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Gaucher’s Disease

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Iqra Mazhar

Gaucher disease is a lysosomal storage disease. The rare, hereditary, metabolic illness is characterized by a buildup of dangerous amounts of certain fats (lipids) throughout the body, particularly, in the bone marrow, spleen, and liver. It is also called Gaucher disease or glucocerebrosidase deficiency. 
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Overview

Gaucher disease is an autosomal recessive metabolic illness in which a form of fat (lipid), called glucocerebroside, is not adequately metabolized and accumulates in different body parts.

Normally, the body produces an enzyme called glucocerebrosidase, which degrades and recycles glucocerebroside - a natural component of the cell membrane. In Gaucher disease, patients have low levels of glucocerebrosidase. Hence, the breakdown of glucocerebroside is affected and it accumulates in cells of the macrophage-monocyte system.&nbsp;This produces a buildup of the lipid in the liver, spleen, bone marrow, and neurological system, interfering with normal function. 
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Approximately one in 50,000 to 100,000 people in the general population are affected by Gaucher disease.1&nbsp;In Europe, Israel, Canada, and the United States, type 1 is the most frequent form. This kind is more common among Ashkenazi (eastern and central European) Jews, affecting 1 in 500 to 1,000 Jewish people of Ashkenazi descent.1Types 2 and 3 are infrequent and do not commonly affect this population. However, countries, such as Egypt, India, Japan, Poland, and Sweden, report more cases of type 2 and 3 than type 1.1 
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Gaucher&#39;s disease is broadly divided into three types, based on the presence and absence of neurological symptoms. 
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Type 1 (Non-Neuronopathic)

Gaucher disease type 1 is the most common type, affecting 90% of people with the condition.3&nbsp;It is also known as non-neuronopathic because the central nervous system (brain and spinal cord) is spared. Instead, the blood, spleen, liver, and bones are affected. The symptoms can begin at any age and range from mild to severe. Most people with Gaucher disease type 1 have the following problems:

<ul>
	<li>Easy bruising due to low platelets (thrombocytopenia)</li>
	<li>Chronic tiredness due to low levels of circulating red blood cells (<a href="https://merisehat.pk/disease/anemia">anemia</a>)</li>
	<li>An abnormally enlarged liver and/or spleen (hepatosplenomegaly)</li>
	<li>Lung and/or renal problems 
	&nbsp;</li>
</ul>

Afflicted people may also have a loss of blood flow (infarction) to various bones in their bodies, resulting in dull or extreme bone pain (bone crises), degeneration (avascular necrosis), deformity of affected bones, and bone thinning and weakening (<a href="https://merisehat.pk/disease/osteoporosis-80">osteoporosis</a>). Such skeletal anomalies make people more prone to fractures. 
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Type 2 (Acute Neuronopathic)

Also called acute neuronopathic Gaucher disease, type 2 affects newborns and babies aged 3 to 6 months. Most children don&rsquo;t live beyond the age of 2 years.3&nbsp;The disease is characterized by neurological difficulties caused by aberrant glucocerebroside buildup in the brain. Spleen enlargement (splenomegaly) is frequently the initial symptom and may appear before the age of six months. Hepatomegaly (liver enlargement) is not always visible. Affected newborns may lose previously learned motor abilities and have low muscle tone (hypotonia), involuntary muscle spasms (spasticity) resulting in sluggish, stiff arm and leg motions, and crossed eyes (strabismus). 
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Furthermore, affected infants may also have 

<ul>
	<li>Difficulty swallowing (dysphagia), which can lead to feeding difficulties</li>
	<li>Abnormal positioning or bending of the neck (retroflexion)</li>
	<li>Failure to gain weight and grow at the expected rate (failure to thrive) </li>
	<li>High-pitched breathing (stridor) due to contraction of the voice box muscles (laryngeal spasm) </li>
	<li>Anemia</li>
	<li>Thrombocytopenia 
	&nbsp;</li>
</ul>

Gaucher disease type 2 frequently leads to life-threatening consequences such as respiratory discomfort or food entering the respiratory airways (aspiration pneumonia). Severely afflicted babies may have skin abnormalities, as well as widespread edema (hydrops), with mortality occurring within the first few weeks of life. 
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Type 3 (Chronic Neuronopathic)

Gaucher disease type 3 manifests itself within the first decade of life. Aside from the blood and bone problems mentioned above, afflicted individuals experience neurological difficulties that emerge and advance more slowly than Gaucher disease type 2. Mental decline, inability to coordinate voluntary movements (ataxia), and myoclonic seizures are all common neurological symptoms. Moreover, some people may have trouble shifting their eyes from side to side (horizontal gaze palsy). Vertical gaze palsy (inability to move the eye in a single vertical direction) can also arise in patients with type 3 Gaucher disease, usually after the horizontal gaze paresis. Moreover, a considerable number of people suffer from pulmonary diseases, such as interstitial lung disease. 

