GM1 gangliosidosis, types I, II and III (GM1 gangliosidosis, types I, II and III) - Gen GLB1.
GM1 Gangliosidosis is an inherited disorder that progressively destroys neurons in the brain and spinal cord. Sometimes this disease is classified into three main types based on age at first appear the signs and symptoms. Although the three types differ in severity, their characteristics may overlap significantly.
Signs and symptoms of the most severe form of GM1 gangliosidosis, called type I or infantile form, usually evident at 6 months of age. Children with this form appear normal until its development slows down and skeletal muscles weaken. Eventually, these children show a regression in development and may develop an exaggerated startle reaction to loud noises. As the disease progresses, children with GM1 Gangliosidosis type I, develop hepatosplenomegaly, skeletal abnormalities, seizures, profound mental retardation and corneal opacity. The vision loss occurs due to a gradual deterioration of the retina. Other signs and symptoms may include additional eyespot cherry red color, distinctive facial features that are described as "thick", gingival hypertrophy and cardiomyopathy. Generally, individuals with type I Gangliosidosis GM1 not survive beyond infancy.
GM1 gangliosidosis type II, or late infantile form, is associated with regression in development, but usually have no eyespots cherry red, characteristic facial features or enlarged organs. Affected children have a beginning of normal development, but begin to show signs and symptoms of the disease between 18 months (late infantile form) and 5 years of age (juvenile form). Type II usually progresses more slowly than type I, but life expectancy is lower. People with the late infantile form usually survive to middle childhood, while those with the juvenile form can live up to early adulthood.
The third type of GM1 gangliosidosis, known as adult or chronic form, represents the mildest of the end of the disease. Although the age at which the first symptoms can vary, most affected individuals develop signs and symptoms in adolescence. The characteristic features of this type include dystonia and Vertebral. Life expectancy varies among people with type III Gangliosidosis GM1.
This process is due to mutations in the GLB1 gene located on the short arm of chromosome 3 (3p21.33). This gene, encoding ?-galactosidase enzyme, located in the lysosomes. In the lysosomes, the enzyme helps break down certain molecules, including GM1 ganglioside and keratan sulfate. The ganglioside GM1 is important for the normal functioning of nerve cells in the brain, and the keratan sulfate is particularly abundant in cartilage and cornea. The GLB1 gene also encodes the protein elastin binding, which interact at the cell surface with cathepsin A 1 and neuraminidase proteins to form the elastin receptor complex. This complex plays a role in the formation of elastic fibers.
They have identified more than 80 mutations in the gene responsible for Gangliosidosis GLB1 GM1. Most mutations change nucleotides in the gene. Often these mutations affect the coding ?-galactosidase both as protein elastin binding. These genetic changes reduce or eliminate the activity of ?-galactosidase. No ?-galactosidase functional enough, GM1 ganglioside and keratan sulfate can not be decomposed. Consequently, these substances accumulate in toxic levels in many tissues and organs. In the brain, progressive damage due to the accumulation of GM1 ganglioside leads to the destruction of nerve cells, which results in many of the signs and symptoms of GM1 Gangliosidosis. Although it is unclear the role of elastin binding protein in the development of Gangliosidosis GM1, disruption of this protein may contribute to cardiomyopathy found in some people with Gangliosidosis GM1. People with higher levels of enzyme activity usually have signs and milder than those with lower levels of activity, because they have less accumulation of ganglioside GM1 in the body symptoms.
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 performed in IVAMI: in IVAMI perform detection of mutations associated with GM1 gangliosidosis, by complete PCR amplification of exons GLB1 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).