If Ive Already Been Diagnosed With Parkinsons Disease Why Do I Need Genetic Counseling
Knowing your genetic variant may help explain a part of why you developed PD or if you may be at higher risk for complications associated with PD, such as cognitive changes.
It may provide beneficial information for your family.
It could also be used to determine potential eligibility for participation in clinical trials.
Genetic Testing Shows Promise For Providing A Bipolar Diagnosis And Identifying Risk
I would gladly give blood, pee in a cup, get a brain scan, or undergo any other type of medical testing to get a definitive diagnosis. That way, I couldn’t argue with myself and pretend it doesn’t exist – as I often do. I am pretty sure people with diabetes don’t question their condition – probably because they have undeniable proof that it exists.
But, what if there was a test that could immediately diagnose a person with bipolar disorder? Imagine how this would change the lives of millions of people who struggle with mental health issues!
Some researchers say we are on the verge of having access to such a test. With the latest developments in genetic testing, more and more people are using this method as a way to determine their risk for bipolar disorder.
People Who Already Have Pd: Should I Get Tested And What Do I Do With The Results
Up until recently, even people with PD with a very extensive family history of PD would not necessarily receive genetic testing because there were no clear uses for the results. There has been research directed at figuring out whether PD caused by or associated with certain mutations have particular clinical characteristics . However, there remains so much variability in clinical characteristics even among people with the same PD mutation, that there are still no clear practical implications in knowing whether a PD patient harbors a particular mutation. There is also, so far, no difference in treatment or management of PD whether or not the patient harbors one of the known mutations. That may change however, with the advent of clinical trials that target particular mutations.
There are two genes that have received particular attention recently because medications are being developed that target those with mutations of these genes.
GBAis a gene that increases the risk of developing PD. The gene encodes for the GBA enzyme, a protein used by the body to break down cellular products. Having two abnormal GBA genes causes Gaucher’s disease, which is characterized by the buildup of these cellular products resulting in fatigue, bone pain, easy bleeding and an enlarged spleen and liver. When a person inherits only one abnormal gene, he or she does not develop Gaucher’s disease, but does incur a small increased risk of PD. Most people with one mutated GBA gene do not develop PD.
Genetic Markers Linked To The Start Of Symptoms Of Parkinson’s Disease
Researchers from the Institute of Neurosciences of the University of Barcelona , Hospital Clínic and the August Pi i Sunyer Biomedical Research Institute have identified a group of genetic variants related to the starting point of Parkinson’s disease. These results, published in the journal Movement Disorders, will enable delimiting the research on new therapeutic targets, and could have implications in the diagnosis of the disease.
The study has been led by the lecturer of the Department of Biomedicine of the Faculty of Medicine and Health Sciences at the UB Cristina Malagelada, as well as Maria Josep Martí, head of the Unit of Parkinson’s and Movement Disorders at the Hospital Clinic, and Mario Ezquerra and Rubén Fernández Santiago, geneticists at IDIBAPS. Núria Martín-Flores, UBNeuro researcher, is the first author of the article, which was fully funded by the Michael J. Fox Foundation for Parkinson’s Research .
Association between genetic markers
Researchers studied genetic markers—DNA segments with chromosome-identifiable locations—that adjust the starting age of the Parkinson’s disease. “There are known genetic markers, such as the genetic markers of the synuclein gene, which are associated with an earlier start of the symptoms, but in this study we focused on the influence of the association of other markers which were not known yet,” says Cristina Malagelada, UBNeuro researcher.
The second most common neurodegenerative disease
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Complex Syndromes With Parkinsonism As Part Of Their Clinical Spectrum
Mutations in several genes can cause rare syndromes of a more complex phenotype with parkinsonism representing only one of several clinical features. Some of them have been designated as “PARK”-genes , but others have not , which can occur with or without parkinsonism). Even elongated repeat expansions in the SCA2 gene have been described in patients with parkinsonism and no overt ataxia .
