# Handbook of Genetic Counseling/Gaucher Disease-2

Gaucher Disease

## Introduction

* Discuss the reason for referral.
* Elicit prior knowledge about Gaucher Disease.
* Assess concerns and set goals for the session.
* Provide overview of topics for counseling session.

## What is Gaucher Disease?

* The most common lipid-storage disorder and the most common genetic disease affecting Jewish people of Eastern European ancestry.
* Gaucher disease results from a specific enzyme deficiency in the body caused by a genetic mutation received from both parents.
* The disease course if variable, ranging from no outward symptoms to server disability and death. Symptoms can appear at any time from infancy to old age.
* Testing is available to identify potential parents who are carriers of the gene and to accurately diagnose people who have the disease.
* There are three types of Gaucher disease, and enzyme replacement therapy is available for one type.

## Etiology and incidence

* History
** Gaucher disease was first described in 1882.
** In 1934, the fatty compound, glucocerebroside was isolated from the spleens of affected individuals.
** In 1965, it was demonstrated that glucocerebroside accumulated because of a deficiency of the enzyme glucocerebrosidase.
* The basis of Gaucher disease
** Cells called macrophages act in humans to remove old cells by degrading and recycling them.
** The old cells are degraded inside cell compartments called lysosomes.
** Glucocerebrosidase is located inside the lysosomes and breaks down glucocerebroside into glucose and ceramide.
** In people with Gaucher disease, glucocereroside remains stored in the lysosomes because people lack the functional enzyme.
** Enlarged macrophages with undigested glucocerebroside are called Gaucher cells.
** Gaucher cells most often accumulate in the spleen, liver, and bone marrow.
** They may also accumulate in the lymphatic system, lungs, skin, eyes, kidney, heart, and nervous system.
** An organ that contains Gaucher cells becomes enlarged and does not function properly.
* Affected organs
** When Gaucher cells accumulate in the spleen, it becomes enlarged and overactive.
*** The spleen breaks down red blood cells more rapidly than they can be produced and a deficiency develops resulting in anemia.
*** A deficiency of white blood cells or platelets can also occur.
** The liver may also become enlarged and function abnormally.
*** The effects of abnormal liver function are usually minor.
*** Some people may develop cirrhosis.
** Concentrated Gaucher cells reduce normal bone marrow function.
*** Gaucher cells can interfere with the production of blood cells.
*** Bones may be thinner or weaker than normal, or they may be deformed.
*** They may become brittle and fracture more easily.
*** If bone fractures occur in the spinal column, they are called compression fractures and can cause nerve damage.
*** "Bone crises" can occur when there is a sudden lack of oxygen in an area where Gaucher cells have interfered with normal blood flow.
*** Blood flow restriction can also result in the destruction of bone tissue (called aseptic necrosis) which leads to permanent mobility problems
* Incidence
** Type 1
*** Approximately 1 in 40,000 people in the general population are affected
*** In Jews of Ashkenazi descent the incidence ranges from 1 in 400 to 1 in 600 people.
*** Approximately 1 in 10 people in the Ashkenazi population are carriers.
** Type 2 and 3
*** Approximately 1 in 100,000 people
*** Does not appear to be concentrated within any particular ethnic group
*** A number of cases with Type 3 symptoms have been reported in Scandinavia, particularly Sweden.

## Clinical Features & Natural History

* Variability
** Timing and severity of symptoms vary greatly.
** In general, the later in life the first symptoms appear, the less likely that the disease will be severe.
** The course of the disease varies upon classification into one of the three types.
* Type 1 Gaucher disease
** The most common type
** Formerly called adult Gaucher disease
** Individuals of all ages can be affected
** May be referred to as "non-neuronopathic Gaucher disease"
** Symptoms vary greatly in severity and include:
*** Generalized fatigue with lack of energy and stamina
*** Abdomen
**** Enlarged spleen and liver
**** Pain
**** Compression of the lungs causing decreased ability to provide oxygen to the blood
*** Skeletal system
**** Growth retardation in children
**** Pain and degeneration of joints and tissue that covers bones
**** Loss of bone density that leads to widening of bones along the knee joint, curvature of the bones, or spontaneous fractures
**** Acute bone infarctions known as "bone crises"
**** Bone necrosis
**** X-rays often reveal a characteristic deformity called the "Erlenmeyer flask deformity" in the thigh bones
*** Disruption of normal kidney function
*** Skin
**** Yellow-brown pigmentation
**** Non-raised, round, purplish-red spots, especially around the eyes
*** Blood
**** Increased bleeding tendency such as nosebleeds and bruising
**** Anemia, thrombocytopenia, and neutropenia
**** Elevated levels of acid phosphatase and plasma proteins
*** Loss of appetite and intestinal complaints
* Type 2 Gaucher disease
** Characterized by severe neurological involvement in the first year of life.
** Rapidly progresses and affects the brain as well as the organs that affect Type 1 Gaucher disease
** Formerly called infantile Gaucher disease
** Also called "acute neuronopathic Gaucher disease"
** Affected child usually does not live past the age of 2 due to nervous system involvement.
* Type 3 Gaucher disease
** Formerly called juvenile Gaucher disease
** Characterized by a slowly progressive neurologic disease
** Signs and symptoms often appear in early childhood.
** Symptoms resemble Type 1 but there is nervous system involvement like Type 2.
** Affected individuals who reach adolescence may survive into the 3rd or 4th decade of life.

