Gaucher Disease

What is Gaucher Disease?

Gaucher disease (pronounced as GO-SHEY) is a genetic condition that occurs when there’s a flaw, also known as a mutation, in a gene that produces an enzyme called glucocerebrosidase (GBA1). This enzyme helps break down a type of fat molecule known as glucocerebroside lipids.

It’s interesting to note that Gaucher disease beautifully illustrates the complex mixture of genetics, biochemistry and clinical medicine. It was named after a French doctor named Philippe Charles Ernest Gaucher, who first identified it in 1882. This disease is a type of inherited metabolic disorder and it causes a buildup of a certain type of fat, specifically glucocerebroside, in different tissues and organs throughout the body. The effects of Gaucher disease can range widely, with people experiencing symptoms that vary from mild to severe, across all age groups and backgrounds.

Inborn defects of metabolism, which are usually genetic disorders that disrupt the body’s ability to turn nutrients into energy and dispose of waste, can be particularly pronounced in children. They usually manifest very early in life, typically, though not always, during the newborn stage. There are five identified types of Gaucher disease: type 1, type 2, type 3, perinatal lethal, and cardiovascular. The perinatal lethal variant is the most severe, and problems can start before birth or in the early weeks of life.

Understanding the main signs of an inborn defects of metabolism is important for diagnosis. These conditions primarily arise due to a lack or insufficient amounts of specific enzymes that the body needs either to convert fats or carbs into energy or to help break down amino acids or other byproducts. If not broken down, these byproducts can build up and become toxic if untreated. Gaucher disease falls into the category of a “toxic buildup” inborn defects of metabolism, because of the accumulation of glucocerebroside lipids. There are three main types of toxic buildups: those that happen within a certain area (localized), those that circulate in the blood (circulating), or a combination of the two. Gaucher disease is an example of a localized toxicity.

What Causes Gaucher Disease?

Gaucher disease is caused by changes or mutations in the GBA1 gene. This mutation causes a deficiency in an enzyme called glucocerebrosidase. Enzymes are like the body’s ‘tools’ that help with chemical reactions. All types of Gaucher disease lead to a buildup of a fat called glucocerebroside in organs like the liver, spleen, and bone marrow.

Gaucher disease is also classified as a lysosomal storage disorder. In simple terms, this means it affects the organ or system of the body responsible for breaking down unwanted substances. Other lysosomal storage disorders include Tay-Sachs disease and Fabry disease among others. All these disorders tend to get worse over time.

Our body cells contain round structures called lysosomes that act like a waste disposal system. They degrade or break down unwanted substances. In people with Gaucher disease, the lysosomes in certain cells called macrophages slowly fill up with the undigested glucocerebroside fat. Picture a trash bin getting filled up overtime with waste. Without proper treatment, the liver can grow up to three times its normal size and the spleen up to fifteen times its normal size.

Even though we know the genetic causes of most Gaucher diseases, we’re still unsure about the exact trigger. Patients with the same mutation can have different symptoms. And oddly, patients with similar symptoms can have very different genetic mutations. This likely means that other factors like the environment or individual genetics may influence how Gaucher disease shows up in a person.

Risk Factors and Frequency for Gaucher Disease

Gaucher disease is the most frequent inherited disease found in the Ashkenazi Jewish population of Eastern European descent. Compared to the non-Jewish population, the disease has a high carrier rate. Other common conditions in this community include cystic fibrosis and Tay-Sachs Disease.

• Gaucher disease is prevalent in the Ashkenazi Jewish population with a carrier rate of 6%, whereas in the non-Jewish population it is 0.7% to 0.8%.
• Cystic fibrosis and Tay-Sachs Disease are also usual in the Ashkenazi community, with carrier rates of 4% and 3.7% respectively.

There are different forms of Gaucher disease. The most common is type 1, which varies greatly in how it affects individuals. Some people may start showing symptoms in their childhood, while others may go through life without any symptoms. This type generally does not involve the nervous system. Types 2 and 3 are less common and they do affect the nervous system. The outcomes for types 2 and the perinatal lethal type are often severe, usually causing death at birth, while type 3 typically leads to death in early to middle adulthood.

