UNDERSTANDING DYSFERLINOPATHY

Names for Dysferlinopathy

UNDERSTANDING DYSFERLINOPATHY

Names for Dysferlinopathy

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Names for Dysferlinopathy

There are many different names that people use to refer to dysferlinopathy – LGMD2B, LGMDR2, Miyoshi Myopathy 1 and, of course, dysferlinopathy.   We prefer the term dysferlinopathy as it encompasses all the clinical diagnoses that are caused by mutations in the DYSF gene.  In fact,  the Clinical Outcome Study for dysferlinopathy (COS) has concluded that despite the early differences that result in the different clinical diagnoses, they are all the same disease.  The different clinical names for dysferlinopathy are used to differentiate which muscles first presented symptoms. For example, Miyoshi Myopathy 1 is a clinical name for dysferlinopathy that first presents in the distal muscles (example: calf muscles). We realize that the different clinical names are still commonly used by clinicians and patients, which is why we continue to use them throughout the Jain Foundation website.  Just remember that regardless of which name is used on the Jain Foundation website, in papers, or by individuals with mutations in DYSF, they all are the same disease and therefore the information presented is relevant if you have dysferlinopathy.  We have provided answers to some of the most commonly asked questions about dysferlinopathy nomenclature.

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, LGMDR2), Miyoshi Myopathy 1, 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.

Limb girdle muscular dystrophy type 2B (LGMD2B) is a recessively inherited form of limb girdle muscular dystrophy caused by mutations in the DYSF gene.  Clinically, LGMD2B is a slowly progressive muscular dystrophy that causes muscle weakness and wasting generally in the pelvic muscles and muscles of the shoulder girdle.  The Clinical Outcome Study for dysferlinopathy (COS) has concluded that despite the differences in the initial muscles that are affected, LGMD2B is the same disease as the other clinical diagnoses that are caused by mutations in DYSF (Miyoshi Myopathy 1, DMAT, etc).

LGMDR2 and LGMD2B are just different ways to refer to the same disease.  As the number of genes associated with the recessive LGMDs grew, the original naming classification used for the LGMDs was no longer viable because it was limited to only 26 genes (A-Z).  Therefore, the classification scheme changed to the following:

The diseases are specified as LGMDLN, where L designates the inheritance pattern (D = dominant, R = recessive) and N is a number assigned in numeric order within each inheritance pattern, following the chronological order in which the genetic cause was discovered.  With this new naming scheme, the LGMD caused by mutations in the DYSF gene went from LGMD2B to LGMDR2.

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 Myopathy is technically categorized as a distal muscular dystrophy, which means that the muscles that are most severely 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 clinical 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 (or MM1), is the type that is caused by mutations in the DYSF gene.  MMD3 is the type that is caused by mutations in Anoctamin 5 (ANO5). 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.

The Clinical Outcome Study for dysferlinopathy (COS) has concluded that despite the differences in the initial muscles that are affected, Miyoshi Myopathy 1 is the same disease as the other clinical diagnoses that are caused by mutations in DYSF (LGMD2B, LGMDR2, DMAT, etc).

The natural history study of dysferlinopathy, which is a clinical outcome study (COS), has not identified any significant differences between individuals having different initial clinical diagnoses and has therefore concluded they are all a dysferlinopathy despite the differences seen in initial muscle involvement.

There is a condition referred to as “Distal Myopathy with Anterior Tibial Onset” (DMAT) or “Distal Anterior Compartment Myopathy” (DACM) which is caused by DYSF mutations and is very similar to Miyoshi Myopathy 1, 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 mutations in the DYSF gene whose symptoms do not precisely match the clinical features of MM 1, LGMD2B/LGMDR2, or DACM or whose only symptom is elevated CK levels (a.k.a. HyperCKemia). The general term for all muscular dystrophies caused by mutations in the DYSF gene is “dysferlinopathy”.

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 incomplete. Tests do not yet exist to identify every type of LGMD, but an individual 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 original classification scheme of the limb-girdle dystrophies was as follows:

The diseases were specified as LGMDNL, where N designated the inheritance pattern (1=dominant, 2=recessive) and L was 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 was the term used to refer to the type of LGMD that is caused by mutations in the DYSF gene because it was the second recessive type to have its genetic locus identified.

The revised classification is as follows:

As the number of gene associated with the recessive LGMDs grew, this naming classification no longer was viable because it was limited to only 26 genes (A-Z).  Therefore, the classification scheme has been changed to the following.  The diseases are specified as LGMDLN, where L designates the inheritance pattern (D = dominant, R = recessive) and N is a number assigned in numeric order within each inheritance pattern, following the chronological order in which the genetic cause was discovered.  With this new naming scheme, the LGMD caused by mutations in the DYSF gene went from LGMD2B to LGMDR2.

In general, the clinical features described for Miyoshi Myopathy 1 also apply to LGMD2B/LGMDR2, except that the initial muscle involvement is different (hip muscles, rather than calf muscles).

Muscular dystrophy is a general term that refers to a hereditary condition marked by progressive weakening and wasting of muscles. 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.