Muscular dystrophy refers to a group of diseases that produce muscle weakness. Muscular dystrophies all involve abnormalities of the muscle cells themselves, rather than the nerves that control the muscles. All muscular dystrophies are caused by genetic mutations. Genetic mutations are not communicable but can be inherited, with different inheritance patterns depending on the particular form of muscular dystrophy. In general, muscular dystrophies cause progressive weakness, although there are a few exceptions. The most common, and best known, type of muscular dystrophy is Duchenne Muscular Dystrophy, which causes symptoms starting in childhood and almost exclusively affects males, because the responsible gene is located on the X chromosome. Some other forms of muscular dystrophy affect both genders equally and cause symptoms that first appear in adolescence or adulthood.
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Myopathy simply means “muscle disease.” Miyoshi Myopathy (MM) is a form of muscular dystrophy that was first described in the medical literature by Miyoshi in 1967. Although first identified in Japan, it occurs worldwide. Miyoshi is caused by defects in the gene for the protein dysferlin.
Miyoshi Myopathy is categorized as a distal muscular dystrophy, which means that the muscles that are most strongly affected initially are in the calves, forearms, hands, or feet. Most forms of muscular dystrophy preferentially affect proximal muscles (those in the hips, thighs, or shoulders), so those that don't follow that pattern were grouped together for classification purposes. There are many forms of distal myopathy. Miyoshi Myopathy is distinctive among the distal myopathies in several respects:
- It has a recessive inheritance pattern. This means that in most cases there is no family history.
- The first muscles to be affected are typically the gastrocnemius (the calf muscles in the back of the legs used to stand on tiptoe).
- Onset of symptoms generally occurs between the ages of 15 and 30. There are exceptions to this age range: genetically confirmed cases have been reported in the literature with onset as late as age 73.
- Levels of CK (creatine kinase, a muscle enzyme) in the blood are very high. Values typically found in Miyoshi patients are several thousand, compared to a normal reading of 100 or less. This is typical of some other muscular dystrophies but not most of the distal forms.
- Muscle biopsies show indications of a muscle disease, including degeneration/regeneration of muscle fibers, and often show evidence of inflammation. Miyoshi Myopathy is distinctive in that most distal myopathies produce "rimmed vacuoles" in muscle biopsies. Miyoshi usually does not, although there are a few rare exceptions where rimmed vacuoles are present, but these are usually not prominent.
- There are typically no symptoms of neuropathy, and tests of nerve conduction generally yield normal results.
There are three genetically identified types of Miyoshi Myopathy - MMD1, MMD2, MMD3. MMD1 is the type that is caused by mutations in the dysferlin gene. MMD3 is the type that is caused by mutations in Anoctamin 5. The gene for MMD2 has not yet been identified, but it is known that MMD2 is distinct from MMD1 or MMD3. These types of Miyoshi Myopathy are indistinguishable clinically and can only be differentiated by the identification of mutations in the particular genes.
Limb-girdle muscular dystrophy refers to a group of diseases (not a single disease) which were lumped together, long before the era of molecular biology and genetic engineering, because they shared some common clinical symptoms. The name refers to the first muscles to show symptoms, which are those around the shoulders and the hips. Beyond that, the different limb-girdle muscular dystrophies have very little in common in terms of inheritance pattern, age of onset, severity of symptoms, prognosis, genetic mutations, or biochemical abnormalities in the muscle cells. More recently, many forms of limb-girdle muscular dystrophy have been tracked to specific locations in the human genome, and many of the specific proteins involved have been identified.
A diagnosis of limb-girdle muscular dystrophy without specifying the particular type is not really a diagnosis at all. Tests do not yet exist to identify every type of LGMD, but a patient can be tested for the most common forms. Also, some forms of LGMD are difficult to distinguish clinically from Becker muscular dystrophy (caused by mutations of the dystrophin gene on the X chromosome), so dystrophin testing is also typically done.
The classification scheme of the limb-girdle dystrophies is as follows. The diseases are specified as LGMDNL, where N is a number which designates the inheritance pattern (1=dominant, 2=recessive). The L is a letter assigned in alphabetical order within each inheritance pattern, following the chronological order in which the genetic cause was discovered. Following this nomenclature, LGMD2B (the specific type of limb-girdle caused by a dysferlin gene mutation) is the second recessive type to have its genetic locus identified.
In general, the clinical features described for Miyoshi Myopathy also apply to LGMD2B, except that the initial muscle involvement is different (hip muscles, rather than calf muscles).
Dysferlinopathy refers to a muscular dystrophy that is caused by mutations in the dysferlin gene regardless of the clinical presentation. The symptoms of dysferlinopathy (for reasons which are not yet understood) vary significantly between individuals. Clinical presentations most commonly associated with dysferlinopathy include Limb Girdle Muscular Dystrophy (LGMD2B), Miyoshi Myopathy, Distal Myopathy with Anterior Tibial Onset (DMAT), Proximodistal weakness, Pseudometabolic myopathy, and HyperCKemia. Therefore, the term dysferlinopathy should not be used unless pathogenic mutations have been identified.
LGMD2B and Miyoshi Myopathy (MMD1) (a.k.a. dysferlinopathy) are both caused by inherited genetic mutations in the gene for dysferlin. They are recessive conditions, so patients with these diseases must have two defective copies of the dysferlin gene. There are many different mutations that disrupt the function of dysferlin, and each patient usually has different mutations in each of his/her two copies of the dysferlin gene. People with only one defective dysferin gene do not have symptoms, because having one good copy of dysferin is enough to prevent the disease.
An individual may have genetic defects in the dysferlin gene for the following reasons:
- Inheritance of a defective gene from each parent (autosomal recessive inheritance)
- Sporadic mutations
We do not yet understand why defects in the dysferlin gene give rise to both Miyoshi Myopathy (MMD1) and LGMD2B, with their slightly different clinical manifestations. Generally, as both clinical presentations progress, patients begin to experience symptoms from both conditions (i.e. weakness in both the proximal and distal limbs) and in later stages, the symptoms are quite similar for both clinical manifestations.
Dysferlin is a protein made from the dysferlin gene that, when mutated or absent, causes both Limb-Girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. 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.
There are currently not many answers to this question. Studies have shown that the dysferlin protein is likely involved in repair of the muscle fiber membrane. Muscle fibers repeatedly stretch and contract, and consequently develop small tears in their outer membranes that must be repaired. Muscle is also a regenerative tissue, and muscle cells fuse together to form fibers throughout life. Both of these processes require restructuring of the cellular membrane. It is not known exactly how dysferlin participates in these processes, or which process is most affected by a lack of dysferlin. There is also evidence for additional functions roles for dysferlin in the muscle. 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 LGMD2B/Miyoshi.
There is a condition referred to as "Distal Myopathy with Anterior Tibial Onset" (DMAT) or "Distal Anterior Compartment Myopathy" (DACM) which is caused my dysferlin mutations and is very similar to Miyoshi Myopathy, except that the first muscles affected are the muscles in the front, rather than the back, of the lower leg. There also have been some patients found to have dysferlin gene mutations whose symptoms do not precisely match the clinical features of MM, LGMD2B, or DACM or whose only symptom is elevated CK levels (a.k.a HyperCKemia). A more general term for all muscular dystrophies caused by mutations in dysferlin is "dysferlinopathy".