Myofibrillar Myopathy

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: DES (HGNC:2770) BAG3 (HGNC:939) FLNC (HGNC:3756)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 09/06/2018
• Curation Status: Released (1.1.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
DES	N/A (0011076)	601419	Moderate Actionability
BAG3	N/A (0013061)	612954	N/A - Insufficient evidence: early rule-out
FLNC	N/A (0012289)	609524	Moderate Actionability

Actionability Assertion Rationale

• The preliminary assertion for DES based on the rubric was strong. However, due to a lack of studies specific to myofibrillar myopathy to clearly inform effectiveness, the experts changed the assertion to moderate. The preliminary assertion for FLNC based on the rubric was moderate, and the experts agreed. There was significant discussion regarding potentially higher actionability with the dilated cardiomyopathy phenotype, which has yet to be assessed for DES and FLNC.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Clinically significant cardiac involvement (DES) / Cardiology management	2	3A	2D	3	10AD
Clinically significant cardiac involvement (DES) / ICD implantation	2	3A	2C	2	9AC
Clinically significant cardiac involvement (FLNC) / Cardiology management	2	2A	2D	3	9AD
Clinically significant cardiac involvement (FLNC) / ICD implantation	2	2A	2D	2	8AD

Severity of Outcome

Prevalence of the Genetic Condition

The overall prevalence of myofibrillar myopathy (MFM) is currently undetermined. The prevalence of DES-related MFM has been estimated to be 0.17 in 100,000. However, the prevalence of BAG3- and FLNC- related MFM was not available.

Clinical Features (Signs / symptoms)

The diagnosis of MFM is traditionally based on common morphologic features on muscle biopsy. Pathogenic variants in DES, FLNC and BAG3 are responsible for a subset of MFM cases. Cardiac manifestations of MFM include cardiomyopathy (dilated, hypertrophic, restrictive or left ventricular noncompaction) and arrhythmia (atrioventricular conduction block, atrial fibrillation, other tachyarrhythmias and cardiac conduction defects). MFM is characterized by slowly progressive muscle weakness, from distal to proximal lower extremities with eventual involvement of upper extremities, trunk, facial and respiratory muscles as the disease progresses.

Natural History (Important subgroups & survival / recovery)

MFM typically presents in adulthood starting around 30-50 years of age (range 2-77 years); the majority of cases present after age 40 years. However, presentation of BAG3-related MFM characteristically occurs earlier, in the first and second decades of life, and is often fatal. Patients with this subtype typically experience rapid progression and are often severely affected by the second decade and require cardiac transplant, respiratory ventilation, and/or a wheelchair. DES-related MFM can also present as early as the first decade (range: first to sixth decade). In cases of childhood onset, the disease is rapidly progressive and leads to debilitating contractures, cardiomyopathy, and cardiorespiratory failure. Cardiomyopathy is more common in patients with pathogenic variants in DES and BAG3. Cardiac involvement onset in DES-related disease has been observed from first to seventh decades of life, with cardiomyopathy occurring more often in males than females. In DES-related MFM, cardiac involvement often precedes muscle weakness. Respiratory involvement can lead to death. While most cases are heterozygous, some homozygous or compound heterozygous cases have been described with pathogenic variants in DES; these cases manifested earlier and had more rapid progression, while heterozygous carriers in these kindreds were unaffected.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

There have been reported cases of compound heterozygotes or homozygotes in DES-related MFM.

Prevalence of Genetic Variants

Unknown

No data have been reported on the population prevalence of pathogenic variants in these genes.

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

The overall penetrance of pathogenic variants in these genes is not known.

Tier 3

5-39 %

The frequency of some symptoms has been reported, although it is a combination of clinically and molecularly identified patients (via family studies). Penetrance data on the basis of molecular identification alone is not available:For individuals with FLNC-related MFM, the following were observed in a systematic review of case series:

Cardiac involvement: 21/57 (37%)

Respiratory involvement: 14/61 (23%)

Musculoskeletal involvement: 63/70 (90%)For individuals with BAG3-related MFM, the following were observed in a systematic review of case series:

Cardiac involvement: 7/7 (100%)

Respiratory involvement: 6/7 (86%)

Musculoskeletal involvement: 7/7 (100%)

Tier 1

>= 40 %

For individuals with DES-related MFM, a systematic review of case series and a meta-analysis of cases reported in the literature (each with over 100 patients but containing overlapping studies/patients), report the following:

Cardiac involvement: 74%-79%

Respiratory involvement: 26%-32%

Musculoskeletal involvement: 74%-86%

Tier 1

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

Inter- and intra-familial variability in symptoms and age of onset is reported. Genotype–phenotype correlations with DES-related MFM are emerging, but they are not yet useful for guiding clinical decisions.

Tier 1

Intervention Effectiveness

Patient Management

Clinicians should refer patients to a multidisciplinary clinic (including cardiology, physical therapy and occupational therapy) designed specifically to care for patients with neuromuscular diseases (NMDs). This recommendation is based on evidence in the setting of amyotrophic lateral sclerosis (ALS), indicating that a multidisciplinary approach is associated with improved survival, higher quality of life, increased use of treatments and interventions, and increased use of adaptive equipment.

Tier 2

Individuals should undergo a baseline cardiac evaluation. Patients may present with cardiac morbidity or sudden cardiac death (SCD), and serious cardiac manifestations are often identified only with cardiology testing. No effectiveness data was presented in the setting of MFM. However, patients with Duchenne muscular dystrophy (DMD) often have improved quality of life following appropriate cardiac interventions.

