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Ashley M. Hardy

Dr. Jessica Monroe

NUTR 750: Nutritional Biochemistry

14 November 2016

Gaucher Disease & Implications of β-Glucocerebrosidase Enzyme Deficiency

Gaucher disease (GD) is a genetic lysosomal storage disorder that impairs glycolipid

metabolism (1-5). The disorder is caused by a mutation in the GBA gene on chromosome 1, which

codes for the lysosomal enzyme, β-glucocerebrosidase, resulting in enzyme deficiency (1,2).

Glucocerebrosidase is responsible for the breakdown of glucocerebroside in an intermediate step

of complex lipid metabolism (3). During this step, glucose is separated from ceramide through

hydrolytic cleavage (3). Without this step in the pathway, glucocerebroside concentrations rise to

toxic levels in body cells, which result in adverse health implications that include hematologic

abnormalities, dysfunction and hypertrophy of visceral organs, skeletal disease, growth

retardation, and neurological impairment (4,5).

Glycolipids, also known as glycosphingolipids, are composed of two parts: a carbohydrate

moiety and a ceramide molecule made up of sphingosine and a long-chain fatty acid (3).

Glycosphingolipid function is determined by the type of monosaccharide bound to ceramide (3).

Glucocerebroside is characterized as a neutral glycosphingolipid containing glucose as its

carbohydrate component (3). Like all cerebrosides, glucocerebroside concentrates in neural tissue,

particularly in the myelin sheath (3). Its role is to interact with the outside environment by binding

to cell surfaces and to facilitate extracellular activity (3). Glucocerebroside also plays a role in

antigenic interactions and immune response (3). Because glycolipids are so important, any

alteration to the metabolism to these molecules can have a great impact on the body (3).
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In the degradation process, glucocerebroside is engulfed by phagocytic macrophages

through the process of endocytosis (3). This process forms a vesicle that then binds to the cells

lysosome (3). The lysosome releases the enzyme, β-glucocerebrosidase, to degrade the

glucocerebroside vesicle (3). Under normal circumstances, β-glucocerebrosidase will effectively

catalyze the hydrolytic reaction that irreversibly cleaves off glucose from the ceramide complex

by breaking its glycosidic bond (3). Glucocerebroside is the substrate in this reaction, producing

glucose and ceramide when bound to β-glucocerebrosidase (3). These products serve as

intermediates for other metabolic pathways (3). Β-glucocerebrosidase is regulated by substrate

concentration as well as induction and repression that regulate gene transcription (3). High levels

of substrate (glucocerebroside) will increase β-glucocerebrosidase production while low

concentrations will decrease enzyme production (3). In GD, the mutation of the GBA gene inhibits

the production of β-Glucocerebrosidase, thus preventing the glucocerebroside degradation reaction

and causing the buildup of contained glucocerebroside vesicles that become known as Gaucher

cells (3). It is the abnormal accumulation of Gaucher cells in various body tissues that result in

multi-organ damage, causing the associated signs and symptoms that are characteristic of this

disease (5).

Clinical manifestations of GD arise as part of the inflammatory response as the body tries

to clear Gaucher cells from body tissues (5). Macrophages recruit cytokines that initiate the

inflammatory cascade that results in the characteristic symptoms of GD (5). While this process

works to target and destroy excess glucocerebroside, the permanent genetic mutation of the GBA

gene continues to allow more and more Gaucher cells to be created and sustains toxic

glucocerebroside concentrations (5).

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Clinical manifestations of GD range in severity from asymptomatic to neonatal death and

are classified by three subtypes (5). Type 1 makes up over 90% of GD cases and is characterized

by non-neuropathic symptoms and normal-to-near normal life expectancy even without treatment

(5). Type 2 and Type 3 are significantly less prevalent and are seen in less than 1 in every 100,000

cases of GD (5). Type 2 GD is considered an acute neuropathic condition with life expectancy

ranging from neonatal death to up to 2 years (5). Type 3 GD is considered chronic neuropathic and

results in a moderate-to-significant decrease in life expectancy without treatment (5). Because of

the prevalence of Type I GD over Type 2 and 3, many research studies and treatment practices

focus on the former subtype of GD (5).

Characteristic symptoms of GD span multiple body systems, affecting the tissues that are

most susceptible to Gaucher cell accumulation (4). High concentrations of Gaucher cells in the

bone marrow prevent adequate blow flow resulting in circulation and skeletal symptoms (4,5).

Hematologic abnormalities include anemia, leukopenia, and thrombocytopenia (4,5). Bone pain,

fractures, and various skeletal diseases are also common due to poor circulation (4,5). As a result

of inflammation, hypertrophy of organs is seen, particularly in the liver and spleen (4,5).

