Dysferlinopathy 101


Dysferlinopathy 101

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If you or a loved one has been diagnosed with dysferlinopathy, also referred to as LGMD2B, LGMDR2 and Miyoshi Myopathy 1, you will have many questions you need answers for and concerns to be addressed. Much of the terminology surrounding dysferlinopathy may be confusing. We have included some of the most frequently asked questions about dysferlinopathy here.  If you can’t find an answer for your question, contact us at patients@jain-foundation.org.


If you or a loved one has been diagnosed with dysferlinopathy, also referred to as LGMD2B, LGMDR2, Miyoshi Myopathy 1, you will have many questions you need answers for and concerns to be addressed. Much of the terminology surrounding dysferlinopathy may be confusing. We have included some of the most frequently asked questions about dysferlinopathy here.  If you can’t find an answer for your question, contact us at patients@jain-foundation.org.

FAQ: Diagnosis, Prognosis, Progression & Inheritance

Diagnosis is generally made based on the following information:

  • CK level analysis from a blood sample
  • A detailed patient and family history (a 3 generation pedigree)
  • The source of the muscle weakness (nerve or muscle)
  • A detailed examination and clinical assessments that locate and measure the strength of the limb girdle muscles, especially the muscle groups that are most affected at the time of the examination as well as a gait analysis.
  • Genetic testing (sequencing of the DYSF gene, also called mutational analysis) to identify disease-causing mutations in DYSF. Go to the Proteins, DNA and Mutations section for more information on types of mutations and the benefits of gene mutation analysis.
  • Determination of the presence of the dysferlin protein via a blood (monocyte) test or muscle biopsy analysis.  This analysis can help clarify a dysferlinopathy diagnosis if other tests (like DNA sequencing) are inconclusive.
  • A session with a genetic counselor who can communicate with you the results from the genetic test and help to investigate if the results were clearly dysferlinopathy

Dysferlinopathy is caused by inherited genetic mutations in the gene for dysferlin. It is a recessive condition, so patients with this disease must have two non-functional copies of the DYSF gene. There are many different mutations that disrupt the function of the dysferlin protein, and each patient usually has different mutations in each of their two copies of the DYSF gene. People with only one non-functional DYSF gene (called carriers) do not have symptoms, because having one working copy of the DYSF gene is enough to prevent the disease.

An individual may have genetic mutations in the DYSF gene for the following reasons:

  • Inheritance of a non-functional gene from each parent (autosomal recessive inheritance)
  • Sporadic mutations – mutations which aren’t inherited from a parent, but that arise directly in the egg or sperm

All of the muscle diseases associated with dysferlin deficiency have an autosomal recessive inheritance, so a person will only have symptoms if he/she inherits a mutated version of the dysferlin gene from both parents. Children of someone with dysferlinopathy will definitely be a carrier of one DYSF mutation because each child inherits one of their DYSF genes from the affected parent who carriers a DYSF mutation on each of their copies of the DYSF gene. In the absence of a spontaneous mutation, the children of an affected individual will only develop symptoms if they inherit a second mutated DYSF gene from the other unaffected parent. Based on the incidence of these conditions in the general population, there are probably only about 3-5 people out of every thousand who have one copy of a mutated DYSF gene (carriers). So, the chance of children inheriting these conditions is quite small unless the other unaffected parent has a family history of these conditions or shares a common ancestry with the affected parent.

If both parents have one copy of a mutated DYSF gene, each child has a 25% chance of getting both defective copies and thus the disease. However, for each child of this same couple there is also a 50% chance of being a carrier of the defective gene, meaning that he/she has a single mutated copy of the gene but does not show any symptoms. Genetic testing in families with recessive disorders is sometimes advisable in order to detect carriers. It might also be good to determine whether the potential spouses of carriers or affected individuals are also carriers. Determination of a person’s carrier status requires testing his/her DNA (rather than antibody testing for the dysferlin protein), since a carrier still expresses dysferlin protein from their good copy of the DYSF gene.

For a more detailed description with visual diagrams please visit the Cause and Inheritance page.

A single defective copy of the DYSF gene cannot cause dysferlinopathy.  For the disease to occur, both copies of the DYSF gene must be defective. Dysferlinopathy is autosomal. This means that it is not a sex-linked gene, and both males and females are affected with the same frequency. One copy of the gene is inherited from each parent. If one working copy and one defective copy are inherited, the single working copy is sufficient for normal muscle function and the individual is only a “carrier” of the disease. If both parents are carriers, each  of their biological children has a one in four (25%) chance of inheriting two defective copies of DYSF and developing dysferlinopathy.