The clinical presentation varies from patient to patient. Some patients may live into their teens or early twenties, but some have lived considerably longer (30s and 40s).5&nbsp;&nbsp;As the disease progresses and worsens, patients may require help in performing daily life tasks, for example, walking, eating, and bathing. 
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Signs and Symptoms

Gaucher&#39;s disease symptoms differ from person to person. Some patients with Gaucher disease experience just minor symptoms or none at all. Whereas, in other people, the disease can lead to major health problems, which can be fatal. The following are symptoms of all three types of Gaucher disease: 
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Neurological Symptoms:

Gaucher disease types 2 and 3 produce neurological problems along with blood, organ, and bone symptoms. In infants with type 2, symptoms appear within the first 6 months. These children may also be born with skin defects. On the other hand, symptoms of Gaucher disease type 3 start at the age of ten and worsen with time. Gaucher disease types 2 and 3 have the following neurological symptoms:

<ul>
	<li>Developmental delays and feeding difficulties (in babies with Gaucher disease type 2)</li>
	<li>Difficulties with cognition</li>
	<li>Eye issues, particularly in side-to-side eye movements</li>
	<li>Problems with coordination and gross motor skills</li>
	<li>Seizures, muscular spasms, and jerky movements. 
	&nbsp;</li>
</ul>

Bone Symptoms

When bones do not receive adequate blood, oxygen, and nutrition, they weaken and break down. Gaucher disease patients may experience bone and joint symptoms such as: 
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<ul>
	<li>Pain - Gaucher disease is commonly characterized by arthritis, joint discomfort, and joint degeneration. The pain results from decreased blood flow. 
	&nbsp;</li>
	<li>Osteonecrosis - Also known as avascular necrosis, it results from a lack of oxygen reaching the bones. Without sufficient oxygen, bone tissue breaks and dies. 
	&nbsp;</li>
	<li>Fractures - Gaucher disease causes osteoporosis, a disorder in which the bones do not receive enough calcium and become weak. Both osteoporosis and osteopenia (low bone density that can lead to osteoporosis) cause bones to break easily. Moreover, skeletal problems can result from weakened bones. 
	&nbsp;</li>
</ul>

Blood Symptoms

As lipids build up in the body, people with Gaucher disease may experience a range of symptoms, ranging from mild to severe, in the blood and organs. Often, brown pigmented spots can appear on the skin. Other common symptoms include: 
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<ul>
	<li>Anemia - This results from an accumulation of lipids in the bone marrow, destroying red blood cells. The red blood cells are responsible for transporting oxygen throughout the body. A reduction in red blood cells results in anemia. 
	&nbsp;</li>
	<li>Organ Enlargement - As lipids accumulate, the spleen and liver grow in size, causing the abdomen to enlarge and become tender. Platelets (blood cells that help blood clot) are destroyed by an enlarged spleen, resulting in a low platelet count and bleeding difficulties. 
	&nbsp;</li>
	<li>Bruising, Bleeding, and Clotting Problems - People with Gaucher disease bruise easily due to a low platelet count. Their blood is unable to clot properly due to low platelet levels. Even minor injuries, surgery, or nosebleeds, puts them at risk of excessive bleeding. 
	&nbsp;</li>
	<li>Fatigue - People with Gaucher disease frequently experience fatigue as a result of anemia (feeling tired all the time). 
	&nbsp;</li>
	<li>Lung Problems: Fatty substances build up in the lungs, making breathing difficult. 
	&nbsp;</li>
</ul>
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Causes

Gaucher&#39;s disease is a hereditary metabolic disorder. People with Gaucher&rsquo;s disease are deficient in the enzyme glucocerebrosidase which is needed for the breakdown of fats (sphingolipids). Thus, a lack of enzymes results in lipids accumulating in the organs, bone marrow, and brain. The excessive fat buildup can affect organ functioning, destroy blood cells, and weaken bones. 
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Diagnosis

Pregnant women with known GBA gene mutation can undergo prenatal screening to determine whether the fetus will be born with the disease. Amniocentesis or chorionic villus sampling (CVS) can be used for screening. However, while prenatal screening can confirm the diagnosis, it cannot determine the type of Gaucher&rsquo;s disease. 
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A complete history that encompasses all of the patient&rsquo;s symptoms is typically the first step of diagnosis. Patients with unexplained anemia, easy bruising, and hepatosplenomegaly are often suspected of having Gaucher&rsquo;s disease.

