Gaucher Disease: Signs, Symptoms, Causes, Affected Populations, Related Disorders, Diagnosis and Treatment

Some people develop few or no symptoms (asymptomatic), others may have serious complications.

Gaucher disease is a rare inherited metabolic disorder in which a deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful amounts of certain fats (lipids), specifically the glucocerebroside glycolipid.

It occurs throughout the body, especially within the bone marrow , spleen, and liver.

The symptoms and physical findings associated with Gaucher disease vary greatly from patient to patient.

Common manifestations of Gaucher disease include:

  • An abnormal enlargement of the liver and / or spleen ( hepatosplenomegaly ).
  • Low levels of circulating red blood cells (anemia).
  • Low platelet levels (thrombocytopenia) and skeletal abnormalities.

Platelets are blood cells that promote clotting, and patients with thrombocytopenia can develop bleeding problems.

Three different forms of Gaucher disease have been identified and are distinguished by the absence or presence and extent of neurological complications.

All three forms of Gaucher disease are inherited as autosomal recessive traits. Gaucher disease is classified as a lysosomal storage disorder (LSD). Lysosomes are the main digestive units in cells.

Enzymes within lysosomes break down or “digest” nutrients, including certain complex carbohydrates and fats.

In Gaucher disease, a certain amount of sugar (glucose) that contains fat, known as glycolipids, accumulates abnormally in the body due to a lack of the enzyme glucocerebrosidase.

This accumulation or “storage” of lipids leads to the various symptoms or physical findings associated with a lysosomal storage disease.

Gaucher disease is the second most common type of lysosomal storage disorder.

Signs and symptoms

Researchers have identified three different forms of Gaucher disease separated by the absence (type 1) or the presence and degree (type 2 or type 3) of neurological complications.

Most affected people have type 1 Gaucher disease, which lacks overt neurological complications.

The specific symptoms present in individuals with Gaucher disease vary greatly from case to case. Some people show few or no symptoms (asymptomatic); others experience chronic, and sometimes serious, complications.

Most people with type 1 Gaucher disease experience:

  • Bruising easily due to low levels of blood clotting cells known as platelets (thrombocytopenia).
  • Chronic fatigue due to low levels of circulating red blood cells (anemia).
  • An abnormally enlarged liver and / or spleen (hepatosplenomegaly).
  • Lack of blood supply (heart attack) to various bones in the body causing dull or severe bone pain (bone crises).
  • Degeneration (avascular necrosis).
  • Deformity of the affected bones.
  • Thinning and weakening of the bones (osteoporosis).

Such skeletal abnormalities result in increased susceptibility to fractures.

Type 2 Gaucher disease, also known as acute neuronopathic Gaucher disease, occurs in newborns and infants and is characterized by neurological complications due to abnormal accumulation of glucocerebroside in the brain.

Spleen enlargement (splenomegaly) is usually the first symptom and can manifest before six months of age. Enlargement of the liver (hepatomegaly) is not always present.

Affected babies may lose previously acquired motor skills and exhibit low muscle tone (hypotonia), involuntary muscle spasms (spasticity) that produce slow, stiff movements of the arms and legs, and crossed eyes (strabismus).

Also, affected babies may experience difficulty swallowing ( dysphagia ), which can lead to:

  • Feeding difficulties.
  • Abnormal positioning or flexion of the neck (retroflexion).
  • Lack of weight gain and growth at the expected rate (lack of growth).
  • Sharp breathing (stridor) due to contraction of the laryngeal muscles (laryngeal spasm).

Anemia and thrombocytopenia can also occur.

Type 2 Gaucher disease often progresses to life-threatening complications, such as shortness of breath or food entering the airways (aspiration pneumonia).

Severely affected newborns may show skin abnormalities (collodion skin or ictiform changes) and generalized swelling (dropsy), with death in the first weeks of life.

Other children with type 2 Gaucher disease have very short lives, and death usually occurs between 1 and 3 years of age. Anemia and thrombocytopenia can also occur.

Type 3 Gaucher disease, also known as chronic neuropathic Gaucher disease, occurs during the first decade of life.

In addition to the blood and bone abnormalities discussed above, affected individuals develop neurological complications that develop and progress more slowly than in type 2 Gaucher disease.

Associated neurological complications include:

  • Mental impairment
  • An inability to coordinate voluntary movements (ataxia).
  • Short, shocked muscle spasms of the arms, legs, or whole body (myoclonic seizures).

Some people with type 3 Gaucher disease may have trouble moving their eyes from side to side (horizontal gaze palsy).

Patients with type 3 Gaucher disease may also have vertical gaze paralysis that usually occurs later than horizontal gaze paresis.