For a more detailed description with visual diagrams please visit the Cause and Inheritance page.

The rate of progression of dysferlinopathy is fairly slow compared to most other types of muscular dystrophy. Among the identified forms of LGMD, type LGMD2B/LGMDR2 is one of the more slowly progressive forms. There have been some reports that Miyoshi myopathy 1 (MM1) has a slower progression than LGMD2B/LGMDR2, while other reports indicate that the two are similar. This may reflect a difference in the initial muscles affected, since weakness in the calf muscles has less impact on a patient’s function than weakness in the hip muscles. However, the reported rates of progression and symptoms do vary significantly, which may be due to differences in the type of mutation or other genetic differences between populations studied. There have not been any reports of cardiomyopathy (dystrophy of the heart muscle) in either LGMD2B/LGMDR2 or MM1, nor have there been any reports that either condition significantly shortens life expectancy.

Please see our page on Symptoms and Care Management for information on physical therapy and exercise for people living with LGMD.

To learn more about the symptoms in the various stages of dysferlinopathy, please look at our Symptoms and Care Management page.

Proteins, DNA and Mutations

Proteins are large molecules that make up the structure of cells and help them do their particular function.  There are two basic types of proteins. Some form the structure of cells – you can think of these proteins as building blocks that are put together to make cells. Others carry out certain functions within the cell – you can think of these proteins as small machines inside your body. The dysferlin protein is one of these machines, and scientists think that dysferlin has many jobs, such as fixing holes in the membrane (the outer wall) of the cell, moving things around in the cell and regulating the amount of calcium, which is important for muscle function. Which of these functions or combination of functions are the most relevant to the underlying pathophysiology of dysferlinopathy has yet to be determined.

All proteins, both building blocks and machines, are actually long chains that are folded up into three-dimensional shapes. Each protein chain is made up of connected links called amino acids. There are 20 different kinds of amino acids, each with a slightly different shape. The different kinds of amino acids are strung together in a specific sequence to form a protein chain. The exact sequence of these amino acids in the protein is very important for the protein to fold up correctly and to carry out its proper function in the cell.

Dysferlin is a protein made from the DYSF gene that, when mutated or absent, causes dysferlinopathy. At the time of dysferlin’s discovery (mid 1998), it had no common features with any other known human proteins, but was most similar to a protein in the nematode worm C. elegans. The C. elegans protein is necessary for reproduction and was named fer-1 for “fertile.” (The lack of dysferlin in humans, however, does not appear to cause any reproductive problems.) The name of the human protein, “dysferlin,” was coined by the discoverers to acknowledge its role in muscular dystrophy and its similarity to the C. elegans gene. Since the discovery of dysferlin, five closely related human proteins have been characterized.

DNA (deoxyribonucleic acid) is the information storage system of the body. DNA is a code that contains instructions telling the cell how to make all of its proteins. There is a separate DNA code (a gene) corresponding to each protein that is made by the cell. For example, instructions for how to make the dysferlin protein are down in DNA in the DYSF gene.

Like proteins, DNA molecules are also long chains. But DNA chains don’t act as machines, they just store instructions for making the protein chains. Each protein is a chain of amino acids, and each DNA molecule is a chain of connected links called nucleotides. There are four different nucleotides: adenine (A), thymine (T), guanine (G), and cytosine (C). Each set of three nucleotides is code for a specific amino acid. For example, if the DNA has the nucleotides adenine, then thymine, then guanine in a row (ATG), that is code for an amino acid called Methionine.

The terminology can be somewhat confusing. Dysferlin is a protein, and “the dysferlin gene” means “the gene which contains the instructions for producing the dysferlin protein.”  The code used to indicate the dysferlin gene is DYSF. Each gene tells the cell how to put together the building blocks for one specific protein. However, the gene (DNA) sits inside a different compartment of the cell (the nucleus) from the location of the cellular machines that make proteins (ribosomes). Therefore, the gene must first make a copy of itself (called messenger RNA – mRNA), which is smaller and more portable than DNA and is able to leave the nucleus to reach the ribosomes. A ribosome then reads each set of three nucleotides in the mRNA code and converts the instructions into a chain of amino acids that attach together to form a protein. The mRNA also tells the ribosome where to start the protein and when the protein is finished; namely, when it should stop attaching new amino acids to the protein. Because the nucleotides are read in groups of three, it is important for the ribosome to know how to group the nucleotides. If the nucleotides are grouped incorrectly, the ribosome will choose the wrong amino acids and the protein will not function. Usually, when a protein is not properly produced, it is because there is some mutation in the gene which contains its instructions.

