GM1 Gangliosidosis

What Causes GM1 Gangliosidosis?

GM1 gangliosidosis is caused by a deficiency of an enzyme called beta-galactosidase. Inside brain and nerve cells, the enzyme is responsible for breaking down compounds called gangliosides. When there is not enough beta-galactosidase in the cells, molecules called GM1 ganglioside accumulate and impair the nerve cells’ function. GM1 ganglioside is essential for normal cell function, but excess levels of the molecule have a toxic effect. As a result, affected cells eventually die, causing the neurological symptoms characteristic of the disease.

Beta-galactosidase is usually stored in cell structures called lysosomes. GM1 gangliosidosis is one of a group of diseases called lysosomal storage disorders. Other disorders in the group include Batten disease and Tay-Sachs disease.

Is GM1 Gangliosidosis Hereditary?

GM1 gangliosidosis is caused by an abnormal variation (mutation) in the GLB1 gene, which plays a role in producing beta-galactosidase. A parent who possesses the abnormal variation can pass the mutation on to their children. The disease follows an autosomal recessive inheritance pattern, meaning that a child must inherit a copy of the mutation from both parents to develop the disease. A person who inherits the mutation from only one parent is unlikely to develop symptoms, but they will carry the mutation and potentially pass it on to their children.

When two people who are carriers of the gene have a child, there is a 25% chance that the child will inherit two copies of the mutation and be affected by the disease. There is a 50% chance the child will inherit only one copy of the mutation and be a disease carrier. There is a 25% chance that the child will inherit two normal copies of the gene and be free of the mutation.

Inheritance of GM1 gangliosidosis appears to be type-specific. That means that only one type of the disease tends to run in an individual family.

How Is GM1 Gangliosidosis Detected?

The early signs of GM1 gangliosidosis disease vary from case to case, and different forms of the disease have various initial symptoms.

Type I

Infants with Type I GM1 gangliosidosis often appear normal in early infancy, but symptoms typically develop a few months after birth. Early symptoms can include:

• Exaggerated startle reflex
• Muscle weakness
• Twitching or jerky movements

Type II

The first signs of juvenile GM1 gangliosidosis usually appear between 1 and 5. Early symptoms can include:

• Problems with coordination
• General clumsiness
• Problems controlling muscle movements

Type III

The first symptoms of late-onset GM1 gangliosidosis may appear from childhood through adulthood. Early signs can include:

• Clumsiness
• Loss of muscle tone or muscle mass
• Mood changes

How Is GM1 Gangliosidosis Diagnosed?

A diagnosis of GM1 gangliosidosis can be achieved using a variety of tests and exams. Possible diagnostic steps may include:

• Blood tests. These tests measure the level of beta-galactosidase in the individual’s blood. A low level of the enzyme could indicate the presence of gangliosidosis.
• Eye exams. A characteristic sign of GM1 gangliosidosis is a red spot inside the eye caused by the degeneration of cells in the middle part of the eye. An exam by the child’s doctor or an ophthalmologist may identify this symptom.
• Molecular genetic tests. These tests can identify whether the individual has the disease-causing mutation of the GLB1 gene and confirm a diagnosis of GM1 gangliosidosis.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is GM1 Gangliosidosis Treated?

Until recently, there was no treatment to cure GM1 gangliosidosis or stop the progression of its symptoms. However, some new therapies are in the investigational stage and may show promise in treating the disease. These therapies include enzyme replacement, stem cell transplants, and gene therapies.

Other treatments focus on managing symptoms, and treatment programs will vary depending on the patient’s pattern of symptoms.

Common treatment approaches include:

• Medications. Anti-seizure medications may be used in cases where seizures are a problem. However, this symptom will not affect all patients, and an individual’s need for drugs may change throughout the disease.
• Nutritional support. As the disease progresses, it will become increasingly difficult for the sufferer to eat and maintain adequate nutrition. A feeding tube inserted through the nose and into the child’s stomach may become necessary.
• Respiratory support. Children with the disease often experience a buildup of mucus in their lungs, and they are at risk of developing lung infections that cause breathing difficulties. Therapeutic programs may be used to help decrease the risk of these complications.
• Other therapies. Depending on the child’s symptoms, physical therapy, speech therapy, vision and hearing therapies, and other therapeutic programs may be recommended.

