Dysferlinopathy

Clinical characteristics.

Dysferlinopathy includes a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapuloperoneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy.

Diagnosis/testing.

Diagnosis depends on a combination of muscle biopsy and molecular genetic testing. Muscle biopsy western immunoblotting almost always indicates a primary dysferlinopathy. DYSF, which encodes the protein dysferlin, is the only gene in which pathogenic variants are known to cause dysferlinopathy.

Management.

Treatment of manifestations: Individualized management may include physical therapy, use of mechanical aids, surgical intervention for orthopedic complications, respiratory aids, and social and emotional support.

Prevention of secondary complications: Stretching exercises to prevent contractures.

Surveillance: Annual monitoring of muscle strength, joint range of motion, and respiratory function; and for evidence of cardiomyopathy for subtypes with cardiac involvement.

Agents/circumstances to avoid: Weight control to avoid obesity; avoidance of steroid treatment.

Genetic counseling.

Dysferlinopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Testing

Muscle biopsy

• Histology. Muscle biopsy shows evidence of a dystrophy with random variation in fiber size and evidence of degeneration and regeneration. Type one fibers may predominate. There is often evidence of inflammation, sometimes leading to a misdiagnosis of polymyositis [Gallardo et al 2001, Fanin & Angelini 2002, Serratrice et al 2002, Prelle et al 2003].
• Immunostaining. Antibodies to dysferlin identify a protein of approximately 230 kd and show that dysferlin is located in the muscle membrane [Anderson et al 1999, Matsuda et al 1999, Eymard et al 2000]. Most individuals with DYSF pathogenic variants show complete deficiency of the protein or sometimes patchy sarcolemmal and cytoplasmic staining on muscle biopsy. Many individuals with partial deficiency of dysferlin have been reported [Piccolo et al 2000, Matsuda et al 2001, Saito et al 2002].
• Immunoblot. Because of variable and nonspecific patterns, immunoblot is generally considered the more reliable method for testing. If possible, both immunostaining and immunoblotting should be performed [Tagawa et al 2003].

Dysferlin expression. In individuals with dysferlinopathy, dysferlin immunoreactivity in peripheral blood monocytes cannot be detected using a commercially available monoclonal antibody [Ho et al 2002, Ankala et al 2014].

Testing Strategy

To confirm/establish the diagnosis in a proband. Because there are number of conditions that lead to muscle weakness with an elevated CK level, a reasonable approach is to test a muscle biopsy for dysferlin using western immunoblotting. Absence of dysferlin protein almost always indicates a primary dysferlinopathy; however, it is important to note that reduced levels of dysferlin may be secondary to other primary muscular dystrophies [Aoki et al 2001]. Further molecular genetic testing can then be pursued.

One genetic testing strategy is molecular genetic testing of DYSF, the only gene in which pathogenic variants are known to cause dysferlinopathy.

• For individuals of Libyan Jewish ancestry or Jews of the Caucasus, targeted analysis for pathogenic variants can be used for confirmation of the diagnosis and genetic counseling purposes.
• For individuals of other ethnic backgrounds, sequence analysis of the entire coding region can be pursued.

An alternative genetic testing strategy is use of a multigene panel that includes DYSF and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Several different clinical presentations have been observed [Ueyama et al 2002] and can occur within families having the same pathogenic variants [Liu et al 1998, Weiler et al 1999, Illarioshkin et al 2000, Nakagawa et al 2001, Ueyama et al 2001]. The weakness and atrophy may be asymmetric with any of these presentations.

Miyoshi myopathy. Young adults have muscle weakness and atrophy most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Early on, affected individuals are not able to stand on tiptoe, but retain the ability to stand on the heels. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles, at which time climbing stairs, standing, and walking become difficult. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. The weakness may eventually include the shoulder girdle muscles [Mahjneh et al 2001].

Limb-girdle muscular dystrophy syndrome. Early weakness and atrophy of the pelvic and shoulder girdle muscles begins in adolescence or young adulthood, with slow progression.

Scapuloperoneal syndrome. Occasionally, affected individuals present with initial weakness of the shoulder girdle muscles combined with distal weakness of the legs.

Distal myopathy with anterior tibial onset. Occasionally, leg weakness may involve the anterior compartment and cause foot drop [Illa et al 2001].