The DNA that makes up the gene that encodes a protein sometimes has mistakes, called mutations, which cause defects in proteins. For example, if there are mutations in the DYSF gene, then the dysferlin protein will not be made correctly. Each individual with dysferlinopathy has two mutations, which can be found by gene mutation analysis (genetic sequencing). Most individuals with dysferlinopathy are unable to make dysferlin protein, regardless of the type of DYSF mutations that they carry. Watch a presentation by the Jain Foundation’s Brad Williams in which he explains about the different types of mutations that can be seen in DNA and relates it to dysferlinopathy.  Different mutation types are described below:

  • A MISSENSE mutation causes just one of the amino acids in the protein to be wrong.
    This mutation is a mistake in one DNA nucleotide in a gene. That one nucleotide is part of a set of three nucleotides that code for a specific amino acid. When a ribosome reads this particular set of three nucleotides, one of them is wrong and the ribosome selects the wrong amino acid for the protein. Missense mutations can range from very mild to severe, depending on where in the protein the affected amino acid is located and how important the affected amino acid is to the protein’s function or stability of the protein.
  • A SPLICE-SITE mutation causes a problem with the DNA instructions.
    This can be caused by a sizeable portion of the DNA instructions for a particular protein being deleted or the adding of instructions that shouldn’t be there.  The end result of either scenario is that the DNA instructions are incorrect which results in the wrong amino acid sequence or in the protein not being made at all.  Splice-site mutations can range from moderate to severe, depending on how much the mutation alters the DNA instructions for the protein. This is a severe defect because much of the protein is missing so the protein cannot function correctly, and the non-functional protein will likely be degraded leading to the complete absence of the protein.
  • A FRAMESHIFT mutation causes all of the amino acids in the protein, after a certain point, to be wrong.
    This mutation is an insertion or deletion of one or more nucleotides in the DNA. Because a ribosome makes the protein by reading sets of three nucleotides, inserting or deleting a nucleotide means that the ribosome can no longer correctly group the sets of three. Every set of three after the insertion/deletion is incorrectly grouped, so the ribosomes pick the wrong amino acid for every set of three after this point in the protein. By analogy, imagine that each word in a sentence stole the first letter of the next word (THE RED CAR would become HER EDC AR) – the words would no longer be read correctly.
  • A NONSENSE or STOP mutation causes the protein chain to stop prematurely.
    This mutation is a mistake in the DNA code that tells the ribosomes to stop attaching new amino acids to the protein while the protein is still incomplete. The ribosomes stop too early and never even make part of the protein.

The majority of mutations in DYSF lead to the absence or severe reduction in the amount of dysferlin protein present in the muscle cells.  The lack of dysferlin in the muscle cells leads to muscle cell death.  Dysferlin is thought to play a number of roles in muscle cells such as fixing holes in the membrane, moving things around in the cell, and regulating the amount of calcium.  It is not yet known which of these functions or combination of functions is most affected by the lack of dysferlin. That is why developing an understanding of the biological role of dysferlin, and the problems that result from its absence, is a high priority in current research into dysferlinopathy.

Getting a dysferlin gene mutational analysis only requires a small blood sample.  Contact the Jain Foundation to obtain information or help obtaining genetic analysis or click here  for additional information and a list of laboratories that perform genetic analysis.

There are two main reasons for getting DYSF gene mutation analysis (gene sequencing) of your two copies of the DYSF gene:

  1. The gold-standard for diagnosis of genetic disorders is the identification of the defects (mutations) in the gene causing the disease. There are several forms of muscular dystrophy and > 30 different subtypes of LGMD which have very similar clinical symptoms, making it difficult to obtain a definitive diagnosis based solely on clinical presentation. Analysis at the genetic level is the only way to definitively confirm your diagnosis of dysferlinopathy. A deficiency of dysferlin protein seen in a biopsy or a blood monocyte dysferlin assay points towards dysferlinopathy, but only the identification of specific mutations in the DYSF gene will confirm that diagnosis.
  2. Knowing the nature and position of your DYSF mutations could help you participate in future clinical trials and benefit from future therapies that target specific mutations. Examples of three such therapies currently in development are given below:
    • Chaperones – Chaperones are small molecules or proteins that can bind to and stabilize the normal 3-dimensional shape of proteins such as dysferlin, so that missense mutants are more likely to fold correctly instead of misfolding and being degraded. This strategy is used to treat cystic fibrosis caused by certain mutations and is still in development for dysferlin deficiency.
    • Stop-codon readthrough: This therapy is currently approved for Duchenne Muscular dystrophy in the US and in clinical development for several other non-muscle diseases. This type of treatment could potentially benefit those individuals with a “nonsense” or “stop” mutation (see explanation above for a stop mutation).
    • Exon skipping: This therapy is in clinical trials for another type of muscular dystrophy and could potentially benefit a subset of patients with mutations in specific areas of the dysferlin gene.

