Myofibrillar myopathy (filamin C)

Overview

Myofibrillar myopathy (filamin C) is a rare inherited muscle disorder that disrupts the internal architecture of muscle cells. The condition arises from pathogenic variants in FLNC, which encodes filamin C, a protein essential for organising and stabilising the structural framework within both skeletal muscle and heart muscle fibres. When this framework is compromised, muscle fibres become unstable and accumulate abnormal protein deposits, leading to progressive weakness and tissue damage.

The condition typically presents in adulthood, though the age of onset and severity vary considerably between individuals and families. Skeletal muscle weakness most often affects the lower legs initially, causing difficulty with walking and balance, but can eventually involve the thighs, arms and other muscle groups. Cardiac involvement is a particularly important feature, as many affected individuals develop abnormal heart rhythms (arrhythmias) or cardiomyopathy, which can be life-threatening if not monitored and managed appropriately.

Myofibrillar myopathy (filamin C) is considered ultra-rare, with exact prevalence figures not well established. The condition affects both men and women equally and has been reported across different ethnic backgrounds.

Symptoms & clinical features

The hallmark feature of this condition is progressive skeletal muscle weakness, which often begins in the lower parts of the legs (distal lower limbs). Individuals may notice difficulty standing on tiptoe, weakness when walking, or frequent tripping due to foot drop. As the condition progresses, weakness may spread to the thighs, hips, hands and forearms, though the pattern and rate of progression varies widely. Some people experience only mild symptoms that remain stable for years, whilst others develop more severe weakness affecting mobility and the ability to perform daily activities.

Cardiac manifestations are a critical component of myofibrillar myopathy (filamin C) and may sometimes appear before skeletal muscle symptoms become obvious. Heart rhythm disturbances can include atrial fibrillation, ventricular arrhythmias or conduction abnormalities that cause the heart to beat irregularly or too slowly. Some individuals develop dilated cardiomyopathy, where the heart muscle becomes weakened and the chambers enlarge, reducing the heart's ability to pump blood effectively. In certain cases, cardiac symptoms may be the presenting feature, particularly in younger adults who develop unexplained arrhythmias or heart failure symptoms such as breathlessness, fatigue or swelling of the ankles.

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Affected organs

This disorder primarily affects skeletal muscle and cardiac muscle. Within skeletal muscle, the characteristic pathological changes include disruption of the organised bands (myofibrils) that allow muscle fibres to contract efficiently, alongside the formation of protein aggregates visible under microscopy. These structural abnormalities progressively impair muscle strength and endurance.

The heart is often significantly affected, with the cardiac muscle experiencing similar structural disruption to skeletal muscle. The electrical conducting system of the heart may also be compromised, leading to rhythm disturbances. Because cardiac involvement can occur independently of the severity of skeletal muscle symptoms, heart monitoring is an essential component of care for all individuals with FLNC-related disease.

Brain

Central nervous system involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of myofibrillar myopathy (filamin C) varies considerably, even within the same family. Some individuals experience only mild muscle weakness and minimal cardiac involvement throughout their lives, whilst others develop severe progressive weakness requiring mobility aids and significant cardiac complications. The condition typically manifests in the third to fifth decade of life, though earlier and later onset has been reported.

Cardiac complications represent the most serious risk associated with this condition. Life-threatening arrhythmias can occur suddenly, and some affected individuals may require an implantable cardioverter-defibrillator (ICD) to protect against dangerous heart rhythms. Progressive heart failure due to cardiomyopathy can also develop. The lifetime risk of serious cardiac events is significant enough that all affected individuals require regular cardiac surveillance, though the exact percentage varies between studies and families.

Genetic causes

Myofibrillar myopathy (filamin C) is caused by pathogenic variants in FLNC, located on chromosome 7. This gene provides instructions for producing filamin C, a large structural protein that cross-links actin filaments and anchors various proteins within the muscle fibre cytoskeleton. Filamin C is particularly abundant at the Z-discs, which are the boundaries of each contractile unit (sarcomere) in striated muscle.

The normal function of filamin C is to maintain the structural integrity of muscle fibres during contraction and relaxation, acting as a scaffold that organises other muscle proteins and transmits mechanical forces. Pathogenic variants in FLNC typically disrupt this scaffolding function, causing Z-disc disintegration, misalignment of myofibrils and accumulation of abnormal protein aggregates within muscle cells. Research suggests that certain FLNC variants may also impair protein quality control mechanisms or alter interactions with other essential muscle proteins, contributing to progressive muscle damage. Over time, these disruptions lead to muscle fibre degeneration and replacement with fibrous tissue, resulting in the clinical features of progressive weakness and cardiac dysfunction.

• FLNC
  filamin C
  FLNC encodes filamin C, a structural protein critical for maintaining the integrity of cardiac and skeletal muscle cells.

