Clinical Guidance

Studies have reported genotype-phenotype correlates with the following two pathogenic variants :

• was associated with a milder form of Miyoshi muscular dystrophy and LGMD2B

• was associated with Miyoshi muscular dystrophy.

Source: GeneReviews — "Dysferlinopathy"

Diagnostic Criteria

No consensus clinical diagnostic criteria for dysferlinopathy have been published.

Suggestive Findings

Dysferlinopathy should be suspected in those with suggestive findings of and considered in those with suggestive findings of . The diagnosis should be informed by .

Major Phenotypes

Dysferlinopathy should be suspected in individuals with suggestive findings of the two major phenotypes, Miyoshi muscular dystrophy and limb-girdle muscular dystrophy 2B, based on the following findings . Miyoshi muscular dystrophy (MMD)

Source: GeneReviews — "Dysferlinopathy"

Differential Diagnosis

Limb-girdle muscular dystrophies. Dysferlinopathy needs to be distinguished from other autosomal recessive limb-girdle muscular dystrophies (see OMIM Phenotypic Series: LGMD, autosomal recessive). Individuals with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Most individuals with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among individuals and genetic subtypes. Multigene panels are increasingly used to identify pathogenic variants and confirm a diagnosis of a specific form of LGMD. Dystrophinopathies.

Source: GeneReviews — "Dysferlinopathy"

Management Guidelines

No clinical practice guidelines for dysferlinopathy have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dysferlinopathy, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Dysferlinopathy: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Musculoskeletal

| Neuromuscular, physical medicine rehab / PT/OT eval | To evaluate extent of disease as determined by:

• Muscle strength function in arms, hands, legs (esp calves), feet

• Balance

• Function

• Fine motor skills

• Impact on activities of daily living

• Need for ongoing PT OT

• Need for AFOs assistive ambulatory devices

• Need for adaptive devices

• Need for handicapped parking

Respiratory

| PFTs incl supine sitting spirometry, MIP, MEP | To evaluate for effects of muscle weakness on respiratory function, esp in nonambulatory persons

Cardiac

| Baseline echocardiogram | To evaluate for evidence of cardiac involvement (cardiomegaly, cardiomyopathy, arrhythmia)

Genetic

counseling | By a genetics professional1 | To review results of genetic testing to inform patients families re nature, MOI implications of dysferlinopathy in order to facilitate medical personal decision making

Family support/

resources | Assess:

• Use of community or , incl patient advocacy organizations;

• Need for social work involvement for caregiver support.

Source: GeneReviews — "Dysferlinopathy"

Clinical Guidance

Control weight to avoid obesity; avoid use of steroids .

Source: GeneReviews — "Dysferlinopathy"

Therapies Under Investigation

Comparison of the effect of prednisolone with vamorolone on dysferlin-deficient myofiber repair showed that vamorolone stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse myofibers . Exon skipping is a therapeutic approach that is feasible for various genetic disorders . designed antisense oligonucleotides (AONs) to bypass the effect of the affected individuals pathogenic variant on RNA splicing. AON-mediated exon skipping corrected the aberrant pseudoexon splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression .

Source: GeneReviews — "Dysferlinopathy"

Surveillance Guidelines

Routine follow up with the multidisciplinary team (annually or more frequently as determined by managing physician) is recommended. See .

Table 6.

Dysferlinopathy: Recommended Multidisciplinary Team Surveillance

System/Concern | Evaluation | Frequency

Neuromuscular

| Evaluate disease progression coordinate care. | At least annually

Rehabilitation

medicine | Eval monitoring of:

• Muscle strength testing using a quantitative scale (e.g., MMT, hand-held dynamometry, QMA1) to evaluate progressive muscle involvement

• Physical function (e.g., 6-min walk test, AMAT2)

• Activities of daily living

| At least annually

PT | Eval mgmt for balance need for AFOs, cane, walker, wheelchair. powerchair | At least annually, or more frequently based on needs

OT | Eval mgmt of fine motor skills hand function, such as Jebsen Hand Function Test3 | At least annually

Respiratory

| PFTs incl supine sitting spirometry, MIP, MEP on affected persons at advanced stages of disease | As needed, if symptomatic or abnormal PFTs

Cardiac

| Follow up not needed unless symptomatic or findings on initial eval were abnormal

Family support/

resources | Assess social emotional support stimulation. | At least annually

AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT = manual muscle testing; OT = occupational therapy; PFTs = pulmonary function tests; PT = physical therapy; QMA = Quantitative Muscle Assessment

1.

2.

3.

Source: GeneReviews — "Dysferlinopathy"