Gaucher disease

This is part of Rare diseases.

Diagnosis: Gaucher disease

Synonyms: Morbus Gaucher


Date of publication: 2012-11-28
Version: 1.2

The disease

Gaucher disease is caused by impaired activity of the glucosylceramidase enzyme (also known as β-glucocerebrosidase, β-glucosidase or cerebroside-β-glucosidase). This enzyme deficiency means that glucosylceramide cannot be broken down but accumulates in the body leading to the enlargement of, and damage to, the spleen, liver and other organs. The disease can be divided into three main clinical types with severity ranging from severe symptoms presenting from birth, to a mild form of the disease presenting first in adulthood.

Gaucher disease is a lysosomal storage disorder. Lysosomes are small units found in all the cells of the body, with the exception of red blood cells. The role of lysosomes is to deal with and break down different substances. They do this with the help of enzymes, types of protein which contribute to chemical processes without themselves being broken down. The breaking-down process frees the component parts of certain substances. In this way proteins, for example, are broken down into amino acids. A recycling system is created as, after they have been freed, these components are transported out of the lysosomes and can act as building bricks in the production of new substances.

In all lysosomal storage disorders, the normal function of lysosomes is impaired. This is caused by impaired activity of the enzymes of the lysosomes, or in the transport proteins which carry substances into or out of lysosomes.

Currently we know of approximately seventy different lysosomal diseases. Some other examples are: aspartylglykosaminuria, cystinosis, Danon disease, Fabry disease, GM2 gangliosidosis, Krabbe disease, mannosidosis, metachromatic leukodystrophy, mucopolysaccharidoses I, II, III, IV, VI and VII, Pompe disease and Salla disease. Separate information on these diseases is available in the Swedish Rare Disease Database.

The disease is named after French physician Philippe Gaucher, who described the disease for the first time in 1882.


In Sweden, the disease is most common in the areas of Norrbotten and Västerbotten. Previously one child in every 10,000 there was born with the disease, but during recent years prevalence has fallen. In the rest of Sweden, fewer than one child in every 100,000 is born with the disease. In Sweden, approximately five people in every million are affected and there are between 50 and 60 people with the disease in the country. Approximately 40 per cent have type 3 (the Norrbottnian type) and the others have type 1. (See under heading “Symptoms”.)

Since the early 1990s, enzyme replacement therapy has been offered to children and young people with the disease, resulting in more people with the condition attaining adulthood in relatively good health.


The disease is caused by deficient activity of the glucosylceramidase enzyme. This enzyme deficiency interferes with the normal process by which glucosylceramide, a fatty acid, is broken down. Instead it accumulates in one particular type of white blood cells, the macrophages. Macrophages filled with glucosylceramide are called Gaucher cells and they accumulate in various organs.

Gene GBA (1q21) codes for the enzyme and is located on the long arm of chromosome 1. More than 300 mutations in the gene causing Gaucher disease have been identified, but most occur within individual families (private mutations). In most mutations, a nucleobase in a portion of DNA has been changed, resulting in the formation of a different amino acid. One or more of the following five mutations, N370S (c.1226A>G), L444P (c.1448T>C), 84GG (c.84dupG), IVS2+1 (c.27+1G>A) and D409H (c.1342G>C) occur in 95 percent of all people with Gaucher disease. Two of them, N370S (c.1226A>G) and L444P (c.1448T>C) are most common, and are found over the whole world. Of all those with the disease, slightly more than half have this mutation.

Gaucher disease develops if a person inherits one copy of the mutated GBA gene from each parent. If the person inherits only one copy of the mutated gene, he or she becomes a healthy carrier. If an individual inherits two copies of gene N370S (c.1226A>G), or this mutation is in combination with another mutation, it is likely that he or she will develop Gaucher disease type 1, without neurological symtoms (non-neuropathic form). If an analysis shows instead that the individual has two copies of gene L444P (c.1448T>C) he or she will usually have a neuropathic form of the disease, affecting the central nervous system.

In rare cases the enzyme is normal but a protein known as saposin C, which is needed to activate glucosylceramide, is absent. This is extremely rare, with only five cases being described globally as yet, and as yet nobody in Sweden has been diagnosed with a deficiency of this activator protein.


