Sandhoff Disease

What Causes Sandhoff Disease?

Sandhoff disease is caused by a deficiency of enzymes called beta-hexosaminidase A and beta-hexosaminidase B. Inside brain and nerve cells, the enzyme is responsible for breaking down fatty compounds called gangliosides. When there is insufficient hexosaminidase in the cells, gangliosides accumulate and impair the nerve cells’ function. As a result, affected cells eventually die, causing the neurological symptoms characteristic of the disease.

Is Sandhoff Disease Hereditary?

Sandhoff disease is caused by an abnormal variation (mutation) in the HEXB gene, which plays a role in producing beta-hexosaminidase A and beta-hexosaminidase B enzymes. 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.

How Is Sandhoff Disease Detected?

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

Infantile Sandhoff Disease

Infants with Sandhoff disease 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

Juvenile Sandhoff Disease

The first signs of juvenile Sandhoff disease usually appear between 2 and 10. Early symptoms can include:

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

Adult Sandhoff Disease

The first symptoms of late-onset Sandhoff may appear from adolescence through adulthood. Early signs can include:

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

How Is Sandhoff Disease Diagnosed?

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

• Blood tests. These tests measure the level of beta-hexosaminidase A and beta-hexosaminidase B in the individual’s blood. A low level of the enzyme could indicate the presence of Sandhoff disease.
• Eye exams. A characteristic sign of Sandhoff disease 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 determine whether the individual has the disease-causing mutation of the HEXB gene. This test can confirm a diagnosis of Sandhoff disease.
• Amniocentesis or chorionic villus sampling. These tests may be conducted before birth if Sandhoff disease is suspected during pregnancy. The tests measure the fetus’s level of beta-hexosaminidase.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Sandhoff Disease Treated?

No treatment will cure Sandhoff disease or stop the progression of its symptoms. Instead, 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 not 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 Sandhoff Disease Progress?

Disease progression in Sandhoff disease can vary considerably from case to case. For example, infantile Sandhoff disease may progress rapidly, while the progression of the late-onset forms may be extremely slow.

Progression of Infantile Sandhoff Disease

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 3-5 years of age.

Progression of Juvenile Sandhoff Disease

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
• Loss of vision

Life-threatening effects usually occur by 15 years of age.

Progression of Late-Onset Sandhoff Disease

The progression of this form of the disease varies greatly from case to case. Not all symptoms develop in every case, and the timing and speed of progression also vary. It is not yet known if adult-onset Sandhoff disease consistently reduces life expectancy.

Later symptoms may include:

• Muscle tremors, spasms, or twitching
• Speech difficulties
• Loss of muscle control
• Difficulty swallowing
• Difficulty walking
• Memory problems
• Changes in personality or behavior
• Depression

How Is Sandhoff Disease Prevented?

There is no way to prevent the development of Sandhoff disease in individuals who carry two copies of the mutated HEXB gene. However, people who have a relative with the disease are encouraged to undergo testing to determine whether they carry the gene mutation. In addition, couples in communities where Sandhoff disease is more common are encouraged to be tested if they plan to have children. A genetic counselor can help prospective parents assess their risk if they are discovered to be carriers of the disease-causing mutation.

Assisted reproductive therapy is one option for carriers of the disease who wish to have children. Using this technique, embryos are fertilized outside the womb and then tested for the disease-causing mutation. Only healthy embryos are then implanted in the mother’s womb.

Sandhoff Disease Caregiver Tips

As a parent or a caregiver for a child with Sandhoff disease, you’re not powerless 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 Sandhoff disease face a pivotal moment when diagnosed. 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 change, and 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 Sandhoff disease. 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 Sandhoff disease.

Some people with Sandhoff disease also suffer from other brain-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with Sandhoff disease:

• People with late-onset Sandhoff disease often also suffer from depression or anxiety.
• Psychotic disorders resembling schizophrenia are common in people with late-onset Tay-Sachs disease, but these psychoses are less common in people with Sandhoff disease.

