Myopathy inclusion body 2 (Inclusion body myopathy 2) - Gen GNE.  

The inclusion body myopathy 2 is a disease that mainly affects skeletal muscles. This alteration causes muscle weakness appearing in late adolescence or early adulthood and gets worse over time.

The first sign of the disease is the weakness of the tibialis anterior muscle. This muscle helps control movement up and down the foot. Weakness in the tibialis anterior muscle alters the way a person walks and makes it difficult to run and climb stairs. As the disease progresses, the weakness also develops in the muscles of the upper legs, hips, shoulders and hands. Unlike most forms of myopathy, inclusion body myopathy 2 generally does not affect the quadriceps, or the eye muscles or the heart, and causes neurological problems. Weakness in the muscles of the legs makes it increasingly difficult to walk, and most people require a wheelchair within 20 years after the signs and symptoms appear.

This process is due to mutations in the GNE gene, located on the short brzo of chromosome 9 (9p13.3), which encodes an enzyme found in body tissues and cells. This enzyme is involved in a chemical pathway that produces sialic acid that binds to the ends of other complex molecules on the surface of cells. By modifying these molecules, sialic acid affects a wide variety of cellular functions including migration, adhesion and cell signaling. The enzyme produced from the GNE gene is responsible for two steps in the formation of sialic acid. First, it converts a molecule known as UDP-GlcNAc in a similar molecule called ManNAc. In the next step, the enzyme transfers a group of oxygen and phosphorus (phosphate group) ManNAc to create ManNAc-6-phosphate. Other enzymes then converted ManNAc-6-phosphate to sialic acid.

Have identified more than 40 mutations in the gene cause myopathy GNE inclusion body 2. Most of these mutations change the amino acids in various regions of the enzyme. Some mutations remove a portion of the enzyme or alter its structure. Mutations reduce the activity of the enzyme produced from the gene, decreasing the sialic acid production. As a result, this simple sugar amounts are less available for binding to cell surface molecules. Work is underway to determine how a decrease in sialic acid causes progressive muscle weakness in people with the disease. Different mutations have been identified in the GNE gene in different populations. A mutation in Iranian Jewish people from the amino acid methionine replaced by the amino acid threonine at position 712 in a region of the enzyme known as the kinase domain (M712T or Met712Thr). In the Japanese population, where the condition is called Nonaka myopathy, frecuentye mutation replaces the valine amino acid by amino acid leucine at position 572 in the kinase domain of the enzyme (Val572Leu or V572L).

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with myopathy inclusion body 2 by the complete PCR amplification of exons GNE gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).