Bilateral Head, Neck, arms & thorax Not legs Associated conditions: Complement C3 deficiency (11%) Glomerulonephritis (11%) Dermatomyositis (22%) Treated type 2 diabetes (56%) Treated hypertension (56%) Type IV or V dyslipoproteinemia (89%) Hepatomegaly [neuromuscular.wustl.edu]
[…] pigmentosa-diabetes mellitus syndrome Muscular channelopathy Muscular dystrophy Muscular dystrophy, Selcen type Muscular dystrophy with progressive weakness, distal contractures and rigid spine Muscular enolase deficiency Muscular glycogenosis Muscular hypertrophy-hepatomegaly-polyhydramnios [orpha.net]
- Long Arm
Myostatin-related muscle hypertrophy (MRMH) develops because of pathological mutations in the MSTN gene on the long arm of chromosome 2. MRMH has a strong familial component but can also occur sporadically. [symptoma.com]
- Muscle Spasticity
Exercise Bodybuilding Pathology: Muscle Spasticity with persistent muscle spasms Orthostatic tremor Muscle Myotonia Congenita Hyperkalemic Periodic Paralysis Paramyotonia congenita Proximal myotonic myopathy (PROMM) Rippling Muscle Syndrome Partial Denervation [neuromuscular.wustl.edu]
- Primary Amenorrhea
[…] teeth in adults Cerebellum pathology Cerebral dysfunction: Seizures Polyostotic fibrous dysplasia Primary amenorrhea Aplastic anemia Hypospadias Cerebral cavernous malformations Neuropathic pain: Especially females Pathology Proliferating cells: Glycoprotein [neuromuscular.wustl.edu]
As I have said Bryan has tremors problems with fine motor skills and Gross motor skills and a chromosome abnormality. Could this lesson his strength a little? His muscles look just like this boys and he has had abs since at lest 2. [melissaloss.blogspot.com]
Antibody & Biopsy, Patient Info LARGE OR PROMINENT MUSCLES Overusage Neural Myokymia / Neuromyotonia Isaac's Syndrome Schwartz-Jampel Dystonia & Athetosis Exercise Bodybuilding Pathology: Muscle Spasticity with persistent muscle spasms Orthostatic tremor [neuromuscular.wustl.edu]
Diagnosis of MRMH rests on a thorough analysis of the family history, clinical findings, imaging techniques, and genetic testing for MSTN mutations as well as genetic counseling .
These discussions should explain the hereditary nature of MRMH to the parents of the infant patient and recommend genetic tests not only for their progeny but also for themselves. Parent testing allows a distinction between a hereditary or sporadic occurrence. In case of a parent mutation carrier, further genetic tests of the patient's siblings should be performed .
Clinical findings in MRMH are evident at birth because functional myostatin restrains perinatal skeletal muscle growth. Significant muscle overgrowth on thighs and upper arms, insufficient fat pads, and increased tendon reflexes are hallmark signs in infants  .
Muscle hypertrophy can be visualized with imaging techniques like ultrasonography, magnetic resonance imaging (MRI) or dual energy X-ray absorptiometry (DXA). On the other hand, loss of subcutaneous fat can be revealed with MRI or simply with a caliper  .
Long-term prophylactic monitoring of cardiac function may be advisable .
Genetic testing is required to support the clinical diagnosis. Mutations in the MSTN gene can be shown with polymerase-chain-reaction (PCR) - assisted restriction analysis .
Clinical Macroglossia Gigantism; Hemihypertrophy Coarse facial features; Prominent mandible Ears: Linear ear lobe creases ; Posterior helical indentations GI: Omphalocele; Exomphalos; Visceromegaly; Prune belly; Umbilical hernia Endocrine: Neonatal hypoglycemia [neuromuscular.wustl.edu]
CLOSE Medical Disclaimer The medical information on this site is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purposes. [diseaseinfosearch.org]
Treatment - Myostatin-related muscle hypertrophy Myostatin-related muscle hypertrophy is not currently known to cause any medical complications. Resources - Myostatin-related muscle hypertrophy Not supplied. [checkorphan.org]
The few treatments being tried to slow its progression have serious side effects. Muscle wasting also is common in the elderly and patients with diseases such as cancer and AIDS. [nbcnews.com]
However you grunt it, the draw to have a treatment that creates muscle – with little exercise needed – is outweighing the medical pursuits of MD cures. [singularityhub.com]
Ironically, learning more about it could lead to treatments for other muscle afflictions, researchers say. [cbsnews.com]
Prognosis - Myostatin-related muscle hypertrophy Not supplied. Treatment - Myostatin-related muscle hypertrophy Myostatin-related muscle hypertrophy is not currently known to cause any medical complications. [checkorphan.org]
Symptoms and Prognosis The major symptoms of myostatin related muscle hypertrophy are reduced subcutaneous fat pad thickness and increased muscle size, according to the US National Library of Medicine. [healthguideinfo.com]
[…] medullary dysplasia; Overgrowth of external genitalia Cardiomyopathy : Occasional Laboratory Hypoglycemia External link: Gene Reviews Myhre Syndrome 8 ● Mothers against decapentaplegic, drosophila, homolog of, 4 (SMAD4) ; Chromosome 18q21.2; Dominant Epidemiology [neuromuscular.wustl.edu]
Relevant External Links for MSTN Genetic Association Database (GAD) MSTN Human Genome Epidemiology (HuGE) Navigator MSTN Atlas of Genetics and Cytogenetics in Oncology and Haematology: MSTN No data available for Genatlas for MSTN Gene Human adaptive evolution [genecards.org]
Prevention - Myostatin-related muscle hypertrophy Not supplied. Diagnosis - Myostatin-related muscle hypertrophy Skeletal muscle size in an individual with myostatin-related muscle hypertrophy is measured by ultrasound examination, DEXA, or MRI. [checkorphan.org]
This protein tells your muscles when to stop growing, and in the last few years we’ve seen two babies born with a mutant gene that prevents them from producing enough myostatin. The result? Super Babies. [singularityhub.com]
But if this gene could be turned off on purpose once a person reached physical maturity then I think it could go a long way to resolving/preventing a lot of the obesity-related medical conditions out there. [theringlord.org]
A genetic mutation prevents some people from producing myostatin. Those individuals can have twice the normal amount of muscle mass, according to medical literature. In Liam's case, the myostatin his body produces is rejected by muscle cells. [ctvnews.ca]
- 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.
- McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94(23):12457-12461.
- Szabo G, Dallmann G, Muller G, Patthy L, Soller M, Varga L. A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice. Mamm Genome. 1998;9(8):671-672.
- Amthor H, Huang R, McKinnell I, et al. The regulation and action of myostatin as a negative regulator of muscle development during avian embryogenesis. Dev Biol. 2002;251(2):241-257.
- Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science. 2002;296(5572):1486-1488.
- Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci USA. 1998; 95(25): 14938-14943.
- Grobet L, Martin LJR, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997;17(1):71-74.
- Lin J, Arnold HB, Della-Fera MA, Azain MJ, Hartzell DL, Baile CA. Myostatin knockout in mice increases myogenesis and decreases adipogenesis. Biochem Biophys Res Commun. 2002;291(3):701-706
- Amthor H, Macharia R, Navarrete R, et al. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Nat Acad Sci USA. 2007;104(6):1835-1840.
- Wagner KR, Cohen JS. Myostatin-Related Muscle Hypertrophy. 2005. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993-2017. https://www.ncbi.nlm.nih.gov/books/NBK1498/?report=reader. Accessed Nov 7th, 2017.
- McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest. 2002;109(5):595-601.