In Gaucher disease the pattern of inheritance is autosomal recessive. This means that a person must inherit one mutated gene from each parent to develop Gaucher disease. If both parents are healthy carriers of the mutated GBA gene there is a 25 per cent risk that their child will receive two copies of the mutated gene (one from each parent). In that case, the child has the disease. (See figure below.) In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one single copy of the mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


Gaucher disease is a lifelong condition. Degrees of severity vary, from a disease with serious symptoms presenting already at birth, to relatively mild symptoms first manifesting in adulthood. The disease is divided into three main clinical types depending on whether the patient has neurological symptoms or not, and how quickly such symptoms develop. Boundaries between different types are not firm and variation in severity may be described as a scale running from the mildest to the most severe forms. There is a wide degree of variation in symptoms between different individuals with the same mutation.

The degree of enlargement of liver and spleen, the extent of red blood cell and platelet deficiencies (anaemia and thrombocytopenia) and the development of bone disease all vary between individuals.

People with severe enlargement of the liver and spleen may not have bone disease. The reverse is also possible. For example, symptoms of bone disease manifest as frequent fractures, which eventually damage the joints.

Gaucher disease type 1 is the most common form of the disease, and primarily affects young people and adults. The accumulation of glucosylceramide in liver and spleen leads to their enlargement (hepatomegaly and splenomegaly). The spleen can swell enormously and cause secondary changes in the blood, including low levels of red blood cells (anaemia), blood platelets (thrombocytopenia) and white blood cells (leukopenia). Splenic infarctions may also occur. Cirrhosis of the liver, leading to dilated veins in the windpipe (oesophageal varices) may also develop. In type 1 of the disease there are no neurological symptoms. However, there have been reports of an increased rate of Parkinson disease and peripheral nerve disease among some people with Gaucher disease type 1.

Gaucher disease in the skeleton results in bone deformities, fractures and the destruction of some bone tissue (aseptic necrosis).

Without treatment, progression varies greatly, from severe blood abnormalities and bone disease manifesting in childhood, to asymptomatic enlargement of the spleen presenting first when individuals are in their 70s or 80s. Bone disease can result in severely limited mobility.

In Gaucher disease types 2 and 3 the nervous system is affected prior to birth. These two types have different symptoms and different progression patterns, depending on how rapidly glucosylceramide accumulates. Accumulation occurs more rapidly in type 2.

No Gaucher cells accumulate in the central nervous system. Nevertheless, nerve cells are destroyed, causing people with Gaucher disease to develop progressive, neurodegenerative diseases including epilepsy. Their memories might also deteriorate. One hypothesis is that a toxic substance (glucosylsphingosine) forms, destroying brain cells. Another theory is that Gaucher cells accumulate around the blood vessels of the brain, cutting off the blood supply and damaging brain cells.

Type 2, or the acute infantile neuropathic (damaging nerve cells) type, is rare but found over the whole world. It is a severe, rapidly progressive disease causing liver and spleen enlargement during the first months of life. At five to six months abnormalities in the cranial nerve nuclei and the basal ganglia cause neurological symptoms. Symptoms include: difficulties opening the mouth (trismus), a squint (strabismus), severe hyperextension and arching of the head, neck and spine and other symptoms and abnormal reflexes associated with the brain stem. These symptoms sometimes lead to problems swallowing. Food may find its way into the airways (aspiration) leading to pneumonia. Involuntary muscular contractions of the laryngeal cords (laryngospasms) may occur. The appearance and distribution of brain damage indicates that injury has occurred, at least partially, prior to birth. Most children die before the age of one. A few children may live to two or three years of age.

Type 3, or the juvenile neuropathic type, is extremely rare apart from in the north of Sweden. Most of those with type 3 come from the Norrbotten and Västerbotten areas of Sweden (Norrbottnian type). Several different mutations can cause type 3, but the Norrbottnian type is caused by the inheritance of two copies of the L444P (c.1448T>C) mutation. Skeletal and blood symptoms are the same as in type 1, and progression patterns may also vary greatly.

Neurological symptoms include: difficulties moving the gaze quickly to the side (ocular motor apraxia), squinting, increasingly severe dementia, certain problems with balance (ataxia), mild spastic stiffness in the leg muscles, and epilepsy. If the spleen is removed at an early stage it appears to accelerate the progression of the disease and to affect the prognosis negatively.


