Each cell in our body , with a few exceptions, contains deoxyribonucleic acid (DNA ), which is the genetic building block. DNA is organized into 23 pairs of chromosomes (see Karyotype figure below), with one member of each chromosome pair inherited from the father and the other member of the chromosome pair inherited from the mother. In this way, each individual inherits an equal amount of their genetic material from their mother and father. The pairs of chromosomes are numbered sequentially by size, with the chromosome 1 pair having the most DNA and being the longest. The 23rd pair of chromosomes determines whether an individual is a male or female. Females have inherited an X chromosome from both their father and mother, while males have inherited an X chromosome from their mother and a Y chromosome from their father. Importantly, by simply viewing the gross structure of chromosomes we cannot know if an individual will develop PD.
Along each chromosome are many genes. Each gene codes for a protein, enzyme or other important compound in our body. For example, there are genes which code for eye color or hair color. Each gene comes in two copies, with one copy inherited on the chromosome from the mother and the other copy inherited on the chromosome from the mother. Each gene consists of a sequence of DNA which is used to code for an amino acid, which is the building block used to make a protein. When the normal DNA sequence of a gene is varied, the production of an altered protein may result or n some cases no protein is made and this lack of a normal protein contributes to the symptoms of PD.
The genetics of PD is quite complex. The genes which have been identified for PD act in different ways. In some cases, only one of the two copies of a gene must be defective in order to result in PD. This type of inheritance is termed autosomal dominant. This pattern of inheritance typically results in a family history in which multiple members of a family report symptoms of the disease and these individuals are in multiple generations. When an individual has PD due to a change in a gene that acts in an autosomal dominant pattern, the offspring of the individual with PD have a 50% risk of inheriting the change in the gene and potentially developing PD. There are two genes which are important in PD and which act in an autosomal dominant pattern: alpha synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2).
There are another series of PD families who have a different type of family history of PD. In these PD subjects, most affected individuals are siblings and there are no other affected members in the family. In this case, we describe the pattern of inheritance as autosomal recessive and believe that both copies of a particular gene must be defective in order to result in PD. There are three genes which are important in PD and which act in an autosomal recessive pattern: parkin (PRKN), PINK1, and DJ-1. In each case, individuals who have inherited a mutation in both copies of the gene have early onset PD, typically prior to age 40.
DNA testing is now available for all five of these genes. However, results from testing may not be easy to interpret and will not affect treatment of disease symptoms.
Individuals with a change in the SNCA gene DNA sequence typically have PD which onsets at a younger age, often prior to age 40 or 50. These individuals will often report an extensive family history of PD, with multiple members also having a younger onset of disease. Several types of changes in the DNA sequence change of SNCA have been reported. Some families have been identified with a single change in the DNA sequence in this gene (called a mutation), which results in the formation of an abnormal form of the protein produced by the SNCA gene. There have also been some families identified in which the sequence of the SNCA gene is entirely normal; however, on one of the two chromosomes that harbor the SNCA gene, there are too many copies of the gene, typically either a duplication (2 copies) or a triplication (3 copies) of the gene. That means that potentially too much SNCA is being made and this results in PD. SNCA was the first gene identified to be important in PD; however, only a small number of families have been identified in which DNA sequence changes in SNCA cause PD.
Mutations in LRRK2 have now been shown to be the most common cause of PD. LRRK2 codes for a protein called dardarin. The most common change in LRRK2 that results in PD is called the G2019S mutation. G2019S means that at position 2,019 of the dardarin protein the amino acid glycine replaces the usual amino acid called serine. Among individuals with PD who also have a family history of the disease, particularly one that is consistent with autosomal dominant inheritance, this DNA sequence change (mutation) occurs at a frequency of about 5%. This mutation occurs at a lower frequency, only 1-2%, among individuals with PD who do not have another family member with the disease. Individuals with this LRRK2 mutation typically develop PD in their 50’s or 60’s. However, researchers have found some individuals who have inherited this mutation and who have not yet developed PD even in their 70’s. This observation suggests that it is possible that some people who have the G2019S mutation may never develop PD.
PRKN codes for the protein called parkin. Over 100 mutations in PRKN have been reported in patients with PD. These mutations include changes in the DNA sequence that result in the change in an amino acid of the resulting parkin protein. There are also some PD patients who have more complex mutations in the PRKN gene. In some cases, an entire region of the PRKN gene is either deleted (missing) or duplicated (doubled). Such changes result in a faulty parkin protein and can result in PD. Mutations in PRKN are the most common cause of early onset PD. Over 100 different mutations in the PRKN gene have been reported. As many as 10-20% of PD patients, who develop PD prior to age 40, have mutations in the PRKN gene. Mutations in PINK1 and DJ-1 are far less common; however, they do typically occur in patients with early onset PD.
However, it is important to weigh what would be learned from DNA testing. There are really two situations when considering DNA testing for genes important in PD. In some cases, the individual is already diagnosed with PD. DNA testing can provide information that may help understand why the individual has developed PD. However, at this time, treatment for PD symptoms is not altered if an individual is known to have a mutation in one of these 5 genes. There are important implications to other family members if an individual is tested for one of these genes. For example, if an individual is known to have a mutation in the LRRK2 gene, then the offspring of that individual are at 50% risk of also inheriting that mutation. This information can have important health insurance implications for the offspring of the person being tested.
DNA testing may also be considered by individuals with a family history of PD, but who are themselves not diagnosed with PD. In this case, DNA testing is termed presymptomatic. While some individuals may wish to know if they have inherited a mutation in one of these 5 genes, such information is difficult to interpret. For example, a growing number of individuals have been identified who have inherited one or two mutations in one of these 5 genes and yet that person does not have PD. This is described as reduced penetrance. The implication is that we cannot predict with certainly from a DNA test whether an individual will develop PD. Importantly, there is no treatment which can be initiated that would then decrease the risk or onset of PD. Therefore, most neurologists and geneticists agree that presymptomatic testing of individuals for any of these 5 genes is not warranted and should not be undertaken.
We have learned a great deal about PD. However, it should also be clear that we have a great deal yet to learn. The PROGENI Study participants, both those with PD and those without PD, are an absolutely critical piece for future research. By studying the DNA of those with PD, those at risk for PD who do not show symptoms, and those without PD who do not have a family history of PD, we will improve our understanding of the factors which determine why some individuals develop PD. It is our hope that this understanding will then translate to better treatments.