How Does GM1 Gangliosidosis Progress?

Disease progression in GM1 gangliosidosis can vary considerably from case to case. For example, the Type I form progresses rapidly, while the progression of the late-onset forms may be extremely slow.

Progression of Infantile GM1 gangliodosis

As the disease progresses, symptoms and complications become increasingly severe. Later effects of the disease can include:

• Seizures
• Difficulty swallowing
• Hearing loss
• Confusion or disorientation
• Vision loss
• Paralysis
• Respiratory failure

Life-threatening effects usually occur by 12 months.

Progression of Juvenile GM1 Gangliosidosis

This form of the disease progresses through childhood and may result in developmental symptoms such as:

• Coordination problems
• Loss of muscle control
• Loss of speech
• Loss of intellectual abilities
• Seizures

Life-threatening effects usually occur by mid-to-late childhood.

Progression of Late-Onset GM1 Gangliosidosis

The progression of this form of the disease is typically much slower than the other forms. As a result, life expectancy varies but is generally shorter than average.

Later symptoms may include:

• Muscle tremors, spasms, or twitching
• Spinal abnormalities

How Is GM1 Gangliosidosis Prevented?

There is no way to prevent the development of GM1 gangliosidosis in individuals who carry two copies of the mutated GLB1 gene. However, people who have a relative with the disease are encouraged to undergo testing to determine whether they carry the gene mutation. A genetic counselor can help prospective parents assess their risk if they are discovered to be carriers of the disease-causing mutation.

GM1 Gangliosidosis Caregiver Tips

As a parent or a caregiver for a child with GM1 gangliosidosis, you have the capacity to help your child and your family live with the disease and treasure the time you have together.

• Be prepared for your life to change. Parents of children with GM1 gangliosidosis face a pivotal moment when receiving the diagnosis. You’ll want to do everything you can to improve your child’s quality of life, and that commitment will affect your relationships, your career, and every other aspect of your life. Understand that fear, anger, frustration, sadness, and confusion are normal reactions to this type of prognosis: don’t hesitate to seek help whenever you need it.
• Take time to grieve. Acknowledging and accepting your child’s diagnosis is a crucial step in living with GM1 gangliosidosis. When you allow yourself to move through the process of grieving, you’ll be better able to appreciate the beautiful moments you have with your child.
• Don’t try to cope by yourself. The support of people who understand what you’re going through is invaluable as you live with the disease. Online resources can help you find support groups, information, and news about GM1 gangliosidosis.

GM1 Gangliosidosis Brain Science

Several research areas aim to find therapies that can potentially treat, prevent, or even cure GM1 gangliosidosis. Current topics of study include:

• Enzyme replacement therapy. This type of therapy involves introducing a synthetic version of a deficient enzyme into cells to stop the destructive action of the disease. This type of therapy has been successfully used to treat other conditions, but it is still in the research stage as a treatment for GM1 gangliosidosis. Part of the problem is the barrier that prevents potentially harmful substances from crossing from the bloodstream into the brain. This blood-brain barrier makes it difficult to introduce replacement enzymes into the brain tissues affected by gangliosidosis.
• Enzyme enhancement therapy. This approach uses very small molecules to protect beta-galactosidase and prevent the enzyme from breaking down prematurely inside brain cells. These “chaperone” molecules can move through the blood-brain barrier and might better treat gangliosidosis. Research into this type of therapy is at an early stage.
• Gene therapy and stem cell transplants. These therapies aim to replace the disease-causing gene mutation with a normal gene, thereby theoretically stopping the course of the disease.

