Clara and Dr. Doug Martin, leading GM1 researcher
What is GM1 Gangliosidosis?
GM1 gangliosidosis is an inherited lysosomal storage disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. The condition may be classified into three major types based on the general age that signs and symptoms first appear. Although the types differ in severity, their features may overlap significantly.
- Infantile (type 1)
- Infantile (type 1) GM1 gangliosidosis is the most severe type, with onset shortly after birth (usually by 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 gait problems. About half of people with this type develop cherry-red spots in the eye and children may become deaf and blind by one year of age. Affected children typically do not live past 2-3 years of age.
- Late Infantile & Juvenile (type 2)
- Late Infantile (Clara’s condition) & Juvenile (type 2) GM1 gangliosidosis are considered intermediate forms 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 onset or chronic (type 3).
- Adult (type 3) GM1 gangliosidosis is the rarest form, and signs and symptoms 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.
What causes GM1 gangliosidosis?
GM1 gangliosidosis is a genetic disease, inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has:
- a 25% (1 in 4) chance to be affected
- a 50% (1 in 2) chance to be an unaffected carrier like each parent
- a 25% chance to be unaffected and not be a carrier
GM1 gangliosidosis is type-specific within families. This means that people with a family history of the condition are generally only at increased risk for the specific type of GM1 gangliosidosis in the family.
All three types of GM1 gangliosidosis are caused by mutations (changes) in the GLB1 gene. This gene gives the body instructions to make an enzyme called beta-galactosidase (β-galactosidase or often abbreviated β-gal), which plays an important role in the brain. This enzyme resides in compartments within cells called lysosomes, where it helps break down certain molecules, including a substance called GM1 ganglioside. GM1 ganglioside is important for nerve cell function in the brain, but must be broken down. Mutations in the GLB1 gene may lower or eliminate the activity of the β-galactosidase enzyme, keeping GM1 ganglioside from being broken down. As a result, it accumulates to toxic levels in tissues and organs, particularly in the brain. This accumulation leads to the destruction of nerve cells, causing the features of the condition. In general, people with higher enzyme activity levels usually have milder features than those with lower activity levels.
What treatments or cures are available?
Currently there are no treatments or cures commercially available. However, researchers at Auburn University and the University of Massachusetts have pioneered a gene therapy that uses has proven highly effective in animal models over the last 5+ years, both extending lifespan dramatically as well as preserving function such as mobility, ability to self feed, and to reproduce. This is the first time that a terminal, neurodegenerative disease has been effectively cured in animal models. The research team believes that there is sufficient evidence from these years of positive results such that the time for a human trial has come, and are aiming for a late 2017 start date. Funding dependant , the trial will take place at the National Institute of Health in Bethesda, MD, and upon successful completion the drug could be made available to all families with children suffering from GM1. The gene therapy also has a lot of cross-application potential for associated Lysosomal Storage Diseases such as Tay Sachs and Sandhoff disease. This gene therapy trial is what A Cure for Clara was founded for- specifically to fund this trial and to ensure that in the near future, no parent has to hear the terrible words that we had to hear at Clara’s diagnosis.
More GM1 references:
National Institute of Health: https://ghr.nlm.nih.gov/condition/gm1-gangliosidosis
Cure GM1 Foundation: https://curegm1foundation.org/