Featured rare disease

On this page, we highlight one of the many rare diseases. We feature a new rare disease periodically; in this way we can raise awareness and understanding of rare diseases one disease at a time, raising people’s awareness not only that the disease exists but what it is and how to recognise it. If you have been diagnosed with one of the diseases highlighted and would like to share a story about your journey please contact us at enquiries@nzord.org.nz and we can arrange to put it up on our website.

Gaucher disease

What is Gaucher disease?

Gaucher disease, pronounced go-SHAY, is an inherited disease, and people with this condition lack sufficient activity levels of an enzyme called glucocerebrosidase. This enzyme normally helps the body break down worn-out cells and if there is not enough enzyme available then a fatty substance called glucocerebroside accumulates in the spleen, liver, bone marrow and sometimes in the central nervous system. It’s a bit like a recycling or waste disposal system becoming clogged with a fatty residue and not having any detergent to remove it, therefore it causes blockages. These blockages led to a range of symptoms depending on the organ and level of blockage.

Lysosome cells are the body’s recycling centres, breaking down chemicals for reuse in the body or for disposal. A key role of lysosomes is to recycle proteins, which the body uses in many critical processes. There are many different types of disease that affect our lysosomal system but Gaucher disease (GD) is the most common. In GD the lysosomes become heavily laden with fatty deposit and as a result dysfunctional.

Normal cell

Symptoms and types of GD

GD is categorized into three clinical types. The disease involves the visceral organs, bone marrow, and bone in almost all people. Type 1 (GD1) is the most common and the swollen GD cells mainly affect the spleen and liver and can cause swelling around this area. It is known as non-neuronopathic GD as the brain and spinal cord (central nervous system) are not normally affected. The features of type 1 range in severity and may include low number of red blood cells (anaemia), easy bruising caused by a decrease in platelets (thrombocytopenia), lung disease and bone abnormalities such as bone fractures, bone pain and arthritis.

Type 2 and 3 GD are known as neuronopathic forms as they cause problems with the central nervous system; this may include abnormal eye movements, seizures and brain damage. Type 2 in infancy can sometimes lead to severe and life-threatening issues. In fact, many babies with Gaucher disease type 2 do not live long enough to develop some of the symptoms found in Gaucher disease type 1 or type 3. Signs of Gaucher disease type 3 usually begin a little later (before age 2) and progress more slowly than type 2. The most severe form of GD is called the perinatal lethal form, this starts before birth or in infancy and can include extensive swelling, dry, scaly skin, swollen liver and spleen (hepatospenomegaly), distinctive facial features and serious neurological problems. Many babies survive for only a few days. Another form affects the heart and can lead to the heart valves hardening.

Prevalence and screening

GD is more common among Jews of Ashkenazi (Eastern European) descent, occurring in approximately 1 in 450 within this population. In the general population Gaucher affects 1 in 40,000 people. There may be some people who are unaware carriers of the disease – people who do not have the disease but can pass the Gaucher gene to their children. This can become evident following diagnosis of a child with GD and then genetic screening with the family can identify carriers. If you have symptoms of GD or the disease runs in your family testing is very important (1).

Diagnosis and testing

As GD is not included in the heel prick test for newborns in New Zealand, any diagnosis will occur due to obvious symptoms. Many physicians are unfamiliar with GD and awareness raising is a very important factor for earlier diagnosis and treatment. A paediatrician may notice an enlarged spleen, bleeding problems and low platelets without considering GD. Many patients undergo invasive bone marrow testing before receiving a diagnosis as doctors try to rule out leukaemia and blood cancers. Physicians rely primarily on a blood test called a beta-glucosidase leukocyte test for enzyme activity, this is because all patients with GD will have low enzyme activity levels. Physicians also use genetic testing to identify specific mutations associated with GD.

Genetic testing for Gaucher disease

Mutations in the GBA gene cause Gaucher disease. The GBA gene provides the instructions for making the enzyme beta-glucocerebrosidase. The mutations greatly reduce or eliminate the activity and function of the enzyme. Carriers may occasionally have borderline low enzyme levels, requiring genetic testing to clarify whether the person actually has GD. Genetic testing can identify a patient’s specific genetic mutations, with just one mutation indicating carrier status. If you are a carrier, it means you do not have GD or symptoms, but you can pass the Gaucher gene to your children. There are more than 400 genetic mutations known to cause GD. However, 4 genetic mutations account for roughly 95 percent of cases in the Ashkenazi Jewish population and 50 percent of cases in the general population.

Treatment and management: A treatable disorder

Treating GD is tailored to the individual and aims to minimise symptoms and permanent damage to your body. An additional goal in treatment in children is optimisation of growth. Each patient should undergo a comprehensive initial assessment of all potentially affected organ systems since there is significant variability in the manifestations, severity and progression of the disease that will affect the treatment options (uptodate.com). There are two types of GD treatments currently available: enzyme replacement therapy (ERT); and substrate reduction therapy (SRT).