The exclusion of these genes from further consideration in this review article is somewhat arbitrary. The developments of recent years clearly show that genotype-phenotype correlations are much more variable than anticipated, and the increasing use of exome sequencing will further increase this diversity. However, due to space limitations, this important topic cannot be discussed here in depth.
Genetic Testing For Parkinson’s Disease And Related Disorders Minutes
Dr. Michael WatsonAlthough the terms are often used interchangeably, testing and screening have two distinct uses. Genetic testing involves the analysis of symptomatic individuals or those with a family history, whereas screening uses a population-based approach. Ethical issues associated with both of these forms of testing include test validation and test performance. The intended use of the test should be specific; it might therefore be helpful to articulate the intended use as if FDA approval were required.
There are 2 stages through which a genetic test can be translated into clinical practice.
Stage 1: includes population-based research to establish scientific links between genes and diseases. Laboratories would not have to be approved under the Clinical Laboratory Improvement Amendments of 1988 because they do not report to the families, but Institutional Review Boards should oversee patient involvement. The FDA regulates manufactured devices and drugs, and provides guidance for informed consent requirements, but genetic “home brew” tests often fall through the regulatory gap. Moreover, while CLIA regulates how laboratories practice, it does not address the issue of clinical validity.
Stage 3: involves the development of practice standards for tests that are found to be adequate and of utility at Stage 2. This involves the development of guidelines for testing and who should be tested.
Dr. Quaid outlined the types of genetic testing as:
Usefulness Of Genetic Testing In Pd And Pd Trials: A Balanced Review
Article type: Review Article
Affiliations: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases , Tübingen, Germany
Correspondence: Correspondence to: Thomas Gasser, Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str., 3 72076 Tübingen, Germany. Tel.: +49 7071 29 80171; Fax: +49 7071 29 4490; E-mail:
Keywords: Parkinson’s disease, genetics, mutation, risk variant
DOI: 10.3233/JPD-140507
Journal: Journal of Parkinson’s Disease, vol. 5, no. 2, pp. 209-215, 2015
Abstract
Blood Test May Distinguish Parkinsons From Multiple System Atrophy
A highly sensitive and specific blood test has been developed that can distinguish Parkinson’s disease from multiple system atrophy , a team at the University of California, Los Angeles Health reported.
The test examines the levels of a protein called alpha-synuclein in exosomes — tiny vesicles released by cells that end up in the blood. In Parkinson’s, alpha-synuclein comes from neuron-derived exosomes, while in MSA it comes from exosomes released by oligodendrocytes, another type of brain cell.
Based on the content and origin of the exosomes, this test can help discriminate between Parkinson’s disease and MSA.
“This is a major breakthrough, because it allows us to analyze what’s going on in the brain using a blood test,” Gal Bitan, PhD, the study’s senior author and a professor of neurology at the David Geffen School of Medicine at UCLA, said in a university press release.
The study, “?-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy,” was published in Acta Neuropathologica.
Parkinson’s and neurodegenerative diseases such as MSA have several symptoms in common, including muscle rigidity and tremors. Because of this overlap in symptoms, many cases are misdiagnosed.
Incorrect diagnoses can also affect clinical trial results, as potential treatments would be tested in people without the disorder under evaluation.
Results
What Does It Mean?
References
Is There A Test That Can Tell You If You Have Bipolar Disorder
I still say that getting a proper diagnosis is perhaps one of the most frustrating aspects of seeking treatment for bipolar disorder. I don’t argue with the fact that finding the right medication is an uphill climb.
Before the medication journey begins, we must first be properly diagnosed. Many of us are told we have ADHD, clinical depression, a personality disorder, or a substance abuse problem before we receive the bipolar diagnosis. This only adds to our frustration.
We cannot acquire the tools we need to manage bipolar disorder until we come to terms with the fact that we have it. This starts the moment a doctor says, “You have bipolar disorder.” The problem is – there is currently no official medical test for this condition.