A genotype refers to the genetic characteristics of an organism. A phenotype refers to the physical characteristics. For example, having blue eyes (an autosomal recessive trait) is a phenotype; lacking the gene for brown eyes is a genotype. Dysferlinopathy will only cause muscle weakness (phenotype) if a person has two mutated copies of the DYSF gene (genotype). The genotype of two defective DYSF genes is associated with different clinical presentations (e.g. LGMD2B, LGMDR2, Miyoshi Myopathy 1), which are the phenotypes or the symptoms of dysferlinopathy.


Some types of limb-girdle muscular dystrophy (LGMD), as well as facioscapulohumeral muscular dystrophy (FSHD) are sometimes misidentified as autoimmune diseases because some of their clinical and laboratory presentations are similar.

Of the various limb-girdle muscular dystrophies, dysferlinopathy is particularly prone to misdiagnosis as polymyositis. It is estimated that around 25% of patients suffering from dysferlinopathy are misdiagnosed with polymyositis. Muscular dystrophy can mimic inflammatory myopathies, leading to misdiagnosis and ineffective treatments, but there are new tools that help provide an accurate diagnosis. It’s important to pursue the correct diagnosis to avoid the side effects of ineffective treatment which can include non-recoverable loss of strength.

Polymyositis is often treated with corticosteroids such as prednisone. Many people with dysferlinopathy have had extremely negative experiences with prednisone and there are publications about the detrimental effects of prednisone on people with dysferlinopathy. However, researchers are exploring ways to manipulate the drug to remove the harmful side effects.

Corticosteroids are used to treat a number of conditions, and are come into play in neuromuscular diseases in a few different ways:

  1. They are commonly used to treat autoimmune issues, including autoimmune muscle diseases like polymyositis. Because people with dysferlinopathy have often been misdiagnosed with polymyositis, for which corticosteroids are the standard treatment, they have often been put on corticosteroids.
  2. It was discovered a number of years ago that corticosteroids slow the progression of Duchenne Muscular Dystrophy. It isn’t clear why this is the case—although it’s known that the immune system is involved in DMD, it appears that the benefit observed in DMD is due to another factor.
  3. Corticosteroids are typically given to a person receiving gene therapy. Because gene therapy is done with viruses, which trigger the immune system, the corticosteroids suppress an adverse reaction that might occur due to the treatment.

It’s known that corticosteroids can have significant side effects, particularly when used over a long period of time. Traditionally, in DMD and polymyositis, the drug is given every day. Recently, studies in mice have shown that the side effects are less if the drugs are given less frequently (once a week, for example). Also, some physicians give steroids to their DMD patients less frequently (only on weekends, for example). The effectiveness vs. side effects of different dosing regimens hasn’t been thoroughly documented yet in the medical literature.

In dysferlinopathy, corticosteroids don’t show the same benefit as in DMD. A clinical trial of deflazacort (the most commonly used corticosteroid in Germany, where the trial was done) administered daily showed side effects including muscle weakness, but no benefit. Some publications have investigated either a different molecular structure of a steroid to minimize side effects, or less frequent dosing (weekly, for instance) which also minimizes side effects.

For a modified steroid treatment to be appropriate for dysferlinopathy, it would have to not only avoid serious side effects, but also show a positive benefit (as it does in DMD). Individuals with dysferlinopathy have taken Prednisone following surgery or for other acute medical situations when advised by their care providers. Long term use, however, has shown to have deleterious side effects for individuals with dysferlinopathy.

Therefore, a diagnosis of muscular dystrophy (likely dysferlinopathy) should be considered if a patient shows atypical polymyositis presentations such as the following:

  • No arthritis, fevers, lung disease, cardiac abnormalities or swallowing problems
  • No detectable autoantibodies
  • No response to immunosuppressive therapy

The Jain Foundation is committed to helping patients or physicians who have questions regarding a possible misdiagnosis. The Jain Foundation is privately funded and does not ask for funds from patients or physicians. The ultimate goal is for everyone to obtain an accurate diagnosis which will lead to the most effective forms of treatment. If you want to learn more about Polymyositis, please visit The Myositis Association at:  www.myositis.org

Yes!  It is estimated that more than 25% of patients suffering from dysferlinopathy are initially misdiagnosed, often with Polymyositis. If you would like to read about some people’s experiences with misdiagnosis, select one of the stories below:

Josh’s Story

Bliss’s Story

Chanry’s Story

Tania’s Story