In order to prevent complications and improve the prognosis, it is important to make the diagnosis early. The initial diagnosis is made on the basis of symptoms, particularly on the presence of an enlarged liver and spleen, but it must be confirmed by establishing low levels of the glucosylceramidase enzyme. The standard method is to measure enzyme activity in a particular sort of white cell (lymphocytes). When the enzyme deficiency is confirmed, a DNA analysis is made to establish which mutation has caused the disease. In extremely rare cases, where glycosylceramidase activity is normal but the clinical picture indicates Gaucher disease, a deficiency in the activator protein saposin C may be suspected.

Both pre-natal and embryo diagnoses are possible. Carrier diagnosis for relatives is possible if the mutation/mutations are known.


There is currently no cure for this disease. Treatment focuses on alleviating symptoms and compensating for loss of function, and is adapted to the individual’s age and lifestyle.

Enzyme replacement therapy (ERT) is first-line treatment. This form of treatment has been used since 1992 and involves a modified form of the deficient enzyme being administered intravenously as an infustion over one to two hours, usually once every two weeks. Small children may receive this treatment once or twice per week, at least at the start of the treatment programme. Enzyme replacement should be initiated at an early stage of the disease, before complications arise.

In type 1 (moderate to severe), ERT has a very positive effect on all symptoms. Enzyme treatment has been tried on some individuals with type 2, without improving the prognosis. In type 3, ERT has a positive effect on the symptoms it shares with type 1. Although ERT is thought to delay neurological deterioration in type 3, long-term follow up examinations are required before definite conclusions can be reached. ERT can be safely used by pregnant women and nursing mothers.

The effects of treatment are measured using biomarkers, such as chitotriosidase and CCL18. The level of glucosylceramide, which has accumulated as the result of enzyme deficiency, can also be measured.

Substrate reduction therapy (SRT) is another treatment option in Gaucher disease. Miglustat is a chemical compound which inhibits the synethesis of the glucosylceramidase enzyme and so reduces the production of glucosylceramide. Treatment with miglustat has been shown to have a positive effect on patients with mild to moderate Gaucher disease type 1. The little residual degradative activity which people with Gaucher disease type 1 have, is sufficient to deal with the glucosylceramide the body produces and to prevent its accumulation. However, miglustat takes longer to act than ERT. Miglustat is taken three times a day, in capsule form. This form of treatment has been approved for treatment of adults with mild to moderate Gaucher disease type 1, where enzyme treatment for some reason is not appropriate. Pregnant women and nursing mothers should not be treated with miglustat as the effects of the treatment have not been fully established in these particular groups of patients. Studies are under way into the effects of combined enzyme and miglustat treatment on the more severe forms of Gaucher disease.

Haematopoietic stem cell transplantation (bone marrow transplantation), was the only effective method of treatment prior to enzyme replacement therapy. It had some success in treating type 3, and the severe form of type 1. As enzyme treatment has been shown to be very safe and effective in Gaucher disease, and bone marrow transplantation is associated with possible risk of early death and serious, chronic complications (for example, graft-versus-host disease) this form of treatment is no longer recommended for Gaucher disease.

There are no reports of bone marrow transplantation being used to treat type 2. As damage to the nervous system is believed to take place at the foetal stage, and the children who receive a diagnosis already show severe neurological symptoms, improvement cannot be expected from this form of treatment.

Surgical procedures to correct abnormalities of the hips and back (kyphosis and scoliosis) may be appropriate.

Removal of the spleen (splenectomy) should be avoided. If essential, only part of the spleen should be removed.

Certain forms of medication to counteract osteoporosis are being tried in attempts to prevent skeletal complications.

Mild chewing and swallowing problems can sometimes occur in type 3, and children with type 2 often have difficulties in sucking and swallowing. Feeding and swallowing difficulties can be so serious that it becomes necessary to make an opening in the abdominal wall, with a feeding tube opening directly into the stomach (percutaneous endoscopic gastrostomy - PEG) through which all essential nutrients can be given in the form of solutions.

In severe forms presenting in childhood, early habilitation is necessary. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. Measures may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. Habilitation services may also provide information on support offered by the local authority, and advice on adapting accommodation and other environments. The family may also need help in coordinating different forms of assistance.

Habilitation focuses on existing needs, may vary over time and should occur in collaboration with individuals close to the child.

Parents may require psychological support when the diagnosis is made, and afterwards. Children and young people should also be offered continuous support according to their age and maturity.

