GM1 gangliosidosis is an inherited disorder that destroys nerve cells (neurons) in the brain and spinal cord. This condition can be classified as one of three major types based on the age at which signs and symptoms first appear. However, the signs and symptoms of these three types can overlap, leading some researchers to believe that GM1 gangliosidosis occurs on a spectrum instead of as three distinct types.

The signs and symptoms of the most severe form of GM1 gangliosidosis, called type I or the infantile form, usually develop by the age of 6 months. Infants with this form of the disorder typically appear normal until their development slows and the muscles used for movement weaken. Affected infants eventually lose the skills they had previously acquired (developmentally regress) and may develop an exaggerated startle reaction to loud noises. Over time, children with GM1 gangliosidosis type I develop an enlarged liver and spleen (hepatosplenomegaly) and skeletal abnormalities. Affected children often have seizures and profound intellectual disability.

People with GM1 gangliosidosis type I can lose their vision due to clouding of the clear outer covering of the eye (the cornea) and the breakdown of the light-sensing tissue at the back of the eye (the retina). Affected individuals also develop a red area in the eye known as a cherry-red spot. In some cases, affected individuals have distinctive facial features that are described as "coarse," enlarged gums (gingival hypertrophy), and an enlarged and weakened heart muscle (cardiomyopathy). Individuals with type I usually do not survive past early childhood.

GM1 gangliosidosis type II occurs in one of two forms: the late infantile or the juvenile forms. Children with type II develop normally early in life, but they begin to show signs and symptoms of the condition around the age of 18 months (late infantile form) or 5 years (juvenile form). Individuals with GM1 gangliosidosis type II experience developmental regression but usually do not have cherry-red spots, coarse facial features, or enlarged organs. Type II usually progresses more slowly than type I, but it still shortens life expectancy. People with the late infantile form typically survive into mid-childhood, while those with the juvenile form may live into early adulthood.

GM1 gangliosidosis type III is the adult or chronic form of the condition, and this is the mildest form. The age at which symptoms first appear varies in people with GM1 gangliosidosis type III, although most affected individuals develop signs and symptoms in their teens. The characteristic features of this type include involuntary tensing of various muscles (dystonia) and abnormalities of the spinal bones (vertebrae). Life expectancy varies among people with GM1 gangliosidosis type III.

Variants (also called mutations) in the GLB1 gene cause GM1 gangliosidosis. The GLB1 gene provides instructions for making an enzyme called beta-galactosidase (β-galactosidase). This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules. β-galactosidase helps break down several molecules, including a substance called GM1 ganglioside. GM1 ganglioside is important for normal functioning of neurons in the brain.

The GLB1 gene variants produce versions of β-galactosidase that are not as effective at breaking down GM1 ganglioside as the normal version of the enzyme. Without enough functional β-galactosidase, GM1 ganglioside cannot be broken down when it is no longer needed. This substance builds up to toxic levels in many tissues and organs, particularly in the brain. Damage caused by the buildup of GM1 ganglioside leads to the destruction of neurons, causing many of the signs and symptoms of GM1 gangliosidosis.

In general, people with GM1 gangliosidosis have milder signs and symptoms if they have higher levels of functional β-galactosidase activity. These individuals are still able to break down some amount of GM1 ganglioside, and less of the enzyme builds up inside lysosomes.

Conditions like GM1 gangliosidosis that cause molecules to build up inside lysosomes are called lysosomal storage disorders.

Normal Function

The GLB1 gene provides instructions for producing two different proteins. The primary protein produced from the GLB1 gene is an enzyme called beta-galactosidase (β-galactosidase). This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. β-galactosidase helps break down certain substances, including GM1 ganglioside and keratan sulfate. GM1 ganglioside is important for normal functioning of nerve cells (neurons) in the brain. Keratan sulfate is particularly abundant in cartilage and the clear covering of the eye (cornea). Keratan sulfate belongs to a group of large sugar molecules called glycosaminoglycans or mucopolysaccharides.

