Inclusion body myopathy 2

Other Names: IBM2; Inclusion body myopathy, autosomal recessive; Inclusion body myopathy, quadriceps-sparing; QSM; Hereditary inclusion body myopathy; HIBM; Distal myopathy with rimmed vacuoles; DMRV; Nonaka myopathy; Rimmed vacuole myopathy; Quadriceps Sparing Myopathy; GNE myopathy

Inclusion body myopathy 2 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. People with the characteristic features of inclusion body myopathy 2 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 mutations in the same gene.

Epidemiology

More than 200 people with inclusion body myopathy 2 have been reported. Most are of Iranian Jewish descent; the condition affects an estimated 1 in 1,500 people in this population. Additionally, at least 15 people in the Japanese population have been diagnosed with this disorder. Inclusion body myopathy 2 has also been found in several other ethnic groups worldwide.

Cause

Mutations in the GNE gene cause inclusion body myopathy 2. 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), attaching cells to one another (adhesion), signaling between cells, and inflammation.

The mutations responsible for inclusion body myopathy 2 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 cell surface molecules. Researchers are working to determine how a shortage of sialic acid leads to progressive muscle weakness in people with inclusion body myopathy 2. 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 the skeletal muscles.

Inheritance

Autosomal recessive inheritance, a 25% chance

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

Signs and symptoms

Inclusion body myopathy 2 causes muscle weakness that appears in late adolescence or early adulthood and worsens over time.The first sign of inclusion body myopathy 2 is often weakness of the tibialis anterior, a muscle in the lower leg that helps control up-and-down movement of the foot. 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 muscles of the upper legs, hips, shoulders, and hands.

Unlike most forms of myopathy, inclusion body myopathy 2 usually does not affect the quadriceps (a group of large muscles at the front of the thigh). This condition also spares muscles of the eye or heart, and does not cause neurological problems. Weakness in leg muscles makes walking increasingly difficult, and most people with inclusion body myopathy 2 require wheelchair assistance within 20 years after signs and symptoms appear. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Fatty replacement of skeletal muscle
• Foot dorsiflexor weakness(Foot drop)
• Mildly elevated creatine kinase
• Muscle fiber inclusion bodies
• Rimmed vacuoles
• Tibialis muscle weakness

30%-79% of people have these symptoms

• Absent Achilles reflex(Absent ankle reflexes)
• EMG: myopathic abnormalities
• EMG: myotonic discharges
• EMG: positive sharp waves
• Hip flexor weakness
• Hypothyroidism(Underactive thyroid)
• Increased variability in muscle fiber diameter
• Limited shoulder movement
• Limited wrist extension
• Shoulder girdle muscle weakness(Weak shoulder muscles)
• Steppage gait(High stepping)

5%-29% of people have these symptoms

• Abnormal right hemidiaphragm morphology
• Abnormality of the foot musculature(Abnormal foot muscles)
• Facial palsy(Bell's palsy)
• Lower limb amyotrophy
• Scapular winging(Winged shoulder blade)
• Shoulder girdle muscle atrophy(Shoulder girdle muscle wasting)

1%-4% of people have these symptoms

• Cardiomyopathy(Disease of the heart muscle)
• Distal lower limb muscle weakness
• Weakness of long finger extensor muscles

Diagnosis

Clinical findings Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated .

Serum CK may be normal or up to four times the upper limit of normal. Muscle histopathology

Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining.

The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration . Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of GNE myopathy but remain necessary when variants of unknown significance are identified on molecular genetic testing. The diagnosis of GNE myopathy is established in a proband with suggestive clinical findings, muscle histopathology (if performed), and biallelic pathogenic variants in GNE identified by molecular genetic testing

Laboratory findings

• Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value.
• Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function.
• Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK.
• Electromyogram and nerve conduction velocity are invasive and do not help with the diagnosis.

Muscle MRI shows fibro-fatty replacement on T1-weighted images; short tau inversion recovery hyperintensity indicates active disease.

Treatment

There is no approved therapy for GNE myopathy. Treatment is symptomatic only . Treatment options for lower limb weakness such as foot drop can be through the use of Ankle Foot Orthoses (AFOs) which can be designed or selected by an Orthotist based upon clinical need of the individual. Sometimes tuning of rigid AFOs can enhance knee stability.

Prognosis

A 2009 review noted that muscle weakness usually begins after age 20 and after 20–30 years, the person usually requires a wheel chair for mobility. There was no mention of increased mortality.

NIH genetic and rare disease info

• NIH info on Inclusion body myopathy 2

Inclusion body myopathy 2 is a rare disease.

Inclusion body myopathy 2 Resources
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