Simple Blood Tests For Parkinsons Disease Derived From Genome
The diagnosis of Parkinson’s disease relies on expert opinion. Autopsy studies, however, have demonstrated that even experienced neurologists misdiagnose Parkinson’s disease in about a quarter out of a hundred cases. Diagnostic accuracy at disease onset, when neuroprotective treatment is anticipated to be most effective, is even lower. Thus, there is a crucial need for biomarkers that are disease-specific and which precisely identify early disease stages.
Traditional studies of blood from Parkinson’s disease patients have analyzed expression levels of one gene or gene product at a time. We plan to take advantage of ‘gene chip’ technology allowing expression analysis of up to 22,000 genes on a single glass slide, known as microarray. We hypothesize that a comparison of the gene chip analyses of blood samples from Parkinson’s disease patients and normal controls or patients with other neurological diseases will identify a set of signature genes with characteristic expression in patients with Parkinson’s disease. These key genes will provide a ‘molecular fingerprint’ of Parkinson’s disease in blood.
Brain Imaging And Other Tools To Aid Diagnosis Of Parkinsons
Helping diagnose Parkinson’s with DaTscan and other tests
Why Genetic Testing For Parkinsons Disease Is Complex:
In addition to the above, it is important to realize that not all genes associated with PD contribute to disease in the same way:
Blood Test Aims To Detect Parkinson’s In Early Stages
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What A 23andme Test Revealed About My Genetics And Ancestry
When the Michael J. Fox Foundation and DNA-testing company 23andMecollaborated to gather genetic data for Parkinson’s research, I quickly signed up. Using 23andMe’s service would allow me to both learn about my ancestry and contribute to important research. It was a win for everyone.
But I also had questions. How much information was too much information? How much did I really want to know?
I had a plan. Discover my ancestry and allow all of my results to be included in the research study? Yes. Access and read the additional reports on my risk factors? No. Learn that I have a genetic variant that may affect my sons? No.
The ancestry report was what I expected — almost. My mother’s family is from Italy, and my father’s is from the former country of Czechoslovakia, Poland, and other parts of Eastern Europe. However, the chart had a tiny sliver that revealed I am 2% Ashkenazi Jewish. I shared the cool charts and graphs with my family and forgot about them.
A few months later, that 2% of my DNA became important for the Parkinson’s Progression Markers Initiative , which aims to identify biomarkers of Parkinson’s disease progression. The study is recruiting people with Parkinson’s of Ashkenazi Jewish descent.
Why Genetic Testing For Parkinsons Disease Is Complex:
- There are many genes that are associated with the development of PD. This list continues to grow as more genes are discovered. Testing of only some of these genes is available in commercial labs.
- The majority of people with PD, even those with a family history of PD, do not harbor one of these identified abnormal genes. The genetic contribution to PD in these people is yet to be discovered.
- For a particular gene there may be a number of different mutations associated with disease, some of which are more common than others. Commercial testing may identify only the most common of the mutations, and therefore not capture everyone who carries a disease-causing mutation.
- Conversely, only particular mutations in a gene may be associated with disease. Commercial testing may identify changes in a gene that may not have clinical consequences. This can be confusing for patients who even after genetic testing may not know whether they harbor a disease-causing mutation.
- Different mutations can be enriched in different ethnic populations. For example, Ashkenazi Jews and North African Berbers have an increased risk of carrying Leucine rich repeat kinase 2 mutations. Glucocerebrosidase mutation frequency also varies greatly with ethnicity and is also increased among Ashkenazi Jews.
In addition to the above, it is important to realize that not all genes associated with PD contribute to disease in the same way:
Drugs And Medication Used To Treat Parkinsons Disease
A number of different drugs can be used to treat Parkinson’s.
Levodopa
Levodopa is the most common treatment for Parkinson’s. It helps to replenish dopamine.
About 75 percent of cases respond to levodopa, but not all symptoms are improved. Levodopa is generally given with carbidopa.
Carbidopa delays the breakdown of levodopa which in turn increases the availability of levodopa at the blood-brain barrier.
