GM1 gangliosidoses

Other Names: Beta galactosidase 1 deficiency; GLB 1 deficiency; Beta-galactosidosis

GM1 gangliosidosis is an inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.

Types

The condition may be classified into three major types based on the general age that signs and symptoms first appear: classic infantile (type 1); juvenile (type 2); and adult onset or chronic (type 3).

Although the three types differ in severity, their features can overlap significantly. Because of this overlap, other researchers believe that GM1 gangliosidosis represents a continuous disease spectrum instead of three distinct types.

Epidemiology

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.

Cause

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

Mutations in the GLB1 gene reduce or eliminate the activity of β-galactosidase. Without enough functional β-galactosidase, GM1 ganglioside cannot be broken down when it is no longer needed. As a result, this substance accumulates to toxic levels in many tissues and organs, particularly in the brain. Progressive damage caused by the buildup of GM1 ganglioside leads to the destruction of nerve cells in the brain, causing many of the signs and symptoms of GM1 gangliosidosis. In general, the severity of GM1 gangliosidosis is related to the level of β-galactosidase activity. Individuals with higher enzyme activity levels usually have milder signs and symptoms than those with lower activity levels because they have less accumulation of GM1 ganglioside within the body.

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

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

There are three general types of GM1 gangliosidosis, which differ in severity but can have considerable overlap of signs and symptoms.

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.

Diagnosis

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.

Treatment

• There is currently no effective medical treatment for GM1 gangliosidosis. Symptomatic treatment for some of the neurologic signs and symptoms is available, but does not significantly alter the progression of the condition. For example, anticonvulsants may initially control seizures. Supportive treatments may include proper nutrition and hydration, and keeping the affected individual's airway open.
• Bone marrow transplantation was reportedly successful in an individual with infantile/juvenile GM1 gangliosidosis; however, no long-term benefit was reported. Presymptomatic cord-blood hematopoietic stem-cell transplantation has been advocated by some as a possible treatment due to its success in other lysosomal storage disorders. Active research in the areas of enzyme replacement and gene therapy for the condition is ongoing but has not yet advanced to human trials.
• Neurologic and orthopedic sequelae may prevent adequate physical activity, but affected individuals may benefit from physical and occupational therapy.

Prognosis

The long-term outlook (prognosis) for people with GM1 gangliosidosis (GM1) depends on the type, age of onset, and severity of the condition in each person.

• Type 1, also known as the infantile form, is the most severe type of GM1. Children with type 1 usually do not survive past early childhood due to infection and cardiopulmonary failure.
• Type 2, which includes the late-infantile and juvenile forms, is an intermediate form of the condition. People with type 2 who have late-infantile onset usually survive into mid-childhood, while those with juvenile onset may live into early adulthood.
• Type 3, known as the adult or chronic form of GM1, is the mildest form of the condition. The age of onset and life expectancy for people with type 3 varies, but life expectancy is usually shortened.

NIH genetic and rare disease info

• NIH info on GM1 gangliosidoses

GM1 gangliosidoses is a rare disease.

GM1 gangliosidoses Resources
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