A significant proportion of patients also develop pulmonary (lung) disease (interstitial lung disease). There may be great variability in presentation and clinical course among patients with type 3 Gaucher disease.

Some affected patients can live into their teens and early 20s, while others have lived much longer (30 and 40 years). With increasing difficulties, affected people may need help to accomplish the task of daily living (eg, eating, bathing, and walking).


All three forms of Gaucher disease are inherited as autosomal recessive traits. Human traits, including classic genetic diseases, are the product of the interaction of two genes, one received from the father and the other from the mother.

In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent.

If an individual receives a normal gene and a gene for the disease, the person will be a carrier of the disease, but usually will not have symptoms.

The risk of transmitting the disease to the children of a couple, both carriers of a recessive disorder, is 25 percent. Fifty percent of your children are at risk of being carriers of the disease, but generally they will not show symptoms of the disorder.

Twenty-five percent of your children can receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Researchers have determined that Gaucher disease can be caused by an alteration or changes (mutations) in the gene that controls the production of the enzyme glucocerebrosidase. Different mutations in this gene are believed to be associated with different types of Gaucher disease.

The gene is located on the long arm of chromosome 1 (1q21). Chromosomes are found in the nucleus of every cell in the body. They carry the genetic characteristics of each individual.

Human chromosome pairs are numbered 1 through 22, with a 23 different pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”.

Chromosomes are subdivided into bands that are numbered. For example, “chromosome 1q21” refers to band 21 on the long arm of chromosome 1.

Affected populations

All forms of Gaucher disease affect men and women in equal numbers. Type 1 Gaucher disease is the most common type, accounting for more than 90 percent of cases.

Individuals with type 1 Gaucher disease generally show symptoms during adolescence, but the age of onset varies from infancy to adulthood. The age of onset for type 2 Gaucher disease is during early childhood.

The age of onset of type 3 Gaucher disease varies, but the disorder usually begins during childhood or adolescence.

Gaucher disease is the most common genetic disorder in people of Ashkenazi Jewish descent, where the incidence can be as high as 1 in 450 births.

Related disorders

The symptoms of the following disorders may be similar to those of Gaucher disease. Comparisons can be useful for a differential diagnosis:

Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism.

At least five types of Niemann-Pick disease (NPD types A, B, C, D, and E) have been identified.

Symptoms of types A and B occur as a result of a deficiency of the acid enzyme sphingomyelinase (ASM), which is necessary to break down sphingomyelin, a fatty substance found in all tissues, especially the brain and nervous system. .

This deficiency causes an abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body, such as the liver, spleen, and brain.

Type C symptoms occur due to the inability to mobilize cholesterol, which causes an excessive accumulation of cholesterol in various organs of the body.

Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and / or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and a liver and / or or abnormally enlarged spleen (hepatosplenomegaly).

The different types of Niemann-Pick disease are inherited as autosomal recessive traits.

Pompe disease is a glycogen storage disease. This inherited metabolic disorder is caused by an innate lack of the enzyme alpha-1,4 glucosidase (lysosomal glucosidase, acid maltase), which is necessary to break down glycogen, a substance that is a source of energy for the body.

This enzyme deficiency causes excessive amounts of glycogen to accumulate in lysosomes, which are structures within cells that break down waste products within the cell.

The symptoms and physical findings of Pompe disease are the result of abnormal accumulation of glycogen in cells. Three different forms of Pompe disease have been identified.

The infantile form is characterized by severe muscle weakness and abnormally decreased muscle tone (hypotonia) without muscle wasting, and usually manifests during the first few months of life.

Additional abnormalities may include enlargement of the heart (cardiomegaly), liver (hepatomegaly), and / or tongue (macroglossia). Progressive heart failure usually causes life-threatening complications by the age of 12 to 18 months.

The childhood form usually begins during late childhood or early childhood. The extent of organ involvement can vary among affected individuals; however, skeletal muscle weakness is generally present with minimal cardiac involvement.

In the adult form of Pompe disease, symptoms include muscle weakness like that found in other chronic muscle disorders.

The onset of symptoms usually occurs between the second and fourth decade. This form of the disorder is slowly progressive without cardiac involvement.

Progressive heart failure usually causes life-threatening complications by the age of 12 to 18 months. The childhood form usually begins during late childhood or early childhood.

The extent of organ involvement can vary among affected individuals; however, skeletal muscle weakness is generally present with minimal cardiac involvement.

Hurler syndrome (MPS I) is one of a group of disorders known as mucopolysaccharidosis (MPS disorders).

These are rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes, resulting in an inability to break down complex carbohydrates (mucopolysaccharides) into simpler molecules.

The accumulation of these large undegraded mucopolysaccharides (also known as glycosaminoglycans) in the cells of the body causes a number of symptoms and physical abnormalities. There are three forms of Hurler syndrome with varying severity.