• Type 1 Gaucher disease is the most common form, with symptoms ranging from early childhood to none at all, and usually does not affect the nervous system.
• Types 2 and 3 of Gaucher disease, although rare, do impact the central nervous system.
• Type 2 and the perinatal lethal type often lead to neonatal death.
• Type 3 results in death in early to middle adulthood.

Signs and Symptoms of Gaucher Disease

Gaucher disease patients show various signs and symptoms, depending on the specific type of the disease. Some of the commonly noticed symptoms are:

• Enlargement of the liver and spleen without pain
• Hypersplenism (overactive spleen) and pancytopenia (low count of all blood cells)
• Severe pain in the joints, specifically hips and knees
• Problems with sense of smell and cognitive abilities (Type 1)
• Severe fits, hypertonia (muscle tension), intellectual disability, and breath-holding (Type 2)
• Myoclonus (muscle jerks), seizures, dementia, eye muscle issues (Type 3)
• Signs of Parkinson’s disease
• Osteoporosis (weakening of the bones)
• Change in skin color to yellowish-brown

Gaucher disease is diagnosed by testing for a low GBA1 enzyme level in white blood cells and confirming the presence of mutant alleles in the GBA1 gene. This usually needs only a blood sample. But sometimes, due to lack of awareness of Gaucher disease signs and symptoms, some patients undergo unnecessary, invasive procedures like bone marrow or liver biopsies to arrive at the correct diagnosis. Prior to an accurate diagnosis, many patients with enlarged liver or spleen are even misinformed that they might have cancer.

Testing for Gaucher Disease

When investigating Gaucher disease, several tests are involved:

Blood and Platelet Count: This test allows the doctor to assess the number and health of your blood cells and platelets. This information helps them understand the severity of the condition.

Liver Function Test: Frequent mild elevation of liver enzyme levels is usual. Still, if you show signs of jaundice or abnormal liver function, more studies could be required to investigate this further.

Coagulation Test: This test, measuring how well your blood clots, should be regularly performed to monitor your health condition.

Enzyme Activity: Gaucher disease is confirmed with a test that measures glucocerebrosidase activity, a specific enzyme, in your white blood cells. If the activity is less than 15% of the average normal activity, it can confirm a diagnosis of Gaucher disease.

Genotype Tests: Genetic testing can help determine if you have Gaucher disease, especially if you are of Ashkenazi Jewish descent, as certain genetic mutations are common in this population. It’s important to note that the presence of certain mutations doesn’t always mean your disease will progress in a known way. A special type of DNA-based test (PCR) may identify some mutations but not all, especially those related to more severe disease types.

Associated Marker Tests: Your doctor might check levels of certain markers in your body, like the angiotensin-converting enzyme, total acid phosphatase, and ferritin, which are usually elevated in Gaucher disease. Monitoring enzymes like chitotriosidase and glucosylsphingosine can also be useful. If you start treatment, these levels might return to normal.

Moreover, some imaging tests can be done:

Ultrasound can identify if your abdomen’s organs are enlarged, a common sign of Gaucher disease.

MRI scans help reveal early signs of skeletal issues related to the disease, like bone death and disease, spine degradation, and how much of the bone marrow is affected.

X-rays and Dual-Energy X-Ray Absorptiometry can show bone issues, measure bone density, and reveal lung involvement.

Echocardiograms can determine if you have pulmonary hypertension, a condition involving high blood pressure in the arteries that supply the lungs.

For more severe types of Gaucher disease that affect the nervous system, doctors might monitor brain activity and nerve responses with an EEG, evaluate swallowing, and perform eye exams.

