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Gaucher Disease

  • Author: Ellen Sidransky, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Aug 18, 2016
 

Practice Essentials

Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase.

Signs and symptoms

While Gaucher disease manifests with vast clinical heterogeneity, it has traditionally been differentiated into the following three clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:

  • Type 1 - Nonneuronopathic Gaucher disease
  • Type 2 - Acute neuronopathic Gaucher disease
  • Type 3 - Chronic neuronopathic Gaucher disease

Patients with type 1 disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both.

Patients with type 2 disease may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.

In addition to organomegaly and bony involvement, individuals with type 3 disease have neurologic involvement.

See Clinical Presentation for more detail.

Diagnosis

Diagnosis can be confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic. Minor elevations of liver and angiotensin-converting enzyme levels are common. DNA analysis is also being used to establish the presence of two mutant alleles, especially in diagnostic panels.

See Workup for more detail.

Management

Enzyme replacement therapy (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. An oral glucosylceramide inhibitor can be an alternate efficacious therapy.

See Treatment and Medication for more detail.

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Background

Gaucher disease is a lipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of a specific lysosomal hydrolase, glucocerebrosidase (also termed acid beta-glucosidase, glucosylceramidase). The disease is characterized by a continuum of phenotypes. The severity widely varies; some patients present in childhood with virtually all the complications of Gaucher disease, whereas others remain asymptomatic into the eighth decade of life.

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:

  • Type 1 - Nonneuronopathic form
  • Type 2 - Acute neuronopathic form
  • Type 3 - Chronic neuronopathic form

However, some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited.

Autosomal recessive inheritance pattern. Autosomal recessive inheritance pattern.

Type 1 Gaucher disease is more common among individuals of Ashkenazi Jewish descent, although all 3 types are panethnic in their distribution.

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Pathophysiology

Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and, to a lesser extent, from erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpled–tissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.[1]

Glucosylceramide accumulation in the bone marrow, liver, spleen, lungs, and other organs contributes to pancytopenia, massive hepatosplenomegaly, and, at times, diffuse infiltrative pulmonary disease. Progressive infiltration of Gaucher cells in the bone marrow may lead to thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. These bony features may also be related to macrophage-produced cytokines.

Disruption of the ceramide-to-glucosylceramide ratio can affect barrier formation in the epidermal layer of the skin, leading to ichthyosis or a collodion skin presentation in individuals who are severely affected (those with type 2).

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Epidemiology

Frequency

United States

Type 1 Gaucher disease more common among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 per 15 population, whereas the disease frequency is 1 per 855 population. Gaucher disease is rare in the non-Jewish population, with an estimated frequency of 1 per 40,000 population.

International

International disease frequency is similar to that in the United States, except for areas of the world with large Ashkenazi Jewish populations. Most patients worldwide are non-Jewish. As many as 60% of patients of Ashkenazi origin are estimated to be homozygous for the mild N370S mutation, which accounts for 75% of disease alleles in this population. Many individuals with this genotype never seek medical attention, contributing to an underestimation of the disease frequency. Type 3 disease is more common in the Norrbottnian region of Sweden (1 per 50,000 population), which has been traced to a common founder in the 17th century.

Mortality/Morbidity

Mortality and morbidity varies with the different types.[2]

Type 1 Gaucher disease often presents in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease, although striking clinical variability occurs in disease severity.

Type 2 Gaucher disease causes rapidly progressive neurovisceral storage disease and death during infancy or during the first years of life. A subset of this type, associated with congenital ichthyosis and hydrops fetalis, is described as neonatal lethal and results in perinatal or in utero death.

Type 3 Gaucher disease is often a less rapidly progressive neurovisceral storage disease. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood.

Race

All forms of Gaucher disease are panethnic. Type 1 Gaucher disease is the most common lysosomal storage disease and is the most prevalent genetic disorder in individuals of Ashkenazi Jewish descent. Type 3 disease is more common in the Norrbottnian region of Sweden.

Sex

All 3 types of Gaucher disease are inherited as autosomal recessive traits and have an equal sex distribution.

Age

Patients with type 1 Gaucher disease may present in childhood with hepatosplenomegaly, pancytopenia, and crippling skeletal disease. Some patients are not diagnosed until adulthood, when they present with low blood counts or bone involvement, whereas others are diagnosed in the seventh to ninth decades of life after an incidental finding of thrombocytopenia or splenomegaly. Many affected individuals never develop signs or symptoms and do not seek medical attention. Types 2 and 3 Gaucher disease typically present in early childhood. Some subjects with parkinsonism have been found to have Gaucher disease at a later age.

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Contributor Information and Disclosures
Author

Ellen Sidransky, MD Senior Investigator, Chief, Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH

Ellen Sidransky, MD is a member of the following medical societies: American Society of Human Genetics, International Parkinson and Movement Disorder Society, Society for Pediatric Research, Society for Inherited Metabolic Disorders

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

Acknowledgements

The author acknosledges the assistance of Mary E. LaMarca, who co-authored the initial version of this chapter prior to her death in 2010.

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Autosomal recessive inheritance pattern.
 
 
 
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