Elevated serum CK concentration only. Some individuals have only a marked elevation of serum CK concentration. This is usually considered a presymptomatic presentation of myopathy in an individual who eventually develops muscle weakness and atrophy. Sometimes the calf muscles are enlarged; this presentation may be confused with a dystrophinopathy (i.e., Duchenne or Becker muscular dystrophy).

Congenital muscular dystrophy. Two sibs with hypotonia beginning between birth and age two months had delayed motor development and serum CK concentrations that were normal or slightly elevated before age three years [Paradas et al 2009].

Of 41 Japanese individuals with proven dysferlinopathy, 20 had Miyoshi myopathy and 21 had LGMD2B (Table 2) [Takahashi et al 2003b]. On occasion, both phenotypes can be observed in affected sibs [Liu et al 1998].

Genotype-Phenotype Correlations

One study reported that the 3370G>T pathogenic variant was associated with a milder form of Miyoshi myopathy and the 3510G>A pathogenic variant was associated with a more severe form [Takahashi et al 2003a, Takahashi et al 2013].

Nomenclature

Dysferlinopathy was originally called LGMD2B because at the time that it was mapped to 2p13 it was the second form (2) of autosomal recessive (B) limb-girdle muscular dystrophy (LGMD) to be mapped. The gene for Miyoshi myopathy and the gene for LGMD2B were mapped to the same genetic interval at chromosome 2p13. Two groups independently identified a novel human skeletal muscle gene, DYSF, at this locus and documented that DYSF pathogenic variants cause both Miyoshi myopathy and LGMD2B.

Prevalence

The prevalence is not known. In the initial (1967) description of Miyoshi myopathy, 50 out of 72 families were from Japan. Tagawa et al [2003] examined a total of 107 unrelated Japanese individuals, including 53 with unclassified LGMD, 28 with Miyoshi myopathy, and 26 with other neuromuscular disorders. Expression of dysferlin protein was observed using immunohistochemistry (IHC) and mini-multiplex western blotting (MMW). They found a deficiency of dysferlin protein by using both IHC and MMW in 19% of individuals with LGMD and 75% of individuals with Miyoshi myopathy.

In Libyan Jews, the prevalence is at least one per 1,300, with a carrier rate of approximately 10% [Argov et al 2000].

A founder variant (Arg1905Ter) has been reported in Spain [Vilchez et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the following evaluations are recommended:

• Assessment of strength and function in the arms, hands, legs, and feet; especially calf muscle
• If needed, measurement of serum CK concentration
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No definitive treatments exist for the limb-girdle muscular dystrophies.

Management should be tailored to each individual and each specific subtype. A general approach to appropriate management can prolong survival and improve quality of life. This general approach is based on the typical progression and complications of individuals with LGMD as described by McDonald et al [1995] and Bushby [1999].

• Physical therapy and stretching exercises to promote mobility and prevent contractures
• Use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility
• Surgical intervention as needed for orthopedic complications such as foot deformity and scoliosis
• Use of respiratory aids when indicated
• Social and emotional support and stimulation to maximize a sense of social involvement and productivity and to reduce the sense of social isolation common in these disorders

Prevention of Secondary Complications

Stretching exercises to prevent contractures are indicated.

Surveillance

The following surveillance is appropriate:

• Annual monitoring of muscle strength, joint range of motion, and respiratory function
• Monitoring for evidence of cardiomyopathy in those subtypes with known occurrence of cardiac involvement

Agents/Circumstances to Avoid

Control weight to avoid obesity; avoid use of steroids [Walter et al 2013].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A double-blinded, placebo-controlled clinical trial of deflazacort in individuals with genetically confirmed dysferlinopathy has been completed [Walter et al 2013]. After six months of treatment, muscle strength did not improve; rather, there was a trend towards worsening muscle strength for affected individuals on deflazacort treatment. Muscle strength improved after the study drug was discontinued. Side effects included a broad spectrum typically seen in those taking steroids. Therefore, deflazacort treatment is not effective as a therapy for individuals with dysferlinopathies; additionally, the authors concluded that steroid treatment in general should be avoided in this condition [Walter et al 2013].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.