Along with a history and physical examination, the doctor may administer a variety of tests. Blood tests that measure enzyme levels are used to diagnose Gaucher&rsquo;s disease. Moreover, a DNA test may be administered to determine whether a patient is a carrier of Gaucher disease. Carriers of Gaucher disease exhibit no symptoms, yet they can pass the condition on to their offspring. If carriers want to have children, the doctor will recommend genetic counseling. 
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The following laboratory tests are used to diagnose Gaucher&rsquo;s disease:

Evaluation of Enzyme Activity:

A measurement of glucocerebrosidase activity in peripheral blood leukocytes can be used to confirm the diagnosis. The test is known as the BGL (beta-glucosidase leukocyte) test. Results less than 15% of normal activity are considered diagnostic.7 
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Genotype Testing:

Genetic testing for common genetic mutations implicated in Gaucher&rsquo;s disease is helpful. Especially in Ashkenazi patients, in whom six GBA1 (glucosylceramidase beta 1) mutations account for the majority of cases. Testing for four common mutations (N370S, L444P, 84gg, and IVS2[+1]) is 90-95% accurate in diagnosing the disease in the Ashkenazi Jewish population.9&nbsp;However, in the rest of the population, genetic testing is only 50-60% accurate.9&nbsp;Therefore, genetic testing is often combined with enzyme testing to help improve accuracy. 
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Complete Blood Count (CBC):

This helps determine the patient&rsquo;s red blood cell levels and platelet count. 
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Liver Function Test for Enzymes:

Even mild cases of Gaucher disease can result in minor increases in liver enzyme levels. However, if jaundice or impaired hepatocellular synthetic function is present, a full hepatic evaluation is needed. Moreover, coagulation studies will also be monitored. 
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Testing for Associated Markers:

Angiotensin-converting enzymes, total acid phosphatase, and ferritin levels are frequently high in Gaucher&rsquo;s disease. These levels may return to normal or remain high after therapy. Monitoring levels of another enzyme, chitotriosidase, is equally effective in illness monitoring, except in the 10% of the population who lack this protein. Monitoring glucosylsphingosine levels, a downstream metabolic product of glucosylceramide, may also be beneficial because it has been shown to correlate with response to medication. 
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Imaging Studies:

<ul>
	<li>Abdominal ultrasound can determine the extent of organomegaly. However, MRI is more accurate in determining organ size. Moreover, MRI can also reveal any skeletal abnormalities, such as avascular necrosis.</li>
	<li>Chest radiography is used to assess pulmonary symptoms.</li>
	<li>Dual-energy X-ray absorptiometry (DEXA) scans are helpful in determining bone density and diagnosing osteopenia. Moreover, bone scans may aid in the diagnosis of bone crises. 
	&nbsp;</li>
</ul>
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Treatment

Gaucher&#39;s disease has no cure, however, therapy can help reduce symptoms and improve quality of life. Enzyme replacement therapy is available for people with type 2 Gaucher&#39;s disease, but there is no effective treatment for the severe brain damage that is anticipated. Some people with moderate type 1 may not require medication, but they should be checked on a regular basis. A variety of treatments may be beneficial to people with type 1 or type 3 Gaucher&#39;s disease. 
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<ol>
	<li>Enzyme Replacement Therapy (ERT):</li>
</ol>

This therapy restores glucocerebrosidase deficiency using intravenous recombinant glucocerebrosidase, or imiglucerase. The treatment is beneficial in patients with type 1 Gaucher&rsquo;s disease, and some type 3 cases.