GM1 Gangliosidosis Research

Title: Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G)

Stage: Recruiting

Contact: Jeanine R. Jarnes, PharmD

University of Minnesota

Minneapolis, MN

The investigators hypothesize that combination therapy using miglustat and the ketogenic diet for infantile and juvenile patients with gangliosidoses, will create a synergy that 1) improves overall survival for patients with infantile or juvenile gangliosidoses and 2) improves neurodevelopmental clinical outcomes of therapy, compared to data reported in previous natural history studies. The ketogenic diet is indicated for managing seizures in patients with seizure disorders. In this study, the ketogenic diet will be used to minimize or prevent gastrointestinal side effects of miglustat. A Sandhoff disease mouse study has shown that the ketogenic diet may also improve the central nervous system response to miglustat therapy. Patients with infantile and juvenile gangliosidoses commonly suffer from seizure disorders, and the use of the ketogenic diet in these patients may also improve seizure management.

Title: A Safety and Efficacy Study of LYS-GM101 Gene Therapy in Patients With GM1 Gangliosidosis

Stage: Recruiting

Principal investigator: Raymond Wang, MD

Children’s Hospital of Orange County

Orange, CA

LYS-GM101 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the central nervous system. In a 2-stage adaptive design, this study will assess the safety and efficacy of treatment in subjects with infantile GM1 gangliosidosis.

GM1 gangliosidosis is a fatal, autosomal recessive disease caused by mutations in the GLB1 gene leading to accumulation of GM1 ganglioside in neurons and progressive neurodegeneration. There are three pediatric subtypes: early infantile, late infantile, and juvenile. This is an interventional, multicenter, single-arm, 2-stage adaptive design study of LYS-GM101. In the first safety and proof-of-concept stage of the study, four subjects with infantile GM1 gangliosidosis will receive a single dose of LYS-GM101 by intracisternal injection. The second stage of the study is confirmatory and will include additional patients with GM1 gangliosidosis.

Title: Study of Safety, Tolerability, and Efficacy of PBGM01 in Pediatric Subjects With GM1 Gangliosidosis (Imagine-1)

Stage: Recruiting

Contact:  Cyrus Bascon  

Benioff Children’s Hospital

Oakland, CA

PBGM01 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the brain and peripheral tissues. This study will assess in a 2-stage design the safety, tolerability, and efficacy of this treatment in patients with early-onset infantile (Type 1) and late-onset infantile (Type 2a) GM1 gangliosidosis. Results from the Type 1 and Type 2a groups will be assessed separately.

PBGM01 is an adeno-associated viral vector serotype Hu68 carrying GLB1, the gene encoding for human beta-galactosidase, formulated as a solution for injection into the cisterna magna. This is a global interventional, multicenter, single-arm, dose-escalation, adaptive design study of PBGM01 delivered as a one-time dose administered into the cisterna magna to patients with infantile GM1 gangliosidosis. There are two infantile subtypes of GM1 gangliosidosis: early-onset infantile (Type 1) and late-onset infantile (Type 2a), which are defined by the age of onset of disease symptoms.

Early Onset Infantile (Type 1):

• Onset <6 months of age
• Age at enrollment: >4 to <24 months of age

Late-Onset Infantile (Type 2a):

• Onset >6 to 18 months of age
• Age at enrollment: >6 to <36 months of age (except Cohort 1 will be >12 to <36 months of age)

In Part 1 of the study, two dose levels of PBGM01 will be studied separately in patients with either Type 1 or Type 2a GM1 gangliosidosis (see table below). The cohorts for patients with Type 1 and Type 2a will be assessed independently from each other. Part 1 will enroll a total of four cohorts, enrolled sequentially with separate dose-escalation cohorts for Type 1 GM1 and Type 2a GM1. Enrollment will initiate in Cohort 1. Following completion of Cohort 1, simultaneous enrollment in Cohort 2 and Cohort 3 will occur. Cohort 4 will follow the completion of cohort 3.

Part 2 of the study will test the safety and efficacy of PBGM01 in confirmatory cohorts for Types 1 and Type 2a GM1 gangliosidosis with a dose chosen based on the data obtained in part 1 of the study. This will be a 2-year study with a 3-year safety extension.