Enzyme replacement therapy (ERT) balances low levels of glucocerebrosidase enzyme with a modified version of the normal human enzyme. This allows your body to break down glucocerebroside, the fatty chemical that builds up in organs and bone marrow. Clinical trials for ERT in the 1980s used human placenta and since then a recombinant preparation is available which includes imiglucerase, velaglucerase alfa or taliglucerase alpha (not approved for use in European Union). Imiglucerase is produced by recombinant DNA technology in a Chinese hamster ovary cell system, Velaglucerase alfa by gene activation technology in a human cell line and taliglucerase alpha by a novel plant cell-based protein expression system. Treatment is continued throughout the patient’s life and treating children may prevent complications that occur later in life, particularly skeletal abnormalities. Guidelines for the use of ERT for neuronopathic GD are less clear as it does not cross the blood-brain barrier and cannot impact the central nervous system well. However other somatic effects of GD respond to ERT, this includes things such as spleen and liver swelling, blood and bone structure issues (uptodate.com).

PHARMAC offer funded ERT for the treatment of GD and have recently changed from imiglucerase (Cerezyme), supplied by Sanofi, to taliglucerase alfa (Elelyso), supplied by Pfizer (2).

The fact that ERT has a high cost and lifelong dependence is the reason why additional therapeutic approaches are being investigated: some examples include: substrate reduction therapy (SRT); chaperone therapy; gene enhancement and gene therapy (3).

Substrate reduction therapy (SRT) aims to prevent storage not by correcting the original defective enzyme but by decreasing the levels of synthesis of the accumulating glycolipid- glucocerebroside. SRT is available as an oral medication (eliglustat), which many patients find more convenient than ERT infusions. Some studies have shown that combination therapy with both ERT and SRT can be useful and one paper details how SRT can be used as maintenance therapy for some patients after stabilization on ERT (4).

Gene therapy

Some recent research has offered exciting potentials for future therapy for GD. A recent study evidenced how prenatal delivery of a gene therapy restored the production of glucocerebrosidase — the deficient enzyme in Gaucher disease — prevented nerve cell death, and prolonged survival in a mouse model of GD type 2 (5).

Given the promising results shown in mice, a team from Singapore performed the test in non-human primates at the early stages of pregnancy. This is when a clinical diagnosis of genetic conditions can be made, and when the immune system is more responsive to gene therapy. The team showed that the delivery of viral vectors through foetal gene transfer to the developing brain is feasible using an established clinical approach that resulted in the distribution of the transgene to the developing brain (6).

Supportive care

Supportive care measures are needed to manage bone disease, bleeding tendency and other associated conditions (Parkinsonism). This also includes the psychosocial aspects that any person with a chronic disease will face (anger, fear, insecurity, isolation), and support for expressing and dealing with these emotions must be factored into care. Other treatments include:

  • Blood transfusions for severe anaemia and bleeding
  • Prescription drugs for bone pain and osteoporosis
  • Orthopaedic surgery such as joint replacement for painful, damaged joints

References

  1. About Gaucher Disease | National Gaucher Foundation [Internet]. [cited 2018 Sep 11]. Available from: https://www.gaucherdisease.org/about-gaucher-disease/
  2. Decision to widen access and change the funded enzyme replacement therapy for Gaucher disease | PHARMAC [Internet]. [cited 2018 Sep 11]. Available from: https://www.pharmac.govt.nz/news/notification-2018-07-06-gaucher-treatment/
  3. Coutinho MF, Santos JI, Alves S. Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders. Int J Mol Sci [Internet]. 2016 Jul 4 [cited 2018 Sep 11];17(7). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964441/
  4. Figueiredo M. Some GD Type 1 Patients May Benefit from ERT-SRT Therapy Combo, Case Report Shows [Internet]. Gaucher Disease News. 2018 [cited 2018 Sep 11]. Available from: https://gaucherdiseasenews.com/2018/02/01/some-gaucher-disease-type-1-patients-may-benefit-from-temporary-ert-srt-combination-therapy/
  5. Gaucher Type 2 May Be Preventable with Prenatal Gene Therapy, Study Says [Internet]. Gaucher Disease News. 2018 [cited 2018 Sep 11]. Available from: https://gaucherdiseasenews.com/2018/08/02/prenatal-gene-therapy-may-prevent-gaucher-disease-type-2/
  6. Fetal gene therapy prevents fatal neurodegenerative disease [Internet]. [cited 2018 Sep 11]. Available from: https://medicalxpress.com/news/2018-07-fetal-gene-therapy-fatal-neurodegenerative.html

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