## Inheritance

* Autosomal recessive
** Chromosome location of the glucocerebrosidase gene is 1q21
** If one parent is a carrier and the other is not, there is a 50% chance of carrier child.
** If both parents are carriers, there is a 25% chance with each pregnancy of having an affected child. There is a 50% chance of having a carrier child, and a 25% chance of having a non-affected, non-carrier child.
** If one parent is affected and the other is not affected nor is a carrier, all children will be carriers but will not be affected.
** If one parent is affected and the other is a carrier, there is a 50% chance of having an affected child and a 50% chance of having a carrier child.
** If both parents are affected, all children will be affected.

## Diagnosis

* Indications for Gaucher disease:
** Gaucher disease is suspected in individuals with characteristic bone involvement, visceral and hematologic changes, or CNS involvement.
*** Clinical findings alone are NOT diagnostic.
** Bone marrow examination may reveal Gaucher cells, but this is not a reliable diagnostic test.
* Definite Diagnosis
** Diagnosis is made by the demonstration of deficient glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells.
*** In affected individuals, enzyme activity in peripheral blood leukocytes is 0-15% or normal activity.
*** This method is unreliable for carrier testing due to overlap in enzyme activity between carriers and non-carriers.
** Mutational analysis of the glucocerebrosidase gene is available in clinical laboratories for the 4 most common gene mutations.
*** N370S, L444P, 84GG, IVS2+1
*** These 4 alleles account for 90% of the disease-causing alleles in the Jewish population and 50-60% in the non-Jewish population.
*** More than 150 gene mutations have been described
*** Abnormal alleles include exonic missense and nonsense mutations, splice junction mutations, deletions and insertions, and complex alleles resulting from gene conversion or recombination.
*** Mutations often result in mRNA instability, and/or a severely truncation protein, or an enzyme with altered activity and/or conformation.
** Molecular testing can identify carriers in famililis in which the disease-causing mutations are known.

## Differential Diagnosis

* No other phenotypes have been associated with mutations in the glucocerebrosidase gene.
* At symptom presentation, it may be necessary to rule out leukemia and arthritis.
* Saposin C deficiency or prosaposin deficiency
** Saposin C is a co-factor for glucocerebrosidase in the hydrolysis of glucosylceramide
* Hepatosplenomegaly is observed in Niemann-Pick disease, Wolman disease, the mucopolysaccharidoses, and the oligosaccharidoses

## Management and Treatment Options

* Management issues
** A comprehensive baseline evaluation and serial monitoring should be done to evaluate severity and rate of disease progression.
** Symptomatic treatment may be necessary especially in patients not receiving enzyme therapy
*** Partial or total splenectomy for splenomegaly and persistent thrombocytopenia
*** Transfusion of blood products for anemia and bleeding
*** Analgesics for bone pain
*** Joint replacement surgery for chronic pain or function restoration
** Therapy to reduce glycosyl/ceramide accumulation
*** Bone marrow transplantation (BMT)
**** Primarily for those with neurologic involvement
**** Engraftment can correct metabolic defect, improve blood counts, and reduce increased liver volume
**** Morbidity and mortality associated with BMT limits its use in type 1 and type 3 Gaucher disease
*** Enzyme replacement therapy (ERT)
**** Imiglucerase or Cerezyme is a recombinant glucocerebrosidase enzyme preparation based on the human gene sequence.
**** Cerezyme is modified to expose the alpha-mannosyl (carbohydrate) residues for enhanced uptake by the macrophage.
**** Regular intravenous infusions have been demonstrated to be safe and effective in reversing the features from hematologic and visceral involvement
**** Patients with type 1 Gaucher report improved health-related quality of life after 24-48 months of ERT
**** The effectiveness of ERT for bone and neurological disease remains to be established.
**** Treatment is usually initiated with a dose of 20-60 units per kg of body weight every 2 weeks.
**** 10-15% of patients develop antibodies to the infused enzyme, although in most cases these patients remain asymptomatic. Patients who show adverse effects such as pruritus and hives can be treated with antihistamines as a premedication.
*** Substrate synthesis inhibitors (SSI)
**** SSI is under clinical investigation.
**** Relies on limiting the production of substrate and on the clearance of accumulated lipids by the residual enzyme activity.
**** A potential concern is its non-specificity
**** Combination therapy with SSI and ERT may be possible
*** Gene therapy
**** Involves the introduction of the glucocerebrosidase gene into hematopoietic stem cells.
**** Gene therapy is currently under investigation.

## Psychosocial Issues

* Uncertainty because symptoms and severity vary widely
** Uncertainly may make goal-setting and future planning problematic
* Feelings of isolation, loneliness, and despair.
* Frustration due to ignorance about the disease.
* Coping with chronic pain and fatigue
* Burden of dealing with a chronic, rare, progressive disease
* Body image and self-esteem issues due to spleen or liver enlargement or growth retardation
* Guilt about passing on the gene to one's children.
* Family dynamic changes
** Stress in the marriage
** Sibling relationships
** Family members may feel guilty or resentful
* Depression and frustration about the requirement for lifelong management.
* Shock, fear, and denial over the diagnosis.

## Offer Resources

* National Gaucher Foundation (NGF)
** Contains many links to other useful websites
** 800-925-8885
** www.gaucherdisease.org
* Living with Gaucher Disease
** A brochure from Genzyme Corporation
* Children's Gaucher Research Fund
** www.childrensgaucher.org
* National Foundation for Jewish Genetic Diseases
** 212-371-1030
** www.nfjgd.org

## References

* National Organization for Rare Disorders
* Online Mendelian Inheritance in Man
* Geneclinics GeneReviews
* Living with Gaucher Disease: A guide for patients, parents, relatives, and friends
** Brochure copyright 1991, Genzyme Corporation
* Charrow, J. et al. "Gaucher Disease: Recommendations on Diagnosis, Evaluation, and Monitoring." Archives of Internal Medicine; vol 158, p 1754, September 14, 1998.

## Notes

The information in this outline was last updated in 2002.