GNE myopathy (Nonaka/IBM2)

Overview

GNE myopathy, also known as Nonaka myopathy or hereditary inclusion body myopathy type 2 (IBM2), is a rare genetic disorder that causes muscles to progressively weaken and waste away [PMID:33678536]. This condition primarily affects the muscles that allow us to move, which are known as skeletal muscles. It typically begins in early adulthood, often between the ages of 20 and 40, though onset can vary. Over time, individuals with GNE myopathy may experience difficulties with walking and performing everyday tasks due to muscle weakness.

The condition is progressive, meaning symptoms tend to worsen over many years. It is a monogenic disorder, meaning it is caused by a change in a single gene. Because GNE myopathy is rare, its exact prevalence in the UK population is not well established. It affects individuals of diverse ethnic backgrounds, with a higher prevalence observed in people of Japanese and Middle Eastern descent [PMID:35777174].

Symptoms & clinical features

The initial symptoms of GNE myopathy often involve weakness in the muscles below the knees, particularly those responsible for lifting the front part of the foot (tibialis anterior muscles). This can lead to a 'foot drop', making walking difficult and increasing the risk of tripping and falling [PMID:35777174]. As the condition progresses, muscle weakness typically spreads to other parts of the legs, such as the thigh muscles, and eventually to the muscles in the hands and arms.

Over time, affected individuals may develop a waddling gait and require walking aids like sticks, frames, or wheelchairs. The muscle weakness and wasting can become quite significant, impacting daily activities such as climbing stairs, standing from a seated position, or grasping objects. Unlike some other muscle conditions, the heart and breathing muscles are generally not severely affected in GNE myopathy, though close monitoring is still part of ongoing care [PMID:33678536].

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Affected organs

GNE myopathy primarily affects the skeletal muscles throughout the body. These are the voluntary muscles that enable movement of limbs, trunk, and head. The muscles most commonly affected first are those in the lower legs, particularly the tibialis anterior muscles. As the condition advances, muscle involvement can spread to the thighs, hips, shoulders, and arms. Crucially, the condition typically spares the heart muscle (cardiac muscle) and the muscles involved in breathing (respiratory muscles) for a significant period. The central nervous system, including the brain, is also not typically affected.

Brain

Central nervous system involvement

Cellular impact

Mechanism at cellular level

Risks & severity

GNE myopathy is a progressive condition, meaning its severity increases over time. The rate of progression can vary significantly between individuals. While some people may experience a slower progression, others may see a more rapid decline in muscle function. Most individuals will eventually require mobility aids, and a significant proportion may need a wheelchair within 10-20 years after symptoms begin [PMID:33678536].

There is a low risk of cardiac or respiratory complications in GNE myopathy, particularly compared to some other muscle disorders. However, individuals with advanced weakness may still be at risk for falls, secondary injuries, and reduced quality of life due to mobility limitations. The condition does not typically affect life expectancy directly but can greatly impact an individual's independence and functional abilities.

Genetic causes

GNE myopathy is caused by pathogenic changes (sometimes called mutations) in the *GNE* gene. This gene provides instructions for making an enzyme called UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. This enzyme plays a crucial role in the biosynthesis of sialic acid, which is a type of sugar molecule. Sialic acid is important for the normal structure and function of many proteins and fats (lipids) found on cell surfaces, particularly in muscle cells.

When there are pathogenic changes in the *GNE* gene, the enzyme it produces may not work correctly or may be produced in insufficient amounts. This leads to a deficiency in sialic acid within muscle cells, which research suggests disrupts muscle function and muscle maintenance, leading to the progressive muscle weakness and wasting characteristic of GNE myopathy [PMID:35777174]. The exact mechanisms by which sialic acid deficiency causes muscle damage are still an active area of research.

Inheritance pattern

GNE myopathy is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the *GNE* gene - one from each parent - to develop the condition. If a person inherits only one altered copy and one typical copy of the *GNE* gene, they are considered a 'carrier'. Carriers typically do not show symptoms of GNE myopathy because their one working copy of the gene is sufficient to produce enough of the necessary enzyme.

When two carriers of a *GNE* pathogenic variant have children, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and develop GNE myopathy. There is a 50% (1 in 2) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two typical copies of the gene and not be affected or a carrier.

Diagnosis & testing

Diagnosing GNE myopathy typically starts with a clinical evaluation based on a person's symptoms and a physical examination. A neurologist will assess muscle weakness, muscle wasting patterns, and look for a foot drop and other characteristic features. Blood tests may show elevated levels of creatine kinase (CK), an enzyme that can indicate muscle damage, though levels are not as high as in some other muscular dystrophies. Electromyography (EMG) and nerve conduction studies might be performed to assess nerve and muscle function.

Definitive diagnosis of GNE myopathy is typically confirmed through genetic testing, often available through the NHS Genomic Medicine Service. A referral to a clinical geneticist or neurologist would usually be made to discuss testing. Genetic tests will analyse the *GNE* gene to identify pathogenic variants. The NHS National Genomic Test Directory includes R-codes for genetic testing for inherited muscle disorders, under which GNE myopathy would be covered when clinically appropriate.

Management & lifestyle

Currently, there is no cure for GNE myopathy, and management focuses on supporting individuals and managing symptoms to maintain quality of life and maximise physical function. This involves a multidisciplinary approach, often coordinated through an NHS specialised neuromuscular centre. Physiotherapy is crucial to help maintain muscle strength and flexibility, prevent contractures, and provide guidance on assistive devices. Occupational therapy can help adapt daily activities and environments to enhance independence. Orthotics, such as ankle-foot orthoses (AFOs), can help improve walking ability and prevent falls by addressing foot drop.

Regular follow-up with a neurologist is important to monitor disease progression and address any emerging symptoms. While heart and lung involvement is less common, monitoring for these aspects may be part of comprehensive care in some cases. Research into potential treatments, including gene therapy and enzyme replacement therapy, is ongoing, offering hope for future interventions [PMID:33678536]. Patients are encouraged to discuss participation in clinical trials with their healthcare team. Genetic counselling is also an important part of care, providing information on the condition, inheritance, and family planning options.

UK care pathway

In the UK, individuals suspected of having GNE myopathy would typically be referred by their GP to a neurologist. If GNE myopathy is suspected, genetic testing can be arranged through the NHS Genomic Medicine Service. This usually involves referral to a clinical genetics service or a specialised neuromuscular centre. Genetic counsellors are available to provide support, information, and discuss the implications of a genetic diagnosis for affected individuals and their families. This aligns with the diagnostic pathways outlined in the NHS National Genomic Test Directory, where appropriate R-codes for inherited muscle conditions would be used.

Related conditions

It is important to differentiate GNE myopathy from other muscle-wasting conditions, as symptoms can sometimes overlap. Other conditions that might present with similar muscle weakness include other forms of muscular dystrophy, such as limb-girdle muscular dystrophies, or other types of inclusion body myopathies. Distinguishing between these conditions often relies on a combination of clinical assessment, muscle biopsy findings (though less frequently used since genetic testing became available for GNE myopathy), and definitive genetic testing.

Frequently asked questions