What is gaucher disease?

Gaucher (go-SHAY) disease is a genetic disorder which causes the buildup of fatty acids around organs. The GBA1 gene encodes the enzyme glucocerebrosidase (GCase) which normally breaks down fatty acids. In Gaucher disease, the GBA1 gene is mutated (changed) which causes a deficiency in glucocerebrosidase so it is no longer able to break down fatty acids. Gaucher cells (cells full of fatty acids) accumulate and cause organs to enlarge in particular the spleen and liver. It may cause a swollen abdomen due to the enlargement of organs, bones may weaken, and there may be bleeding and bruising. Worldwide, Gaucher disease is quite a rare disease, with approximately 125,000 total individuals affected. It is most common amongst people of Eastern and Central European Jewish (Ashkenazi) descent. 1 in 450 people within this population are affected and 1 in 10 carry the mutated (changed) gene. 

Types of gaucher disease 

• Type 1: This is the only type which does not affect the nervous system therefore individuals often have the best prognosis. For this reason, it is the only type where fertility can be assessed 
• Type 2 and 3: These types affect the nervous system and present symptoms early in life. Without treatment, children rarely make it to adulthood

Type 1 symptoms and treatment

People with type 1 Gaucher disease may experience the following symptoms:

• Painful swollen abdomen 
• Loss or lack of appetite 
• Bleeding problems - nosebleeds, gum bleeding, excessive bleeding after pregnancy or internal bleeding 
• Bone problems - severe bone pain and prone to breaks 
• Anaemia 
• Fatigue 
• Shortness of breath
• Delayed puberty 

Some individuals with type 1 may experience no symptoms and live normal lives whilst in others the condition can be debilitating. In addition, symptoms can begin at any age and sometimes in women only begin to present during pregnancy.¹ 

Treatment for type 1 Gaucher disease can be classified into two broad classes:

• Enzyme therapy (e.g. imiglucerase, velaglucerase alfa and taliglucerase alfa)
• Substrate reduction therapy (e.g. eliglustat, miglustat) 

Enzyme therapy is given intravenously (injection) to replace the enzyme glucocerebrosidase to break down fatty acids and prevent the build-up of Gaucher cells. Whereas substrate reduction therapy is an oral medication, which slows the synthesis of fatty acids to reduce the accumulation and quantity of glucocerebrosidase.²

Female fertility 

Reproductive health in adolescents

Two-thirds of people assigned female at birth (AFAB) with Gaucher disease will experience delayed puberty.⁴ This is more common if symptoms are severe. Although most will experience a delay in puberty, individuals typically reach sexual maturity and all secondary sex characteristics (e.g. development of breasts, growth of pubic hair, widening of hips etc) will develop as normal.⁵

Another common issue is 73% of people AFAB Gaucher patients have heavy menstrual bleeding (known as menorrhagia). Unlike the late onset of puberty, it is not related to the severity of the presentation of the disease, but rather thrombocytopenia - which is the altered function of platelets. This is particularly prevalent in the Ashkenazi Jewish population.⁶ However, the duration of menstruation is normal. Heavy menstrual bleeding exacerbates anaemia, so iron supplementation or oral contraceptives may be prescribed. 

Fertility 

Historically it was thought that Gaucher disease decreases the fertility of women, because fatty acid storage abnormalities may disrupt ovarian processes. It was initially thought this may lead to a decline in oocytes (immature eggs). However, more recent evidence shows that Gaucher disease has no impact on fertility, and people assigned female at birth should have no more difficulty conceiving than the general population.^3,4 

Many people with AFAB with Gaucher disease suffer severe anaemia therefore taking folic acid supplements when trying to conceive and during the first 12 weeks of pregnancy is useful. Folic acid is not only thought to increase fertility but can support foetal brain development, protecting from neural tube defects. Folic acid might be considered more important for people AFAB with Gaucher disease since they naturally have low numbers of red blood cells. 

Contraception

Reproductive planning is an increasingly common concern in women with Gaucher disease.

In most cases, the use of contraception has no contraindications. However, there are a few exceptions so it is important to provide a comprehensive medical history and mention any concerns to your physician.⁵ Oral contraceptives are acceptable to use unless you have developed coexisting liver disease with Gaucher disease.³ In addition IUDs are not recommended for use if you have a history of heavy menstrual bleeding, which as previously mentioned is common in Gaucher disease.⁵

 On the other hand, contraception should always be used if you are using substrate reduction therapy since it is toxic to the foetus leading to the end of pregnancy.⁷ If you are planning a pregnancy it is recommended to stop substrate reduction therapy 3 months before conception. Enzyme therapy is safe to use as an alternative during pregnancy. Moreover, there is no evidence that using enzyme therapy has any negative impact on fertility. 

Pregnancy 

Although Gaucher disease does not affect an individual’s ability to conceive, it increases the chance of miscarriage and termination during pregnancy.³ This is because pregnancy is more risky amongst women with Gaucher disease. They are at high risk of bone damage and bleeding during pregnancy as well as postpartum bleeding. For this reason, if you are planning a pregnancy, or become pregnant, you should consult your healthcare provider for support and advice. 

They will normally recommend:

• Genetic counselling - if you or your partner have Gaucher disease or are carriers (have one copy of GBA1 gene) there is a chance your child will have Gaucher disease. If you both have the gene, your child will develop Gaucher disease
• Health assessment 
• Medication review⁵

Where possible, you should attend a Gaucher disease centre with a specialist team. As people with AFAB are at a high risk of bleeding during labour, it is advised to give birth in a hospital and to stay 24-48 hours in case of unforeseen complications. As with pregnancy, you should not breast/chestfeeding is not advised whilst taking substrate reduction therapies, due to its toxic nature.⁵

Male fertility 

There has been limited research on the effect of Gaucher disease on fertility in people assigned male at birth (AMAB). However, there have not been any reports of higher infertility in people with AMAB with Gaucher disease than in the general population. 

In clinical trials, the use of substrate reduction therapies such as eliglustat and miglustat was found to have no effect on the production of sperm and fertility.8  Similarly, substrate reduction therapies were found not to affect fertility, with people AMAB able to produce healthy infants. However there is no research into the long-term effects on offspring following substrate reduction therapy use in people with AMAB, so it should be used with caution.⁷ Therefore, safe alternatives may be recommended, but this should be discussed with healthcare professionals.

Summary

Gaucher disease, in particular, type 1 poses significant reproductive challenges that differ in people assigned female or male at birth. Whilst fertility in people assigned female at birth is unaffected, delayed puberty and heavy menstrual bleeding present unique challenges to contraception and pregnancy. Pregnancy carries an increased risk of bleeding and bone problems, with a greater risk of miscarriages and termination, necessitating careful management and planning. The fertility of people assigned male at birth is less well researched, but hormonal function and fertility seem to be unaffected by Gaucher disease.