The GLB1 gene also provides instructions for making the elastin-binding protein. This protein is smaller than β-galactosidase and is found on the surface of cells rather than in lysosomes. Elastin-binding protein interacts with other proteins called cathepsin A and neuraminidase 1. This group of proteins forms the elastin receptor complex. This complex plays a role in building elastic fibers, which are a component of the connective tissue that forms the body's supportive framework.

Health Conditions Related to Genetic Changes

GM1 gangliosidosis

Many variants (also called mutations) in the GLB1 gene have been found to cause GM1 gangliosidosis. The signs and symptoms of this condition primarily result from the loss of neurons in the brain and spinal cord over time. Most variants change single DNA building blocks (nucleotides) in the GLB1 gene. These variants often affect the production of both β-galactosidase and elastin-binding protein.

The GLB1 gene variants that cause GM1 gangliosidosis produce versions of β-galactosidase that are not as effective at breaking down GM1 ganglioside and keratan sulfate as the normal version of the enzyme. As a result, these substances build up to toxic levels in many tissues and organs. In the brain, damage caused by the buildup of GM1 ganglioside leads to the loss of neurons, which causes intellectual disability, movement problems, and many of the signs and symptoms of GM1 gangliosidosis.

It is not clear how changes in the elastin-binding protein affect the development of GM1 gangliosidosis. The altered protein may cause the weakened heart muscle (cardiomyopathy) found in some people with GM1 gangliosidosis.

Mucopolysaccharidosis type IV

Variants in the GLB1 gene have been found to cause mucopolysaccharidosis type IV (MPS IV). This is a progressive condition that mainly affects the skeleton. Most of the variants that cause MPS IV change single nucleotides in the GLB1 gene. All of the variants that cause MPS IV disrupt the breakdown of keratan sulfate by β-galactosidase. The breakdown of GM1 ganglioside is not affected by these variants.

Because keratan sulfate is predominantly found in cartilage and the cornea, the buildup of this substance causes skeletal abnormalities and cloudy corneas. Researchers believe that a buildup of glycosaminoglycans may also cause the features of MPS IV by interfering with the functions of other proteins inside lysosomes and disrupting the movement of molecules inside the cell.

Other Names for This Gene

• BGAL_HUMAN
• EBP
• elastin receptor 1, 67kDa
• ELNR1

Genomic Location

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.

• Classic infantile (type 1) GM1 gangliosidosis is the most severe type, with onset shortly after birth (usually within 6 months of age). Affected infants typically appear normal until onset, but developmental regression (loss of acquired milestones) eventually occurs. Signs and symptoms may include neurodegeneration, seizures, liver and spleen enlargement, coarsening of facial features, skeletal irregularities, joint stiffness, a distended abdomen, muscle weakness, an exaggerated startle response to sound, and problems with gait (manner of walking). About half of people with this type develop cherry-red spots in the eye. Children may become deaf and blind by one year of age. Affected children typically do not live past 2 years of age.
• Juvenile (type 2) GM1 gangliosidosis is considered an intermediate form of the condition and may begin between the ages of 1 and 5. Features include ataxia, seizures, dementia, and difficulties with speech. This type progresses more slowly than type 1, but still causes decreased life expectancy (around mid-childhood or early adulthood).
• Adult (type 3) GM1 gangliosidosis may cause signs and symptoms to develop anywhere between the ages of 3 and 30. Affected people may have muscle atrophy, corneal clouding and dystonia. Non-cancerous skin blemishes may develop on the lower part of the trunk of the body. Adult GM1 is usually less severe and progresses more slowly than other forms of the condition.

A diagnosis of GM1 gangliosidosis (GM1), can be made by either enzyme analysis of the beta-galactosidase enzyme, or by molecular genetic testing of the GLB1 gene. Despite the availability of molecular genetic testing, the mainstay of diagnosis will likely continue to be enzyme activity because of cost and difficulty in interpreting unclear results. However, enzyme activity may not be predictive of carrier status in relatives of affected people. Carrier testing for at-risk family members is done with molecular genetic testing, and is possible if the disease-causing mutations in the family are already known.

GM1 gangliosidosis is estimated to occur in 1 in 100,000 to 200,000 newborns. Type I is reported more frequently than the other forms of this condition. Most individuals with type III are of Japanese descent.