Finally, Bone Marrow Aspiration and Liver Biopsy: In previous days, Gaucher disease was diagnosed by finding particular cells in a bone marrow sample. However, because tests for the enzyme activities in the blood are more sensitive, specific, and less invasive, bone marrow tests aren’t usually the first choice for diagnosis these days. Similarly, a liver biopsy (a procedure where a small sample of liver tissue is taken for testing) might be done to check for unexplained enlargement of the liver. This procedure is rare because other more specific and less invasive tests are available.

Treatment Options for Gaucher Disease

Gaucher disease is a genetic condition where the body is deficient in a particular enzyme, leading to various health issues. The treatments available for Gaucher disease fall under two main categories: enzyme replacement therapy and substrate reduction therapy.

Enzyme replacement therapy involves receiving an intravenous infusion of the enzyme that our body lacks. For Gaucher disease, the missing enzyme is called GBA1. The FDA has approved certain enzymes for Gaucher disease therapy. This therapy can’t treat enzyme deficiency in the brain due to a barrier that prevents substances in the bloodstream from reaching the brain. So, it’s not helpful for brain problems related to Gaucher disease. However, it can relieve other symptoms associated with Gaucher disease, such as enlarged organs and skeletal problems. This therapy does not fix the genetic defect causing the disease; it only reduces the symptoms and further damage coming from the build-up of toxins in the body. Some patients may develop antibodies against the replacement enzyme.

Substrate reduction therapy is a different approach. Patients take a pill that aims to decrease the level of certain substances in the body, making less of the toxin that accumulates in Gaucher disease. The ultimate goal is to lower the toxic impact. There are various FDA-approved drugs for Gaucher disease that work by inhibiting the creation of these harmful substances. However, these drugs don’t always cross the blood-brain barrier, meaning they may not treat brain-related effects of Gaucher disease. The safety and effectiveness of these in children are not yet known.

While hematopoietic stem cell transplantation, a process where healthy stem cells are introduced into the body, has been used to treat Gaucher’s disease, this method has largely fallen out of favor due to the associated health risks. This treatment option remains as a last resort primarily for severe cases of the disease.

Splenectomy, or removal of the spleen, is used in rare cases when patients have serious blood issues or severe abdominal pain. It’s crucial for patients to understand that removing the spleen can increase the risk of infections.

Moving forward, treatments may involve gene editing and gene therapy, which could potentially correct the genetic defect causing Gaucher disease.

What else can Gaucher Disease be?

When a doctor is trying to diagnose Gaucher disease, they might also consider the following conditions that may have similar symptoms:

• Multiple myeloma
• Lewy body dementia
• Niemann-Pick disease
• Parkinson disease
• Sphingomyelinase deficiency

What to expect with Gaucher Disease

The future health situation or “prognosis” of Gaucher disease can differ quite a lot. This variation is based on several factors: the type of the disease, the age it was identified, how quickly treatment starts, and the overall health of the individual. Here’s a quick rundown of what to expect for different types of Gaucher disease:

Type 1 Gaucher Disease (Non-Neuropathic)

* People with Type 1 Gaucher disease can usually expect a near-normal lifespan if their disease is treated well.
* Symptoms like an enlarged liver or spleen, anemia, and a low platelet count often get better with enzyme replacement therapy (ERT), a treatment that essentially provides the body with missing or non-functioning enzymes.
* Bone issues often either progress slower or stabilize with ERT, though some skeletal abnormalities might last regardless.

Type 2 Gaucher Disease (Acute Neuropathic Form):

* Type 2 Gaucher disease is a much more severe form of the disease that typically affects babies.
* The outlook for Type 2 is generally poor and it significantly reduces a patient’s lifespan.
* Infants affected often significantly decline in terms of brain function in infancy or early childhood and have severe complications.

Type 3 Gaucher Disease (Chronic Neuropathic Form):

* Type 3 Gaucher disease is a more mild form than Type 2, with symptoms typically appearing in childhood or adolescence.
* The outlook varies a lot; some people have a stable disease course while others can have more impactful brain involvement.
* Lifespan is generally reduced compared to people with Type 1 Gaucher disease, but it is less severe than Type 2.

