GNE myopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

GNE myopathy is a condition that primarily affects skeletal muscles, which are muscles that the body uses for movement. This disorder causes muscle weakness that appears in late adolescence or early adulthood and worsens over time.

Difficulty lifting the front part of the foot (foot drop) is often the first sign of GNE myopathy. For individuals with GNE myopathy, foot drop is caused by weakness of a muscle in the lower leg called the tibialis anterior. This muscle helps raise the foot up. Weakness in the tibialis anterior alters the way a person walks and makes it difficult to run and climb stairs. As the disorder progresses, weakness also develops in the muscles of the upper legs, hips, shoulders, and hands. Unlike most forms of myopathy, GNE myopathy usually does not affect the quadriceps, which are a group of large muscles at the front of the thigh. This condition also does not affect the muscles of the eye or heart, and it does not cause neurological problems. Weakness in leg muscles makes walking increasingly difficult, and most people with GNE myopathy require wheelchair assistance within 20 years after the signs and symptoms of the disorder appear.

People with the characteristic features of GNE myopathy have been described in several different populations. When the condition was first reported in Japanese families, researchers called it distal myopathy with rimmed vacuoles (DMRV) or Nonaka myopathy. When a similar disorder was discovered in Iranian Jewish families, researchers called it rimmed vacuole myopathy or hereditary inclusion body myopathy (HIBM). It has since become clear that these conditions are variations of a single disorder caused by changes in the same gene.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Many different variants (also called mutations) in the GNE gene have been found to cause GNE myopathy. The GNE gene provides instructions for making an enzyme found in cells and tissues throughout the body. This enzyme is involved in a chemical pathway that produces sialic acid, which is a simple sugar that attaches to the ends of more complex molecules on the surface of cells. By modifying these molecules, sialic acid influences a wide variety of cellular functions, including cell movement (migration), the attachment of cells to one another (adhesion), signaling between cells, and inflammation.

The variants responsible for GNE myopathy reduce the activity of the enzyme produced from the GNE gene, which decreases the production of sialic acid. As a result, less of this simple sugar is available to attach to molecules on the cell surface. Researchers are working to determine how a shortage of sialic acid leads to progressive muscle weakness in people with GNE myopathy. Sialic acid is important for the normal function of many different cells and tissues, so it is unclear why the signs and symptoms of this disorder appear to be limited to skeletal muscles.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Worldwide, fewer than 9 in 1,000,000 people are estimated to have this condition. Some researchers have suggested that the number of people with GNE myopathy may be higher, since many people with this condition are believed to be undiagnosed. GNE myopathy is more frequent among the Japanese, Iranian Jewish, and Indian subcontinent populations.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Fatty replacement of skeletal muscle · Very frequent (99-80%)

Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers

Foot dorsiflexor weakness · Very frequent (99-80%)

Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.

Lower limb muscle weakness · Very frequent (99-80%)

Weakness of the muscles of the legs.

Rimmed vacuoles · Very frequent (99-80%)

Presence of abnormal vacuoles (membrane-bound organelles) in the sarcolemma. On histological staining with hematoxylin and eosin, rimmed vacuoles are popcorn-like clear vacuoles with a densely blue rim. The vacuoles are often associated with cytoplasmic and occasionally intranuclear eosinophilic inclusions.

Tibialis muscle weakness · Very frequent (99-80%)

Muscle weakness affecting the tibialis anterior muscle.

Mildly elevated creatine kinase · Very frequent (99-80%)

Muscle fiber inclusion bodies · Very frequent (99-80%)

Absent Achilles reflex · Frequent (79-30%)

Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.

Other findings in the same source

From: Orphanet

Additional reported features include EMG: myopathic abnormalities (Frequent (79-30%)); EMG: myotonic discharges (Frequent (79-30%)); EMG: positive sharp waves (Frequent (79-30%)); Hip flexor weakness (Frequent (79-30%)); Hypothyroidism (Frequent (79-30%)); Increased variability in muscle fiber diameter (Frequent (79-30%)); Limited shoulder movement (Frequent (79-30%)); Shoulder girdle muscle weakness (Frequent (79-30%)); Steppage gait (Frequent (79-30%)); Limited wrist extension (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing GNE myopathy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for GNE myopathy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.