Myofibrillar Myopathy
What is Myofibrillar Myopathy?
Most people with MFM begin to develop muscle weakness in mid-adulthood, but features of the disease can appear anytime between infancy and late adulthood. MFM is caused by a genetic change in any of several genes, including DES, CRYAB, MYOT, LDB3, FLNC, BAG3, FHL1, TTN, and DNAJB6. The signs and symptoms of MFM can vary depending on the genetic cause.
When does it begin?
Resilience
We cannot help that the fact we have a bad gene but we can control how we live our lives. Spend your time improving your mind and maintaining your body to keep as fit as possible. Always do your best to stay positive.
Search for hope
We try to update this website with the latest information on treatments for MFM. Keep in mind these diseases are very rare therefore there is not much incentive for companies to look at our problem. Visit our Advocate page.
We are a group of people who have Myofibrillar Myopathy (MFM) - people from every country in the world who have lived with and searched for details about this disease for many years. This space is dedicated to collecting MFM information and current news along with helpful links and connections. This website is a spin off of the Facebook page Myofibrillar Myopathy. Check it out and mingle and ask questions of others dealing with MFM.
Follow Mark's story. Download his PDF. His graphic, in general, encompasses most MFMs. It’s just a different protein within the sarcomere that had broken down: LDB3, Titin, Actin, Myosin, etc…
Myofibrillar myopathy (MFM) is a group of rare genetic neuromuscular disorders that primarily affect skeletal muscles, causing progressive muscle weakness and wasting over time. These conditions can also impact cardiac muscles in some cases, leading to heart-related complications. MFM is characterized by the disintegration of myofibrils—the contractile units within muscle fibers—and the accumulation of abnormal protein aggregates in muscle cells, often involving proteins like desmin. It is considered a type of muscular dystrophy, though it's morphologically similar across cases but genetically diverse.
### Symptoms
Symptoms typically begin in adulthood, often after age 40, but can appear in childhood in some forms. Common signs include:
- Progressive weakness in the limbs, particularly the distal muscles (e.g., hands and feet), which may spread to proximal muscles (e.g., hips and shoulders).
- Muscle stiffness, cramps, or pain.
- Difficulty with walking, swallowing, or breathing if respiratory muscles are affected.
- Cardiomyopathy or arrhythmias in cases where the heart is involved.
- Variability in severity and progression depending on the specific genetic mutation.
### Causes
MFM is caused by mutations in genes that encode proteins essential for maintaining the structure and function of muscle fibers. Key genes include DES (desmin), CRYAB (alpha-B crystallin), MYOT (myotilin), LDB3 (ZASP), FLNC (filamin C), and others. These mutations lead to protein misfolding, aggregation, and myofibrillar breakdown. The condition is usually inherited in an autosomal dominant pattern, though recessive and sporadic cases occur.
### Diagnosis
Diagnosis often involves:
- Clinical evaluation of symptoms and family history.
- Electromyography (EMG) to assess muscle electrical activity.
- Muscle biopsy, which reveals characteristic myofibrillar disorganization, protein aggregates (often staining positive for desmin), and degeneration.
- Genetic testing to identify specific mutations.
### Treatment and Management
There is no cure for MFM, but management focuses on supportive care to improve quality of life. This may include:
- Physical therapy to maintain mobility.
- Assistive devices like braces or wheelchairs.
- Cardiac monitoring and treatment if the heart is affected.
- Respiratory support if breathing is impaired.
- Emerging research explores potential therapies targeting protein aggregation, but none are widely available yet.
Myofibrillar myopathy (MFM) is a rare group of genetic neuromuscular disorders characterized by the progressive breakdown of muscle fibers due to protein accumulation and structural disorganization within the cells. In contrast, more common forms of muscular dystrophy (MD), such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and limb-girdle muscular dystrophy (LGMD), are inherited conditions that primarily involve muscle fiber degeneration due to defects in proteins that support the muscle cell membrane or extracellular matrix. While MFM is sometimes classified under the broader umbrella of muscular dystrophies due to its genetic and progressive nature, it differs significantly in its underlying mechanisms, pathology, and clinical presentation from these more prevalent types.
Below is a comparison of the key differences, organized for clarity:
| Aspect | Myofibrillar Myopathy (MFM) | Common Forms of Muscular Dystrophy (e.g., DMD, BMD, LGMD) |
|--------|-----------------------------|-----------------------------------------------------------|
| Pathology | Involves disorganization and disintegration of myofibrils (contractile elements inside muscle fibers), starting at the Z-disk, with accumulation of abnormal protein aggregates (e.g., desmin, myotilin), congophilic deposits, vacuoles containing degraded material, and ectopic protein expression. Muscle biopsies show hyaline or granular deposits, reduced oxidative activity, and sometimes inflammatory cells, but less emphasis on widespread necrosis or fibrosis. | Focuses on muscle fiber necrosis, regeneration, and replacement by fat and fibrous tissue due to membrane instability or extracellular matrix defects. Biopsies typically reveal fiber size variation, central nuclei, inflammation, and fibrosis, without the specific Z-disk streaming or protein aggregates seen in MFM. |
| Genetics and Causes | Caused by mutations in genes encoding Z-disk-associated proteins, such as DES (desmin), CRYAB (alpha-B crystallin), MYOT (myotilin), FLNC (filamin C), BAG3, and LDB3/ZASP. Inheritance is usually autosomal dominant, with rare recessive cases; mutations disrupt protein folding, chaperoning, or stability, leading to intracellular buildup. | Linked to mutations in genes like DMD (dystrophin for DMD/BMD) or those encoding sarcoglycans (for certain LGMD types), affecting sarcolemmal (cell membrane) proteins or laminin. Primarily X-linked (DMD/BMD) or autosomal recessive/dominant, focusing on membrane or matrix support rather than intracellular structural proteins. |
| Onset and Progression | Often adult-onset (typically after age 20–40), though some subtypes (e.g., BAG3-related) can start in childhood. Progression is variable and generally slower, with symptoms worsening over decades. | Usually childhood or early adolescent onset (e.g., DMD by age 5), with rapid progression leading to loss of ambulation by teens in severe cases like DMD. BMD and some LGMD types may have later onset but still earlier and more aggressive than most MFM. |
| Clinical Features | Progressive weakness often starting distally (e.g., hands, feet, or scapuloperoneal distribution), with possible proximal, axial, or limb-girdle involvement. Symptoms include muscle stiffness, cramps, aching, atrophy, and myotonic discharges on EMG. Respiratory insufficiency and rigid spine may occur early in some subtypes. | Predominantly proximal weakness (e.g., hips, shoulders), with features like calf hypertrophy (DMD/BMD), waddling gait, and frequent falls. EMG shows myopathic patterns without myotonic discharges; less emphasis on distal onset unless in specific subtypes. |
| Associated Complications | Prominent cardiomyopathy (e.g., arrhythmias, conduction blocks, heart failure) in most subtypes, often a leading cause of morbidity. Peripheral neuropathy, cataracts, and respiratory failure are common; creatine kinase (CK) levels are mildly elevated. | Cardiomyopathy occurs in some (e.g., DMD), but it's often secondary and later-stage. Respiratory issues arise from weakness but less from direct involvement; scoliosis and joint contractures are frequent. Neuropathy is rare; CK levels are often markedly elevated. |
In summary, while both involve genetic mutations leading to muscle weakness, MFM stands out due to its focus on intracellular protein mishandling and Z-disk pathology, resulting in a distinct set of symptoms and complications compared to the membrane-focused degeneration in common MDs. Diagnosis typically requires muscle biopsy and genetic testing to differentiate them, as clinical overlap can occur.