GM1 gangliosidosis

There are three general types of GM1 gangliosidosis, which differ in severity but can have considerable overlap of signs and symptoms.^[1]

• Classic infantile (type 1) GM1 gangliosidosis is the most severe type, with onset shortly after birth (usually within 6 months of age).^[1] Affected infants typically appear normal until onset, but developmental regression (loss of acquired milestones) eventually occurs.^[1] 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.^[3][4][5] Affected children typically do not live past 2 years of age.^[1]
• 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).^[1]
• 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.^[3][4][5] Non-cancerous skin blemishes may develop on the lower part of the trunk of the body.^[3] Adult GM1 is usually less severe and progresses more slowly than other forms of the condition.^[3][4][5]

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), which plays an important role in the brain. The 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.

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.^[1]

GM1 gangliosidosis is a hereditary condition that is inherited in an autosomal recessive manner.^[4][5] 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.^[5]

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.^[6] 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.^[6]

The Genetic Testing Registry (GTR) provides information about the labs that offer genetic testing for this condition. The intended audience for the GTR is health care providers and researchers. Therefore, patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

There is currently no effective medical treatment for GM1 gangliosidosis.^[3][4] Symptomatic treatment for some of the neurologic signs and symptoms is available, but does not significantly alter the progression of the condition.^[4][7] For example, anticonvulsants may initially control seizures. Supportive treatments may include proper nutrition and hydration, and keeping the affected individual's airway open.^[3]

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.^[4] Active research in the areas of enzyme replacement and gene therapy for the condition is ongoing but has not yet advanced to human trials.^[4][7]

Neurologic and orthopedic sequelae may prevent adequate physical activity, but affected individuals may benefit from physical and occupational therapy.^[4]

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.^[1][4]