ERT can reduce hepatosplenomegaly, improve anemia and low platelet count, and improve skeletal abnormalities by increasing bone density. The main objective of ERT is to alleviate symptoms and avoid permanent effects. In patients with types 2 and 3, ERT does not address nervous system disorders, such as brain injury. 
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<ol start="2">
	<li>Substrate Reduction Therapy (SRT):</li>
</ol>

SRT strives to limit substrate generation and waste material buildup in cells. It decreases waste formation in cells by lowering the synthesis of glucocerebroside, the substrate for the defective enzyme. Miglustat, also known as Zavesca, is an oral prescription drug authorized by the US Food and Drug Administration (FDA) for individuals with mild to moderate type 1 Gaucher&#39;s disease. The drug&#39;s producers recommend that patients use Zavesca only if they are unable to be treated with ERT. Patients must have never received ERT or have been off it for at least 6 months. A woman should not use Zavesca if she intends to conceive, is pregnant, or is breastfeeding. 
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<ol start="3">
	<li>Bone Marrow Transplant:</li>
</ol>

Bone marrow is the spongy substance present within certain bones. Blood cells, including red and white blood cells, as well as platelets, are produced by bone marrow cells. A bone marrow transplant, also known as a stem cell transplant, replaces damaged bone marrow stem cells with healthy bone marrow stem cells. Bone marrow transplantation is reserved for the most severe instances of Gaucher&#39;s disease. Serious problems, including infection and rejection, are possible. 
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The complications of Gaucher&rsquo;s disease typically depend on the symptoms and severity of the disease. Common complications include:

<ul>
	<li>Growth and puberty delays in children</li>
	<li>Obstetric and gynecological issues</li>
	<li>Parkinson&#39;s disease (PD)</li>
	<li>Higher risk of cancers like lymphoma, leukemia, and myeloma</li>
	<li>Trouble walking</li>
	<li>Fatigue 
	&nbsp;</li>
</ul>
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People of Eastern and Central European Jewish (Ashkenazi) heritage are more likely to get Gaucher disease type 1. While types 2 and 3 affect people of all ethnicities. 
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Gaucher&rsquo;s disease cannot be prevented if gene mutations are present. Those at risk should undergo testing as early treatment can prevent organ and bone damage from Gaucher disease type 1.

Carriers planning on starting a family are generally advised of genetic counseling. A genetic counselor can help develop a plan to decrease the risk of passing the gene to the offspring. 
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Key Points

<ul>
	<li>Gaucher disease is an autosomal recessive metabolic illness in which a form of fat (lipid), called glucocerebroside, is not adequately metabolized and accumulates in different body parts.</li>
	<li>Normally, the body produces an enzyme called glucocerebrosidase, which degrades and recycles glucocerebroside, a natural component of the cell membrane. Gaucher disease patients do not produce enough glucocerebrosidase; hence, the breakdown of glucocerebroside is affected and accumulation of glucocerebroside occurs in cells of the macrophage-monocyte system.</li>
	<li>Gaucher disease type 1 is sometimes known as non-neuronopathic since it does not affect the central nervous system (brain and spinal cord). It is the most frequent form of the disorder.</li>
	<li>Gaucher disease type 2, often regarded as acute neuronopathic Gaucher disease, affects newborns and babies and is characterized by neurological difficulties caused by aberrant glucocerebroside buildup in the brain.</li>
	<li>Gaucher disease type 3 (chronic neuronopathic Gaucher disease) manifests itself within the first decade of life. Aside from bone and blood abnormalities, afflicted individuals experience neurological difficulties that emerge and advance more slowly than Gaucher disease type 2.</li>
	<li>Gaucher disease symptoms differ from person to person. Some patients with Gaucher disease experience just minor symptoms or none at all. Symptoms in other people can lead to major health problems and can be fatal as well.&nbsp;</li>
	<li>When the body lacks glucocerebrosidase enzyme, fatty compounds (called Gaucher cells) accumulate in the organs, bone marrow, and brain. Excess fats produce a variety of difficulties and symptoms. They have an effect on how the organs perform, as well as destroying blood cells and weakening bones.</li>
	<li>Gaucher disease is diagnosed with a blood test that measures enzyme levels. </li>
	<li>A DNA test utilizing your saliva or blood is performed by your physician to identify if you are a carrier for Gaucher disease. Carriers of Gaucher disease exhibit no symptoms, yet they can pass the condition on to their offspring. If you are a carrier and want to have children, your provider will recommend you to a genetic counselor so you may make a family plan.</li>
	<li>Gaucher&#39;s disease has no cure, however, therapy can help reduce symptoms and improve quality of life. Enzyme replacement therapy is available for people with type 2 Gaucher&#39;s disease, but there is no effective treatment for the severe brain damage that is anticipated. Some people with moderate type 1 may not require medication, but they should be checked on a regular basis. 
	&nbsp;</li>
</ul>
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