Inheritance pattern

Myofibrillar myopathy (filamin C) follows an autosomal dominant inheritance pattern. This means that a single pathogenic variant in one copy of FLNC is sufficient to cause the condition. An affected individual has a 50 per cent chance of passing the variant to each of their children, regardless of the child's sex.

Because of autosomal dominant inheritance, the condition often appears across multiple generations in a family, though the severity and age of onset can differ considerably between relatives carrying the same variant. In some cases, an individual may be the first in their family to have the condition due to a new (de novo) pathogenic variant that arose spontaneously. Family members of an affected individual should be offered genetic counselling to discuss their own risk and the option of predictive genetic testing.

Diagnosis & testing

Diagnosis of myofibrillar myopathy (filamin C) typically involves a combination of clinical assessment, specialist investigations and genetic testing. Individuals presenting with unexplained muscle weakness, particularly affecting the lower legs, or with cardiac arrhythmias and a family history of similar problems, may be referred to a neurologist or clinical geneticist.

Confirmation of the diagnosis requires genetic testing to identify a pathogenic variant in FLNC. This is usually performed through targeted gene sequencing or via a multigene panel that includes genes associated with inherited myopathies and cardiomyopathies. Within the NHS Genomic Medicine Service, testing for FLNC-related conditions may be accessed via the Inherited cardiac conditions or Inherited neuromuscular disorders pathways, depending on the presenting features. In some cases, your specialist may arrange a muscle biopsy, which typically shows characteristic features such as myofibrillar disorganisation and protein accumulation, though genetic testing has increasingly become the primary diagnostic tool. Cardiac investigations including electrocardiogram (ECG) and echocardiogram are essential to assess for arrhythmias and cardiomyopathy.

Management & lifestyle

Management of myofibrillar myopathy (filamin C) is focused on monitoring disease progression, managing symptoms and reducing the risk of serious cardiac complications. There is currently no cure for the condition, but supportive care can significantly improve quality of life and outcomes.

Regular cardiac monitoring is essential for all individuals with a confirmed FLNC pathogenic variant, even those without current cardiac symptoms. This typically includes periodic ECGs, echocardiograms and sometimes ambulatory ECG monitoring (Holter monitoring) to detect arrhythmias. Some individuals may require medications to control heart rhythm abnormalities or manage heart failure, and in those at high risk of life-threatening arrhythmias, an implantable cardioverter-defibrillator may be recommended. For skeletal muscle symptoms, physiotherapy can help maintain strength, mobility and function, whilst occupational therapy may assist with adaptations to support independence. Orthotics such as ankle-foot orthoses can be helpful for managing foot drop. Genetic counselling is recommended for affected individuals and their families to discuss inheritance risks, family screening options and reproductive choices.

UK care pathway

Within the NHS, individuals suspected of having myofibrillar myopathy (filamin C) are typically referred to specialist services via their GP or from cardiology or neurology clinics. Genetic testing is accessed through the NHS Genomic Medicine Service, with FLNC included in testing panels for inherited cardiac conditions (including familial cardiomyopathy and arrhythmias) and inherited neuromuscular disorders, depending on the clinical presentation.

Following a genetic diagnosis, ongoing care is coordinated through specialist multidisciplinary teams, often involving cardiologists with expertise in inherited heart conditions, neurologists or neuromuscular specialists, genetic counsellors and allied health professionals. Genetic counselling is an integral part of the care pathway, providing affected individuals and their relatives with information about the condition, inheritance risks and options for predictive testing in asymptomatic family members. Regular cardiac surveillance forms a cornerstone of long-term management to identify complications early and initiate appropriate interventions.

Related conditions

Myofibrillar myopathy (filamin C) is part of a broader group of myofibrillar myopathies caused by variants in different genes encoding proteins of the muscle cytoskeleton, including DES, MYOT, LDB3 and BAG3. These conditions share overlapping features such as progressive muscle weakness and protein aggregation within muscle fibres, but differ in their specific patterns of muscle involvement, age of onset and degree of cardiac involvement.

FLNC pathogenic variants are also associated with other phenotypes beyond myofibrillar myopathy, including isolated hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. These cardiac presentations may occur in isolation or alongside skeletal muscle involvement, reflecting the broad phenotypic spectrum of FLNC pathogenic variants. Some individuals may present primarily with cardiac features and little or no skeletal muscle involvement. Differentiating between these conditions and other inherited myopathies or cardiomyopathies requires careful clinical assessment, appropriate imaging and muscle studies, and comprehensive genetic testing. Understanding these overlapping phenotypes is important for guiding clinical management and family screening strategies.

• Restrictive cardiomyopathy (familial)
  Cardiovascular
  Shares 1 gene

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