Perinatal Lethal Type Gaucher Disease:

* Perinatal lethal Gaucher disease is the most severe and also very rare form of Gaucher disease.
* Symptoms usually appear before birth or during the newborn period.
* The outlook is extremely poor.
* Most babies with this type do not survive past infancy, and the disease is usually fatal shortly after birth.

Since this disease is so severe, the treatment options are limited. Enzyme
replacement therapy (ERT) or substrate reduction therapy (SRT), therapies aim to regulate the speed of biochemical reactions, might not work well. Doctors generally focus on providing comfort and support for these infants during their short lives.

Cardiovascular Type Gaucher Disease:

* Cardiovascular type Gaucher disease is an incredibly rare and not typical variant of the disease.
* It mainly affects the heart and blood vessel system, leading to the build-up of a specific fat molecule, glucocerebroside, in structures like the heart valves and arteries.

Severity can vary a lot among those affected; some may have mild symptoms, while others have more severe heart issues. The heart involvement may not respond as well to standard enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) as other forms of the disease. How quickly one is diagnosed, the extent of heart involvement, and the available specialized heart care can impact on the future health situation.

It’s worth mentioning that early diagnosis and timely start of treatment, especially with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), can significantly improve the outlook for Gaucher disease patients. These treatments can relieve many symptoms of the disease, prevent complications and improve the overall quality of life.

Possible Complications When Diagnosed with Gaucher Disease

Gaucher disease can lead to many health issues due to the buildup of specific types of lipids (fats) in various body tissues and organs. Some of the common problems include issues related to the bones, causing bone weakness, brittle bones, and fractures that cause chronic pain and difficulty moving.

Another related problem is an enlarged liver and spleen that can cause stomach discomfort and increase the risk of bleeding and infection. Blood-related complications can also happen, such as anemia and low platelet count that can result in fatigue and causing a person to bruise and bleed more easily.

Additionally, Gaucher disease can also affect the lungs, causing a specific type of lung disease, and even the central nervous system, leading to neurological complications in some people. Knowing and managing these complications is key to improving the quality of life for those living with Gaucher disease.

Common Complications:

• Bone issues leading to weakness, brittle bones, and fractures
• Chronic pain and impaired mobility
• Enlarged liver and spleen
• Stomach discomfort
• Increased risk of bleeding and infection
• Blood complications like anemia and low platelet count
• Fatigue, easy bruising, and bleeding
• Specific type of lung disease
• Possible neurological complications

Preventing Gaucher Disease

Prevention and education are critical elements in managing Gaucher disease. Prevention strategies mainly include providing genetic counseling and testing for people in high-risk groups, such as individuals of Ashkenazi Jewish descent. These services help people understand their chances of having the genetic mutation responsible for Gaucher disease and the risk of passing this onto their children. Identifying individuals who carry the Gaucher gene can help them make informed decisions about starting a family.

Education plays a crucial role in supporting individuals with Gaucher disease and their families. It’s necessary to teach patients about the nature of the disorder, possible complications, and available treatment options, such as enzyme replacement therapy and substrate reduction therapy. It’s also essential to stress the importance of regular medical checkups. Such education helps patients take an active role in their treatment plan, leading to better adherence to the recommended therapy. Early recognition of disease progression or complications can lead to timely medical care, improving the overall prognosis and quality of life for those with Gaucher disease.

Patients should also be aware of the research linking Gaucher disease to a slightly higher chance of developing Parkinson’s disease later in life. This link is also observed in individuals who carry the Gaucher gene without having the disease themselves. Roughly, individuals with Gaucher disease have a 5% chance of developing Parkinson’s disease by the age of 70, and this risk increases to about 8% by the age of 80. Gaucher disease carriers, by comparison, have approximately a 3% risk of developing Parkinson’s disease by age 70, with a small further increase noticed by age 80. Changes in the GBA gene account for the most frequently identified genetic risk of Parkinson’s disease.