There should be close contact with the local authority, which can offer different kinds of help including personal assistance, a contact family or short-term accommodation, to make daily life easier.

Before treatment was developed lifespans were short, but if enzyme treatment is started in time many adults with mild to moderate type 1, or mild type 3, live a relatively normal life. Adults with severe type 3, even with treatment, develop increased neurological disabilites and require continued habilitation.

Practical advice


National and regional resources in Sweden

Gaucher Centre North is a clinic for children and young people at Umeå University Hospital in Norrland, Sweden.

At the Stockholm Gaucher Center at Karolinska University Hospital in Stockholm there is a network of specialists working with children and adults with the disease. www.gauchercenter.org. Contact Senior Physician Maciej Machaczka. See under “Resource personnel.”

Another network of specialists for children and adults with Gaucher disease is located at Skåne University Hospital in Lund, Sweden. Contact Associate Professor Johan Richter. See under “Resource personnel.”

The Laboratory for Clinical Chemisty and Neurochemistry, Department of Neurochemistry, Sahlgrenska University Hospital/Mölndal, and the Centre for Inherited Metabolic Diseases, (CMMS), Karolinska University Hospital, Solna in Stockholm, Sweden, carry out enzyme diagnosis and glucosylceramide analysis of plasma and red blood cells (to follow up enzyme replacement treatment). They also investigate the most common types of mutations using DNA analysis.

The Department of Clinical Genetics, Umeå University Hospital in Norrland, Sweden, has expertise in the Norrbottnian mutation, L444P (c.1448T>C).

Resource personnel

Senior Physician Isa Lundström, Paediatric Clinic, Umeå University Hospital, SE- 901 85 Umeå, Sweden. Tel: +46 90 785 00 00, fax: +46 90 785 17 17, email: isa.lundstrom@vll.se.

Senior Physician Maciej Machaczka, Stockholm Gaucher Center and Haematology Centre Karolinska, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 826 63, fax: +46 8 585 825 25, email: maciej.machaczka@karolinska.se.

Professor Jan-Eric Månsson, The Laboratory for Clinical Chemistryand Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden. Tel: +46 31 343 24 07, fax: +46 31 343 24 26, email: jan-eric.mansson@vgregion.se.

Acting Senior Physician Domniki Papadopoulou, Paediatric Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00, email: domniki.papadopoulou@skane.se.

Associate Professor Johan Richter, Haematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 046 17 10 00.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations etc.

Morbus Gaucher Association in Sweden, Chairperson Lars Magnusson, Akvilejagången 29, SE-507 52 Borås, Sweden. Tel: +46 705 15 84 33, email: lars.em.magnusson@tele2.se
Vice chairperson Bo Johansson, email: bo.johansson@ltu.se, www.morbusgaucher.se. The association sends out information to members four or five times a year, and holds an annual meeting. The association coordinates direct contacts between members.

Rare Diseases Sweden, Box 1386, SE-172 27, Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a federation of rare disease organizations, serving the interests of people with rare disorders and various disabilities.

There is a British Gaucher Association, www.gaucher.org.uk.
Here information is available on diagnosis and treatment, as well as news and links to patient associations in other countries.

Courses, exchanges of experience for personnel


Research and Development

In several places in the world, work is under way to develop small molecules to act as pharmacological chaperones. These small molecules bind to the defective enzyme glucosylceramidase, and help transport it to the lysosomes. It is hoped that these small molecules will facilitate treatment of neurological symptoms.

Many studies are under way to find suitable substances which can relate to the mutations causing Gaucher disease.

Skåne University Hospital/Lund is working on the development of an appropriate form of gene therapy. Experiments are under way on mice.


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Database references

OMIM (Online Mendelian Inheritance in Man)
Search: gaucher disease, type I, gaucher disease, type II, gaucher disease, type III.

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: gaucher disease

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Anders Eriksson, Norrland University Hospital, Umeå, Sweden.

The material has been revised by Senior Physician Isa Lundström, Norrland University Hospital, Umeå, Senior Physician Maciej Machaczka, Karolinska University Hospital, Huddinge in Stockholm, and Acting Senior Physician Domniki Papadopoulou, Skåne University Hospital in Lund.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2012-11-28
Version: 1.2
Publication date of the Swedish version: 2012-03-07

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


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