Most people living with Gaucher disease know the common symptoms such as bone pain, bruising, and fatigue. But Gaucher disease can also affect the central nervous system (brain and spinal cord) causing neurological manifestations to occur. How and when those neurological manifestations develop directly relates to the “type” of Gaucher disease.
We spoke with Neal Weinreb, MD, FACP, to understand the neurological manifestations of Gaucher disease. Dr. Weinreb is a regional coordinator and former chair of the International Collaborative Gaucher Group. His career centers around researching and managing lysosomal storage disorders, including Gaucher disease.
How Does Gaucher Disease Affect the Brain?
Gaucher disease affects the body in many ways—the buildup of the fatty lipid glucocerebroside interferes with how the blood, bones, brain, and other organs function. Most symptoms of Gaucher disease, including bone issues and blood-related disorders, can develop with all types of Gaucher disease. But not all Gaucher disease is neuronopathic, involving the central nervous system (CNS). And experts still aren’t sure why.
“As far as understanding all the causes of neurological manifestations, we are still quite far,” Dr. Weinreb says. “We can predict CNS involvement for certain genotypes and associate it with severe enzyme deficiency. But we still don’t know exactly how to account for all the different types of neurological deterioration that we observe.”
The good news is Gaucher disease research continues to expand worldwide. Researchers are working to understand the development of Gaucher disease in the brain and how it affects different brain cells and structures. They are also trying to determine how abnormal Gaucher disease biochemistry impacts communication pathways between different brain areas.
The Role of Genotype in Diagnosing Neuronopathic Gaucher Disease
The timing and type of neurological symptoms often play a critical role in diagnosing Gaucher disease type. But some specific gene mutations can help guide diagnosis before neurological symptoms appear:
- N370S gene mutation: Strongly associated with non-neuronopathic type 1 disease.
- L444P mutation: Having two copies of this gene is often a predictor of neuronopathic disease (types 2 or 3).
The important takeaway, notes Dr. Weinreb, is that these gene mutations provide information about possible neurological involvement. But the mutations are not a final prognosis. An N370S mutation negates type 2 or type 3 disease, but not everyone with type 1 will have an N370S gene mutation. The presence of L444P raises concerns about possible neuronopathic disease. But it doesn’t shed any light on the onset and severity of neurological involvement. And some people with this mutation seem to have Gaucher disease type 1.
“Genotype is not an absolute predictor of the type of Gaucher disease,” Dr. Weinreb says. “But it raises certain suspicions.”
Neurological Symptoms Associated with Different Types of Gaucher Disease
Neurological manifestations help distinguish the three main types of Gaucher disease. The severity and onset of neurological symptoms, or their absence, can vary depending on the type of disease.
Gaucher disease type 1
Type 1 disease, considered non-neuronopathic, doesn’t typically affect the central nervous system. But that doesn’t mean patients with Gaucher disease type 1 will never experience neurological involvement:
- Infants or children diagnosed as type 1 without an N370S mutation need monitoring to ensure they don’t develop classic neurological manifestations associated with types 2 or 3.
- Systemic inflammation associated with Gaucher disease may cause cognitive issues such as memory lapse, confusion, and depression.
- People living with type 1 may develop peripheral neuropathy (nerve-related numbness or pain in the hands or feet).
- Anyone with a GBA gene mutation—including Gaucher disease carriers—is at increased risk for Parkinson’s disease, particularly with older age. It is estimated that, for every 100 individuals with Gaucher disease who live to 70 years or older, three to five will develop manifestations of Parkinson’s disease.
Learn more about Parkinson’s disease and the Gaucher community.
Gaucher disease type 2
Both Gaucher disease types 2 and 3 involve the central nervous system and manifest neurological symptoms. But symptoms of type 2, called acute neuronopathic disease, may appear either at birth or in infancy (within the first three to six months of life) and worsen quickly.
“The neurological manifestations define this type of Gaucher. The symptoms occur so early and rapidly that it limits possibilities for variation,” Dr. Weinreb says. Babies with Gaucher disease type 2 don’t usually survive long enough to develop more typical bone and blood symptoms.
Gaucher disease type 2 typically leads to death in infancy or early childhood. Babies born with this disease type may exhibit neurological symptoms including:
- Inability to suck or swallow
- Poor development
- Severe brain damage
- Spasticity (jerking movements)
Gaucher disease type 3
Gaucher disease type 3 is known as a chronic neuronopathic disease. Compared to type 2, the symptoms develop more slowly, usually beginning during childhood or adolescence. Neurological symptoms of type 3 vary in severity from person to person and may include:
- Cognitive problems
- Developmental delays
- Eye movement disorders
- Poor coordination
Many people with Gaucher disease type 3 survive into adulthood. Accordingly, they may experience non-neurological Gaucher disease symptoms as well. But treatment with enzyme infusions can usually prevent or reverse those symptoms.
“In distinguishing between type 1 and type 3 disease, the eye abnormalities are critical and often diagnostic. But that symptom can develop at different times and can be very subtle,” Dr. Weinreb says. “There are also individuals with type 3 who don’t seem to have any neurological symptoms other than the eye changes.”
Managing Neurological Symptoms of Gaucher Disease
Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) help with non-neurological symptoms in people with Gaucher disease. However, treating neurological manifestations is a challenge. The brain’s “blood-brain barrier” protects it from bacteria, chemicals, and toxins. It also prevents standard Gaucher disease therapies from reaching the brain.
Current treatments don’t stop the neurological manifestations of Gaucher disease, but there are ways to manage the symptoms. Taking steps to reduce inflammation can help. When appropriate, Dr. Weinreb also recommends using adjunctive therapies such as:
- Anti-convulsant therapies
- Occupational therapy
- Parkinsonism medications
- Physical therapy
“Patients can see improvements on those medications and with those therapies,” he says, “as long as they’re prescribed properly.”
Researchers continue to study new treatments and combination therapies to address neurological symptoms. Experts are also looking at the link between Gaucher disease and Parkinson’s disease. That connection means advances in treating Parkinson’s disease may also show promise for Gaucher disease and vice versa.
“There are still lots of questions that remain unanswered about the central nervous system and Gaucher disease. But we are entering a very exciting period of investigation,” Dr. Weinreb says. “We’re starting to develop the tools needed to examine metabolism in single cells, not only outside the body, but even within the tissues and organs in which these cells reside. People with the disease may be asked to participate in trials involving all sorts of new techniques.”
How the National Gaucher Foundation Can Help
If you or a loved one lives with Gaucher disease, the National Gaucher Foundation is here for your family. We offer resources to optimize your health with Gaucher disease and connect you with the support you need.
- National Library of Medicine. The Spectrum of Neurological Manifestations Associated with Gaucher Disease — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456331/
- National Library of Medicine. Are there Neurological Symptoms in Type 1 of Gaucher Disease? — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904744/
- National Organization for Rare Disorders. Gaucher Disease — https://rarediseases.org/rare-diseases/gaucher-disease/
- Children’s Gaucher Research Fund. Gaucher Disease, A Layman’s Overview — http://www.childrensgaucher.org/recent-news/gaucher-disease-a-laymans-approach/
- National Library of Medicine. GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523296/