Quadriceps-sparing myopathy is the name formerly used for the commonest clinical condition among a group of syndromes called the hereditary inclusion body myopathies (HIBM). They are characterized by progressive disability with marked sparing of muscle strength in the quadriceps muscles of the thigh. They all show a similar picture at biopsy.

Quadriceps-sparing myopathy has been called by several names, such as hereditary inclusion body myopathy, inclusion body myopathy type 2 and GNE myopathy, of which GNE myopathy has now become the official name.

Cause

The condition is autosomal recessive, caused by inheriting two abnormal copies of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene which encodes an enzyme that is crucial in the biosynthesis of the mucopolysaccharide molecule, sialic acid. The exact mechanism through which this defect leads to clinical disease is not known as of now, but several hypotheses are being tested.

GNE myopathy was first thought to be confined to the Iranian Jewish population, though a few cases of other ethnic origins have been reported. However, it is now known to affect all races, though Iran-Jewish or Japanese ancestry greatly increases the risk. The prevalence is very low, about 1/1,000,000.

Clinical Features

Quadriceps-sparing autosomal recessive hereditary inclusion body myopathy is characterized by a relatively early onset during the second or third decade of life.

The initial manifestation is weakness and atrophy of the muscles of the lower leg, which gradually spreads upwards but always spares the quadriceps even when the other muscles are severely affected.

The upper limb muscles become weak as the stage of the disease advances. However, clinical variations are known. For instance, quadriceps sparing is sometimes seen in other non-GNE myopathies as well. Again, foot drop involving one leg, weakness of the proximal muscles of the leg, or upper limb muscle weakness, may be the presenting features, but almost always with distinctive quadriceps sparing (in 95% of the patients).

The distinctive atrophy of the muscles of the posterior thigh with quadriceps function remaining intact helps to make the diagnosis in such cases, even though this pattern may be delayed in its appearance.

Measurement of serum creatine kinase shows it to be between two and four times the expected value.

Some patients with GNE myopathy are asymptomatic until late adulthood or throughout life, even up to the sixth or seventh decade, though they have two copies of the p.M712T or p.A578T mutations.

Heart disease may accompany GNE myopathy in a few patients, so individuals with this condition may therefore need ECG surveillance every few years. In the late stages, some patients may show involvement of respiratory muscles, though they retain the capacity of independent respiration in almost all cases.

The disease progresses slowly over a decade or two until the patient becomes wheelchair-bound.

Diagnosis and Management

The diagnosis of GNE myopathy is made on the basis of the history and clinical features, with biopsy of the affected muscles showing rimmed vacuoles and filamentous inclusions in muscle fibers. Many patients have no positive family history.

Management is based on the symptoms and may include medical as well as physical and occupational therapies.

A follow-up should be performed every year to detect new complications, if any. Care should be taken while prescribing drugs in such patients to avoid inadvertent worsening of the condition by drugs which cause muscle-weakening adverse events. Carrier testing should be carried out in the family to facilitate early detection.

Electromyography (EMG), imaging of the muscle using MRI or CT scan, and nerve conduction velocity studies may help for early detection before clinical signs and symptoms appear.

New investigational therapies include oral sialic acid and other sialic acid metabolites, immune globulins for intravenous administration, and gene replacement.