Myofibrillar myopathies (MFM)

Overview

Myofibrillar myopathies (MFM) are a group of genetic conditions causing progressive muscle weakness, unified by a shared finding on muscle biopsy — 'myofibrillar degeneration', a breakdown of the muscle fibre's internal structure. MFM is now generally grouped with the distal myopathies, since weakness often starts in the hands, feet, lower legs or forearms.

Symptoms

Onset is usually in mid-adulthood (40s to 60s), though it can start anywhere from infancy to late adulthood, and both the pattern and severity vary widely. Weakness most often starts distally — hands, forearms, ankles, lower legs — before spreading toward the shoulders and thighs, though occasionally the reverse pattern occurs. Distal weakness shows up as tripping, falling, or difficulty gripping and turning things; weakness closer to the trunk makes standing from a chair, using stairs, or lifting things overhead harder.

Other features can include muscle pain, joint contractures, scoliosis, numbness or tingling from peripheral nerve involvement, and cataracts. Heart muscle weakening (cardiomyopathy) affects around 3 in 10 people, with the risk varying by which gene is involved, and can cause an irregular or fast heartbeat, fainting or breathlessness. Breathing muscles can weaken too, sometimes to the point of respiratory failure, and — particularly with desmin-related MFM — can cause significant fatigue, unrefreshing sleep and morning headaches. Speech and swallowing can be affected in some forms (most notably CRYAB-related MFM, though this is rare in other types), causing coughing or choking with food and drink.

Inheritance and cause

Several genes are linked to MFM — DES, MYOT, ZASP, BAG3, FLNC and CRYAB are the most common, though others exist and around half of cases don't yet have an identified genetic cause, with diagnosis instead resting on the characteristic biopsy findings. These genes normally provide instructions for proteins (myofibrils) that give muscle fibres their contract-and-relax strength; in MFM, faulty versions of these proteins clump together inside the muscle, causing the breakdown seen on biopsy. Most MFM is autosomal dominant (one changed copy from a parent); a smaller number of forms are autosomal recessive (a changed copy from both parents), and some cases arise fresh with no family history.

Getting a diagnosis

A GP refers to a neurologist, who combines symptom and family history, a physical exam, nerve/muscle electrical testing and muscle MRI. A blood sample for gene panel testing — now able to screen around 80 genes linked to inherited muscle conditions in one go — has become a key part of diagnosis; a muscle biopsy is still used if the genetic test is negative or needs clarifying, though a known change in the DES or MYOT gene alone can sometimes confirm MFM without one.

Management and outlook

A multidisciplinary team, usually led by a neurologist and including physiotherapists, occupational therapists, orthotics specialists and speech and language therapists as needed, manages care. Because some forms affect the heart, regular cardiac monitoring (ECG, 24-hour ECG, echocardiogram) is often needed, and a pacemaker or implantable defibrillator may be recommended if arrhythmias or conduction problems develop.

Where breathing muscles are affected, non-invasive ventilation can help, with overnight sleep studies used to check for and diagnose nocturnal hypoventilation. Staying active matters too — a physiotherapist can help build a plan combining regular stretching (to keep joints and muscles flexible), strengthening work (to slow muscle weakening), and aerobic exercise like walking, swimming or cycling to support heart and lung health.