Dopamine agonists
Dopamine agonists can imitate the action of dopamine in the brain. They’re less effective than levodopa, but they can be useful as bridge medications when levodopa is less effective.
Drugs in this class include bromocriptine, pramipexole, and ropinirole.
Anticholinergics
Anticholinergics are used to block the parasympathetic nervous system. They can help with rigidity.
Benztropine and trihexyphenidyl are anticholinergics used to treat Parkinson’s.
Amantadine
Amantadine can be used along with carbidopa-levodopa. It’s a glutamate-blocking drug . It offers short-term relief for the involuntary movements that can be a side effect of levodopa.
COMT inhibitors
Catechol O-methyltransferase inhibitors prolong the effect of levodopa. Entacapone and tolcapone are examples of COMT inhibitors.
Tolcapone can cause liver damage. It’s usually saved for people who do not respond to other therapies.
Ectacapone does not cause liver damage.
Stalevo is a drug that combines ectacapone and carbidopa-levodopa in one pill.
MAO-B inhibitors
Other Factors Influencing Parkinson’s Disease Risk
Other factors besides genetics can influence someone’s chances of developing Parkinson’s disease, including:
- Age: The risk of developing Parkinson’s disease increases as a person ages.
- Sex: Males have a higher chance of developing Parkinson’s disease than females.
- Family history: First-degree relatives of an individual with Parkinson’s disease have a higher chance of developing Parkinson’s disease.
- Exposure to certain chemicals increases the risk of developing Parkinson’s disease.
Who Should Consider A Genetic Test For Parkinsons
There are two groups of people who might consider getting genetic testing and we will discuss each group separately.
Genetic testing for PD is a common request and a number of commercial labs perform panels of genetic testing for PD. You may ask: “How can I test myself for Parksinon’s?” Whether you’re considering getting a genetic test through your doctor, or performing one at home, it’s important to note that at-home test don’t map the entire gene for mutations. Genetic testing through your doctor will test for GBA, PARK7, SNCA, LRRK2, parkin and PINK1.
Both groups are faced with two questions: Should I get genetic testing? And if so, what should I do with the results? Before we address these two questions, we need to learn more about the complexity of genetic testing in PD.
Common Genetic Risk Factors For Pd Of Weak Effect
Genome-wide association studies to date have led to the discovery of as many as 28 genetic risk loci for sporadic PD . The associated risk variants can be common in the population , but convey only a mildly increased risk to develop the disease. Even if all known risk factors are considered together, they are only associated with an odds ratio of 3 to 4 and thus explain only a part of the expected heritability of PD . This could be due to the fact that many of the rarer risk variants are probably still unknown, or that “balancing protective”factors are not yet accounted for. Interestingly, common risk variants occur in some of the same genes that had been identified as Mendelian disease genes, such as SNCA , LRRK2 or MAPT , emphasizing shared pathogenic pathways between inherited and sporadic forms of PD.
Is There A Genetic Marker For Bipolar Disorder
Some scientists now believe mutations to the GRK3 gene in the brain can increase the risk of someone developing bipolar disorder. If you undergo a genetic test for this condition, this is the gene that will be examined – along with family history, symptoms, and other factors.
A company called Psynomics is leading the charge when it comes to genetic testing and bipolar disorder. It is the first and only company in the world to offer DNA-based diagnostic tests designed to help the millions of people who battle this illness.
Psynomics runs two tests that might be of interest to someone who wants to undergo genetic testing for bipolar disorder.
The first test, Psynome™, tests for two mutations of the GRK3 gene associated with bipolar disorder. Psynomics says that white people who have either of the two gene mutations with a Northern European ancestry and a family history of bipolar are three times more likely to have bipolar disorder themselves.
The second test , Psynome2™, tests for genetic mutations in the Promoter L allele gene. This gene predicts a person’s response to serotonin-based drugs , which are the most commonly prescribed psychiatric medications. This is the only test of its kind. No other genetic test currently exists to identify an individual’s positive or negative response to SSRIs.