Sandhoff Disease Brain Science

Several research areas aim to find therapies that could potentially be used to treat, prevent, or even cure Sandhoff disease. Current topics of research 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 has not been effective at treating Sandhoff disease. Part of the problem is the barrier preventing potentially harmful substances from crossing the bloodstream into the brain. This blood-brain barrier makes it difficult to introduce replacement enzymes into the brain tissues affected by Sandhoff disease.
• Chaperone therapy. This approach uses very small molecules to protect beta-hexosaminidase and prevent the enzyme from breaking down prematurely inside brain cells. These “chaperone” molecules can move through the blood-brain barrier and might offer better treatment of Sandhoff disease. Research into this type of therapy is at an early stage.
• Gene therapy. This type of therapy replaces the disease-causing gene mutation with a normal gene, thereby theoretically stopping the course of the disease. A gene therapy for Sandhoff disease is currently undergoing clinical trials.

Sandhoff Disease 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: N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)

Stage: Recruiting

Principal investigator: Heather Lau, MD

NYU Langone School of Medicine

New York, NY

The primary purpose of the study is to evaluate the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease), investigating the effectiveness in terms of improving symptoms, functioning, and quality of life against the defined endpoints in patients with GM2 Gangliosidosis.

Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If, within six weeks before the initial screening visit, a patient has received any of the prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration), a wash-out study run-in of 6 weeks is required before the first baseline assessment.

All patients will receive the study drug during this study.

For each patient, the study lasts for approximately 3.5 – 4 months, during which there are 6 study visits to the study site.

Title: Nervous System Degeneration in Glycosphingolipid Storage Disorders

Stage: Recruiting

Principal investigator:  Cynthia J Tifft, MD  

National Institutes of Health Clinical Center

Bethesda, MD

The GM1 and GM2 gangliosidoses are lysosomal storage disorders that primarily affect the brain and are uniformly fatal. The glycoproteinoses sialidosis and galactosialidosis are ultra-rare disorders involving predominantly the skeletal and central nervous systems that are likewise fatal or severely debilitating. No effective therapy for patients with these diseases has yet been demonstrated. Historically, since these disorders are fatal, very little natural history information or disease characterization using modern medical techniques has been collected. This information is vital for establishing the disease progression pattern and identifying clinical, biochemical, and biophysical markers that can be used as endpoints in future therapeutic trials.

This protocol aims to study the natural history of the GM1 and GM2 gangliosidoses in affected individuals of all ages, races, and genders using medical technologies including MRI/MRS, hearing evaluation and auditory evoked response testing, and EEG, as well as subspecialty evaluations in rehabilitative medicine, ophthalmology, speech-language pathology, neurology, and psychology. Biomarkers of disease progression will be explored in CSF and blood samples for correlation with disease staging. Fibroblast cultures will be established for testing potential therapeutic agents. Some fibroblast lines will be used to create induced pluripotent stem cells (iPSC) for differentiation into neural tissues, more relevant for studying these disorders that primarily affect the central nervous system (CNS). We hypothesize that relevant biomarkers will correlate with disease progression and shed light on the pathophysiology of disease progression in these devastating disorders.

As a means of acquiring additional information, subjects or their parents may also be asked to complete a questionnaire regarding their medical and developmental history, the initial clinical presentation of the disease, and steps toward diagnosis. At their request, the same questionnaire may be sent to families who do not wish to undergo clinical evaluation at the NIH, who are medically fragile and unable to travel, or whose affected member(s) are already deceased.

We know that children with infantile GM2 gangliosidosis develop increasing macrocephaly as part of their disease. No standard curves for head circumference vs. age currently exist for this disorder. To provide such curves to the clinical community, parents may also be asked to provide head circumference data on their children whether they are being seen at NIH or whether a clinical questionnaire is being completed for children too medically fragile to travel already deceased.

We know with infantile-onset disease, ganglioside storage in neurons begins during the second trimester of pregnancy. In rare situations where carrier couples learn from prenatal diagnosis that they are carrying a fetus with infantile disease and have decided to terminate the pregnancy, we will accept samples of fetal tissue for analysis of biomarkers, including gene expression analysis that may lend clues as to the underlying pathogenesis of the disease. This may lead to an increased understanding of the early events in disease pathogenesis and suggest possible therapies.

We anticipate that information obtained from the small population of patients with glycosphingolipid and glycoprotein disorders evaluated in this study will have a broader impact on patients with other neurodegenerative lysosomal storage disorders and perhaps more common disorders of neurodegeneration.