Tier 2

Cardiac evaluation should be performed before anesthesia/sedation in patients with MFM.

Tier 2

In the setting of reduced ejection fraction (EF), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) are recommended in combination with beta-adrenergic blockade. Though evidence of the effectiveness of these interventions in MFM were not available, early initiation of ACEIs has been shown to prolong survival relative to late initiation in open-label cross-over trials with DMD. Beta blockade initiated in the pre-symptomatic stages of HF in DMD improved survival over blockade initiated after symptomatic HF onset.

Tier 2

Consider ICD placement in an individualized manner, with decisions in DES-related MFM not dependent on EF alone.

Tier 2

In a meta-analysis of 159 DES-related MFM patients, ICD was placed in 7 and pacemaker in 36. Sudden cardiac death occurred in two patients with a pacemaker, suggestive of ventricular tachyarrhythmia, indicating ICD may be a more appropriate consideration in cases due to DES.

Tier 1

More data are available on ICDs in the settings of cardiac conduction defects due to LMNA pathogenic variants or of non-ischemic cardiomyopathy. One prospective cohort study of 19 patients with an LMNA pathogenic variant and an ICD showed that 42% (N=8) received appropriate ICD therapy in response to ventricular tachycardia (N=2) and ventricular fibrillation (N=6) across a 34 month period. A meta-analysis of randomized control trials of patients with non-ischemic cardiomyopathy reported an overall reduction in mortality with ICD therapy (RR=0.69, 95% CI=0.56-0.86; p=0.002).

Tier 2

Clinicians should order pulmonary function testing or refer for pulmonary evaluation to identify and treat respiratory insufficiency at the time of diagnosis and if symptoms develop. Patients with respiratory failure from NMDs often do not have symptoms that precede the onset of respiratory failure, which is often identified only with pulmonary function tests. Historically, non-invasive ventilation was recommended in the setting of respiratory failure in MFM. Newer guidelines withhold making a recommendation about non-invasive ventilation, citing more recent evidence that this treatment may increase mortality.

Tier 2

Glucocorticoid use should be guided by noncardiac indications for treatment. No data are available on glucocorticoid effectiveness in MFM, though daily glucocorticoid treatment has been shown to reduce the risk of scoliosis in DMD and is the recommended standard of care treatment of DMD.

Tier 2

Glucocorticoid treatment in pediatric DMD has been shown to improve muscle strength and respiratory function, prolong walking function, and reduce the need for scoliosis surgery, with 13 of 24 (54%) untreated patients requiring spinal stabilization versus 0 of 30 treated patients (0%).

Tier 5

Clinicians should refer patients experiencing dysphagia, frequent aspiration, or weight loss for swallowing evaluation and/or gastroenterology evaluation to assess and manage swallowing function and aspiration risk. There is evidence from related conditions (including ALS) that maintenance of nutrition and body weight prolongs survival.

Tier 2

Surveillance

In asymptomatic patients, annual cardiac evaluation with examination, ECG and structural evaluation (echocardiography or cardiac MRI) is reasonable.

Tier 2

Clinicians should obtain periodic pulmonary function testing or periodic referral for pulmonary evaluation to identify and treat respiratory insufficiency.

Tier 2

Patients should be monitored for the development of spinal deformities to prevent resultant complications and preserve function.

Tier 2

Circumstances to Avoid

Avoid dehydration, exercising to exhaustion, and supramaximal, high-intensity exercise due to the risk of exercise-induced muscle damage, myoglobinuria, and subsequent overwork weakness.

Tier 2

Nature of Intervention

Nature of Intervention

Identified interventions include non-invasive surveillance, pharmacotherapy, possible ICD implantation, and anesthetic precautions.

Context: Adult

Chance to Escape Clinical Detection

Patients with respiratory failure from neuromuscular-related weakness often do not have symptoms that precede the onset of respiratory failure. For DES-related MFM, cardiac involvement can occur prior to the onset of muscle weakness. As such, presenting symptoms can be serious, including sudden cardiac death.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			DES			601419	0011076	0018943
BAG3			612954	0013061	0018943
FLNC			609524	0012289	0018943

References List

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Feingold B, Mahle WT, Auerbach S, Clemens P, Domenighetti AA, Jefferies JL, Judge DP, Lal AK, Markham LW, Parks WJ, Tsuda T, Wang PJ, Yoo SJ. (2017) Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association. Circulation. 136(13):e200-e231.

Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN. (2010) HFSA 2010 Comprehensive Heart Failure Practice Guideline. Journal of cardiac failure. 16(6):e1-194.

MYOPATHY, MYOFIBRILLAR, 1; MFM1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 601419, (2018) World Wide Web URL: http://omim.org/

MYOPATHY, MYOFIBRILLAR, 5; MFM5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 609524, (2016) World Wide Web URL: http://omim.org/

MYOPATHY, MYOFIBRILLAR, 6; MFM6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 612954, (2016) World Wide Web URL: http://omim.org/

Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, Wicklund M, Barohn RJ, Ensrud E, Griggs RC, Gronseth G, Amato AA. (2014) Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 83(16):1453-63.

Sussman, M.. Duchenne muscular dystrophy. J Am Acad Orthop Surg (2002) Accessed: 2018-09-06. URL: https://www.ncbi.nlm.nih.gov/pubmed/11929208

van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JD, de Walle HE, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP. (2011) Desmin-related myopathy. Clinical genetics. 80(4):354-66.