Babies with Hurler syndrome usually appear normal at birth, but they may have:

  • Inguinal and umbilical hernias.
  • Cloudiness of the cornea.
  • Enlarged liver and spleen.
  • Big tongue.
  • Skeletal abnormalities.
  • Poor growth and stiffness of the joints.

Hurler syndrome is caused by a deficiency of the enzyme alpha-L-iduronidase.

Tay-Sachs disease is a rare neurodegenerative disorder in which a deficiency of an enzyme (hexosaminidase A) causes an excessive accumulation of certain fats (lipids) known as gangliosides in the brain.

This abnormal accumulation of gangliosides leads to a progressive destruction of cells in the central nervous system.

Symptoms associated with Tay-Sachs disease can include:

  • An exaggerated startle response to sudden noises.
  • Apathy.
  • Loss of previously acquired skills (i.e., psychomotor regression).
  • Severely decreased muscle tone (hypotonia).

With the progression of the disease, affected infants and children can develop:

  • Cherry-red spots on the middle layer of the eyes.
  • Gradual loss of vision and deafness.
  • Increased muscle stiffness.
  • Restricted movements (spasticity).
  • Eventual paralysis.
  • Uncontrolled electrical disturbances in the brain (seizures).
  • Impairment of cognitive processes (dementia).

The classic form of Tay-Sachs disease occurs during childhood and can resemble some cases of type II Gaucher disease.


The diagnosis of Gaucher disease should be considered in individuals with unexplained anemia and easy bruising, especially if they have an enlarged spleen and liver and fractures.

The diagnosis of Gaucher disease can be confirmed by a thorough clinical evaluation.

Similarly, there are a variety of specialized tests, particularly tests (i.e., enzyme assays) that measure acid beta-glucosidase activity in white blood cells (leukocytes) or skin cells (fibroblasts) and genetic (DNA) analyzes of the causal genetic defects (mutations).

Prenatal diagnosis of Gaucher disease is possible through amniocentesis or chorionic villus sampling (CVS).

During amniocentesis, a sample of fluid that surrounds the fetus (amniotic fluid) is removed and tested, while CVS involves removing tissue samples from a portion of the placenta.

The researchers then study these fetal cells to reduce the beta-glucosidase activity that is characteristic of Gaucher disease.

Treatment and management of Gaucher disease

Enzyme replacement

Enzyme replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase alfa (Elelyso). This preparation is highly effective in reversing the visceral and hematological manifestations of Gaucher disease.

However, skeletal disease is slow to respond, and lung involvement is relatively resistant to the enzyme.

Treatment is usually given once every two weeks at a high dose, but, in some patients, treatment is given every week at a medium dose or up to 3 times a week at low doses.

ERT is indicated for patients with type 1 Gaucher disease who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly.

The severity and rate of progression of the disease vary widely, especially in adults, making treatment decisions extremely difficult for some patients.

In general, children with symptomatic symptoms, rather than a family history, may present with severe manifestations of the disease that require early treatment.

Presymptomatic treatment with ERT remains controversial due to the lack of prognostic correlation between genotype and disease severity and the high cost of therapy.

ERT has a marked effect on hepatosplenomegaly, with an overall average decrease of 25% in liver and spleen volume after 6 months of treatment.

In most patients with anemia, hemoglobin levels increase by 1.5 g / dL during the first 4-6 months of treatment.

A further increase of 1 g / dL is observed in the next 9-18 months in patients with persistent anemia. The platelet count responds more slowly, doubling on average over 1 year.

The hematologic status of patients with splenomegaly must be closely monitored, and splenectomy is still necessary on occasion.

Skeletal disease is the slowest response, with symptomatic improvement described by some within the first year of treatment, although a much longer ERT period is required to achieve a radiological response.

Patients with bone crises require pain relief, hydration, and close monitoring. Sometimes a bone scan is needed to differentiate between a bone crisis and an infection.

Other effects of ERT in children with Gaucher disease include increased growth rate, weight gain, increased energy levels, and a correction of both late puberty and hypermetabolic state.

The response of patients to ERT varies widely and does not correlate with genotype, disease severity, splenectomy, or age.

However, several factors, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement, augur poor response to therapy.

Symptoms in patients with Gaucher disease who have associated hematologic malignancies respond relatively poorly to ESRD. To overcome these difficulties, attempts have been made to increase the dosage and frequency of enzyme infusions.

Symptoms in patients with decompensated liver disease do not appear to respond well to ERT, and these patients remain at risk of life-threatening bleeding from variceal bleeding.

There is no evidence to show that ERT produces neurological improvement. Although the enzyme affects visceral involvement in types 2 and 3 disease, the associated brain involvement may persist or progress.