Abstract
There are multiple autosomal recessive disorders in which carriers may be at risk for other diseases. This observation calls into question the previous understanding that carriers of autosomal recessive disorders escape clinical consequences. We also know that childhood genetic conditions may have adult disease counterparts (Zimran et al., The Israel Medical Association Journal: IMAJ, 16(11), 723–724, 2014). Individuals who have Gaucher disease and carriers of the disorder are at increased risk for a seemingly unrelated and complex neurological condition, Parkinson disease. Parkinson disease is, in part, caused by the same mutations in the GBA gene that lead to Gaucher disease, and the two conditions are thought to have shared pathophysiology. Briefly reviewed are how these two diseases historically became linked, where their paths cross, potential problems and considerations in disclosure of the link, and current guidelines and research in this area. Genetic counseling experience with a large Parkinson disease cohort is used as a starting point to question the state of clinical and nonclinical practice in disclosing this unusual connection We conclude that more research and discussion are needed to inform practice regarding the crossroads of Gaucher and Parkinson disease.
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Acknowledgements
This study was funded by the Michael J. Fox Foundation as part of the Parkinson’s Progression Markers Initiative (PPMI).
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Lola Cook and Jeanine Schulze declare that they have no conflict of interest.
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Appendix 1 Fact Sheet
Appendix 1 Fact Sheet
Parkinson Disease and Gaucher Mutations
Parkinson disease is a chronic and progressive movement disorder. About 1–2% of all people will develop Parkinson disease in their lifetime. The age of onset is typically around age 60, though it can occur earlier or later. In Parkinson disease, the parts of the brain controlling movement slowly begin to lose proper function, which can result in tremors, gait impairment and other symptoms. It is important to remember that symptoms vary from person to person, as does the rate of progression. Although there is not yet a cure or way to reliably slow the progression of Parkinson disease, there are medications that can improve the symptoms.
Parkinson disease is a complex disorder. To date, the exact causes of Parkinson disease remain unknown. Scientists believe that both environmental and inherited genetic factors are involved and that the interaction between these factors is important.
DNA is our hereditary material. Every cell in our body has an almost identical copy of our DNA. Our genes are sections of our DNA. We have over 25,000 genes and each gene has specific functions. Some genes determine our hair color, eye color, or regulate how our body digests food. Other genes protect our bodies from developing diseases, like cancer or diabetes. We have two copies of every gene. One copy of each gene is inherited from our mother and the other copy is inherited from our father. When changes (mutations) are present in our genes, this can often contribute to a disease or risk of a disease.
An important gene association was made in 2009, linking mutations in the GBA gene that cause Gaucher disease with Parkinson disease. It was discovered that individuals with Gaucher disease and some of their relatives have an increased risk of developing Parkinson disease. The GBA gene instructs the body to make an enzyme called beta-glucocerebrosidase, an enzyme that breaks down a fatty substance in the body. Mutations in the GBA gene either reduce or eliminate the amount of beta-glucocerebrosidase enzyme available to break down fatty substances, causing these substances to accumulate in the body. Individuals with two mutations in the GBA gene will usually have Gaucher disease, while those with just one GBA mutation are called carriers and are not affected with Gaucher disease.
Studies have shown that individuals with a mutation in one copy (carriers) or both copies of the GBA gene (have Gaucher disease) are at an increased risk to develop Parkinson disease. However, many people who carry GBA mutations will never develop Parkinson disease. Parkinson disease is a complex disorder, and it is likely other risk factors are needed in addition to the mutation for an individual to develop Parkinson disease.
A change in the DNA sequence (mutation) can occur anywhere with the GBA gene, and these changes are found more often among individuals with Parkinson disease. Approximately 20% of patients with Parkinson disease who are of Eastern European (Ashkenazi) Jewish descent will carry a GBA mutation, while approximately 7% of patients with Parkinson disease who are of non-Jewish ancestry will carry a GBA mutation. The most common GBA gene mutation found among individuals with Parkinson disease is the N370S mutation, however there are many other mutations that can occur. Some mutations may have a higher risk for Parkinson disease than others, and researchers are studying whether having two GBA mutations may be associated with a higher lifetime risk for Parkinson disease.
Mutations in the GBA gene are inherited or passed on through families, and therefore each person who is a carrier of a GBA mutation will have a 50% chance to pass that mutation on to each child. Individuals with Gaucher disease have two GBA mutations, one inherited from each parent; therefore, parents of a child with Gaucher disease are assumed to be carriers of at least one GBA mutation. A child of an individual with Gaucher disease will carry at least one of the GBA mutations inherited from that parent. If a person’s sibling, parent, or child is known to be a carrier, then that individual is at a 50% chance of also being a carrier.
Both males and females can pass on and inherit the mutation. Only one GBA mutation is needed to have the associated Parkinson disease risk. However, most GBA carriers and individuals with Gaucher disease will not develop Parkinson disease as many factors contribute to causing Parkinson disease.
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Published: September 19, 2016
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Cook, L., Schulze, J. Connecting Gaucher and Parkinson Disease: Considerations for Clinical and Research Genetic Counseling Settings. J Genet Counsel 26, 1165–1172 (2017). https://doi.org/10.1007/s10897-017-0123-6
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DOI: https://doi.org/10.1007/s10897-017-0123-6