Austin McLean

Disease Analysis Outline

Introduction:

➢ The glucocerebrosidase (GBA) gene encodes for the lysosomal enzyme responsible for

cleaving the beta-glucocidic linkage in glucosylceramide .

➢ A mutation in the GBA gene leads to a deficiency in this lysosomal enzyme, creating an

accumulation of glucocerebrosides and causing Gaucher’s disease (Sidransky & Lopez,

2012).

➢ This mutation is a shared risk factor for Parkinson’s disease and many other similar

diseases involving the nervous system.

➢ Diseases involving the nervous system are often multifactorial and there is much

unknown about them. (Sidransky & Lopez, 2012).

➢ A better understanding of mutations in the glucocerebrosidase (GBA) gene may be

useful in developing treatments for neurological diseases such as Parkinson’s disease.

Description of the diseases:

Parkinson’s Disease (PD)

➢ Parkinson’s disease is a progressive neurodegenerative disorder that is associated with

uncontrollable tremors of the body and stiffness in limbs.

➢ The symptoms of Parkinson's disease are a result of the loss of brain cells that produce

dopamine.

➢ Those over the age of 70 with PD will often develop dementia.

➢ Parkinson’s disease is an autosomal recessive disorder when inherited. Two copies of the

mutated gene (one from each parent) are required for expression of the disease in this

fashion.

➢ PD can cause cognitive issues leading to depression and hallucinations.

➢ Mutations in the LRKK2 gene have been identified as the the most common genetic

cause of PD.

➢ Physicians combine observed symptoms with test results to accurately diagnose a person

with PD.

○ Observable symptoms that are effective in indicating that a person may have

Parkinson’s disease.

■ Body tremors

■ Rigidity of limbs and trunk

■ Bradykinesia (slow movement)

■ Impaired coordination

○ Tests that can be done in addition to symptom observations to produce a more

accurate diagnosis.

■ A positron emission tomography (PET) scan is used to analyze the

functionality of cells in the brain.

■ A computer tomography (CT) scan is used to scan the brain for

abnormalities that could indicate that the person has PD.

➢ There are approximately 10 million people around the world that are currently living with

PD
 ○ There are 60,000 Americans diagnosed with PD each year.

○ It is predicted that the number of people living with PD in the US will have

almost reached 1 million by the year 2020.

➢ After 15 years of living with PD, the risk of mortality begins to slightly increase above

that of a person without PD.

➢ PD is treated with medications, such as Levodopa, that cause the body to produce more

dopamine. This helps relieve some of the symptoms PD and can be effective in keeping

the disease in check during the earlier stages of the disease.

Gaucher’s disease:

➢ Gaucher’s disease is an autosomal recessive disorder (requires two copies of mutated

gene) that is associated with lysosomal storage issues caused by a deficiency in

glucocerebrosidase (Sidransky & Lopez, 2012). This causes glucocerebrosides to

accumulate to the point where the amount of glucocerebrosides in the body has reached a

toxic level.

➢ Ashkenazi Jewish population has a higher frequency of Gaucher’s disease than any other

ethnic group, it occurs in 1 in every 500-1,000 people among this specific population.

➢ There are three main types of Gaucher’s disease.

○ Type one

■ Type one is the most is non neuropathic, which means that it has no effect

of the central nervous system. It affects various other parts of the body

such as the spleen and liver which become enlarged

 ■ Other symptoms include painful bone abnormalities such as arthritis and

fractures. Those with type one may also develop anemia and lung disease.

■ Type one can be treated through the use of enzyme replacement therapy.

○ Type two

■ Type two is a much less common than type one. Unlike type one, type two

affects the central nervous system.

■ Type two has all of the same symptoms as type one, but with the addition

of neurological deterioration. The neurological deterioration progresses

rapidly and death usually occurs within a year of diagnosis.

■ Enzyme replacement therapy is ineffective in treating the neurological

damage caused by type two.

○ Type three

■ Type three is similar to type two when it comes to non neuropathic, but

when it comes to neurological deterioration, the damage caused by type

three progresses at a slower pace than damage caused by type two.

■ The damage to the nervous system caused by type three cannot be treated

by enzyme replacement therapy

➢ Prenatal screening for Gaucher’s disease is performed through testing of blood and

saliva. This is done in response to the parents having a higher probability of producing

offspring with Gaucher’s disease based on their genetic information.

➢ 1 in every 50,000-100,000 people worldwide will develop Gaucher’s disease

➢ According to studies, the average life expectancy of a person with Gaucher’s disease is

approximately 9 years less than that of the general population.

Issues related to the specific disease:

➢ There is little known about the role that GBA mutation plays in the occurrence of

Parkinson’s disease.

○ Discovering the role of GBA mutations in the manifestation of PD could lead to

the development of treatments and preventative measures for GBA associated PD.

➢ A clinical study was done that found instances of parkinsonism more frequently in

obligate carriers of Gaucher’s and those with full expression of Gaucher’s disease.

➢ Studies show that those with Parkinson’s disease have a higher frequency of GBA

mutations than those without Parkinson’s disease. (Sidransky & Lopez, 2012)

➢ GBA associated Parkinson’s disease tends to have an earlier onset than GBA

nonassociated Parkinson’s disease.

➢ The complexity of Parkinson’s disease makes it difficult to understand every exact

pathway that contributes to the disease.

References:

Sidransky, E., & Lopez, G. (2012). The link between the GBA gene and parkinsonism. The

Lancet Neurology. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141416/

Parkinson disease - Genetics Home Reference - NIH. (n.d.). Retrieved from

https://ghr.nlm.nih.gov/condition/parkinson-disease
Diagnosis. (2019, March 06). Retrieved from https://www.parkinson.org/understanding-

parkinsons/diagnosis