Hypertrophy may further result in dysfunction of respective organs and increased risk for

associated chronic illnesses (4,5).Medical intervention involves the comprehensive treatment of

these individual symptoms as well as Enzyme Replacement Therapy (ERT) and Substrate

Reduction Therapy (SRT) to directly address the enzyme deficiency (5).

Enzyme therapy is a viable and effective treatment option for patients with Type 1 GD.

ERT was developed in the early 1990's and has become the gold standard treatment option for

individuals with Type 1 GD (5). Β-glucocerebrosidase is delivered to the body intravenously to

increase the degradation rate of glucocerebroside (5). The most common type of ERT is
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Imiglucerase (5), which is a recombinant form of β-glucerebrosidase (4). Clinical research has

shown a significant improvement of GD symptoms with continuous Imiglucerase treatment (4).

One study cross-compared clinical data collected from GD 1 patients at initial infusion and again

at a ten year follow-up to assess improvement with Imiglucerase treatment (4). Results showed

significant improvement of hepatospleenomegaly and hematologic symptoms including anemia

occurrence, platelet count, and hemoglobin levels (4). Patients also reported less bone pain (4). At

the ten year follow-up, most patients on average were receiving <15U/kg-45U/kg of Imiglucerase,

a smaller dosage than at the first infusion, which ranged from <15U/kg - 90U/kg (4). An alternative

treatment option is SRT, which is an oral medication that eliminates glucocerebroside substrate

(5). This treatment may be a viable alternative for GD1 patients who develop an autoimmune

response to ERT in order to eliminate the risk for anaphylactic shock (5). SRT is used exclusively

in adults and is not Food & Drug Administration (FDA) regulated (5). The only treatment option

that is approved by the FDA is ERT for type 1 GD (5).

National morbidity rates show that there are roughly 6,000 GD patients living in the United

States with incidence rates as high as 1 in every 20,000 live births (5). There is a significant

correlation between the occurrence of GD and Ashkenazi Jewish decent, making GD the most

devastating in-born error of metabolism among this population (2,5). Incidence rates among this

group are roughly 1 in every 450 live births (5) and an estimated 6% of the Ashkenazi population

are carriers of the disease (2). A retrospective analysis found that incidence and carrier rates may

be higher than this number when geographic region of origin is taken into account, suggesting that

further research is needed (2). Ashkenazi Judaism is prominent in the European countries of

Poland, Hungary, Romania, Moldavia, Czech Republic, Germany, Austria, Belarus, the Baltic sea

islands, Ukraine, as well as some areas of Russia (2). Traditionally, studies have viewed the
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Ashkenazi population as an isolated cohort due to historic religious isolation (2). Because the gene

coding for β-glucocerebrosidase is recessive, an individual will inherit the gene mutation if both

parents are carriers (2). Due to the genetic similarity of individuals from a similar ethnicity, culture,

or cohort, such as the Ashkenazi Jews, the frequency of two carrier parents is much higher, thus

the incidence of gene mutation and disease prevalence is greater (2). Genetic testing and

counseling is available at clinics for individuals and populations most affected by the disease (2).

Gaucher disease is an inherited lysosomal storage disorder that directly impairs the

breakdown of glucerebroside in glycolipid metabolism. This disease is caused by a genetic

mutation of the GBA gene, resulting in the deficiency of β-glucocerebrosidase, a crucial enzyme

needed to activate the glycolipid pathway. The accumulation of glucerebroside cells, known as

Gaucher cells, adversely affects several body organs, causing hematologic symptoms, growth

retardation, and inflammation and dysfunction of the bone marrow, spleen, and liver. Viable

treatment options and support are available for patients, especially in populations where the disease

is most prevalent, such as the Ashkenazi Jewish community. Further research is needed to fully

understand this metabolic disorder in order to develop more effective treatment options for all

populations.
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References

1. Murphy KE, Gysbers AM, Abbott SK, Tayebi N, Kim WS, Sirdranky E, Cooper A, Garner

B, Halliday GM. Reduced glucocerebrosidase is associated with increased α-synuclein in

sporadic Parkinson's disease. Brain 2014 Mar;137(3):834-48.

2. Bronstein S, Karparti M, Peleq L. An update of Gaucher mutations distribution in the

Ashkenazi Jewish population: prevalence and country of origin in the mutation of R496H.

Isr Med Assoc J 2014 Nov;16(11):683-685.

3. Harvey R, Ferrier D. Lippincott's illustrated reviews: biochemistry. 5th ed. Baltimore:

Lippincott Williams & Wilkins, 2011.

4. Weinreb NJ, Goldblatt J, Villalobos J, et al. Long-term clinical outcomes in type 1 Gaucher

disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 2013;36(3):543-

553.

5. Van Rossum A, Holsopple M. Enzyme replacement or substrate reduction? A review of

Gaucher disease treatment options. Hosp Pharm 2016 Jul;51(7):553-563.