Can Parkinsons Be Passed From Parent To Child
It’s rare for Parkinson’s disease to be passed down from parent to child. Most cases of Parkinson’s aren’t hereditary. But people who get early-onset Parkinson’s disease are more likely to have inherited it.
Having a family history of Parkinson’s disease may increase the risk that you’ll get it. This means that having a parent or sibling with Parkinson’s slightly increases the risk.
In most cases, the cause of Parkinson’s disease remains unknown. But researchers have identified multiple risk factors that can increase your chances of getting this disease.
Risk factors for Parkinson’s disease include:
- mutations in specific genes associated with Parkinson’s
- having a family history of Parkinson’s or a first-degree family member with Parkinson’s
- being older, especially above the age of 60
- exposure to herbicides and pesticides
- being assigned male at birth
- history of brain injury
Cause Of Loss Of Smell In Parkinsons Disease
It’s unclear why olfactory dysfunction occurs in Parkinson’s disease. Experts have found that smell loss correlates with a lower number of cholinergic neurons in the nucleus basalis of Meynart—a region of the brain that projects to the primary olfactory cortex where you get the sensation of smell.
With this information, smell tests that focus on detecting cholinergic dysfunction may be ideal. It’s still too early to tell, though, so more investigation needs to be done.
Additionally, some researchers have suggested that Parkinson’s disease may actually begin in the digestive system and the olfactory bulb , and not the substantia nigra . This may be why early symptoms, like constipation and loss of smell, begin years prior to motor symptoms like resting tremor and muscle stiffness.
Blood Test For Parkinson’s: Study Details
When brain cells die, Nagele says, they explode ”like a water balloon breaking.”
The contents of those dying cells spill partially back into the blood. “Their debris is released and your body will sense it and develop autoantibodies to clear that debris,” he says.
The new test looks for these autoantibodies in the blood specific to the disease. The researchers narrowed down a list of more than 100 of these autoantibodies to 10 that looked most promising. When these antibodies rise to a certain level, it signals disease, Nagele says.
To evaluate the Parkinson’s test, Nagele’s team looked at more than 150 blood samples, including:
What Genes Are Linked To Parkinson’s Disease
In 1997, we studied a large family that came from a small town in Southern Italy in which PD was inherited from parent to child . We found the gene that caused their inherited Parkinson’s Disease and it coded for a protein called alpha-synuclein. If one studies the brains of people with PD after they die, one can see tiny little accumulations of protein called Lewy Bodies . Research has shown that there is a large amount of alpha-synuclein protein in the Lewy Bodies of people who have non-inherited PD as well as in the brains of people who have inherited PD. This immediately told us that alpha-synuclein played an important role in all forms of PD and we are still doing a lot of research to better understand this role.
Currently, seven genes that cause some form of Parkinson’s disease have been identified. Mutations in three known genes called SNCA , UCHL1 , and LRRK2 and another mapped gene have been reported in families with dominant inheritance. Mutations in three known genes, PARK2, PARK7 , and PINK1 have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson’s disease . There is some research to suggest that these genes are also involved in early-onset Parkinson’s disease or in dominantly inherited Parkinson’s disease but it is too early yet to be certain.
What Determines Who Gets Parkinson’s Disease
In most cases inheriting a non-working copy of a single gene will not cause someone to develop Parkinson’s disease. We believe that many other complicating factors such as additional genes and environmental factors determine who will get the condition, when they get it and how it affects them. In the families we have studied, some people who inherit the gene develop the condition and others live their entire lives without showing any symptoms. There is a lot of research on genes and the environment that is attempting to understand how all these factors interact.
Genetic Testing in Parkinson’s Disease
Genetic testing has recently become available for the parkin and PINK1 genes. Parkin is a large gene and testing is difficult. At the current stage of understanding, testing is likely to give a meaningful result only for people who develop the condition before the age of 30 years. PINK1 appears to be a rare cause of inherited Parkinson’s disease. A small percentage of those developing the condition at an early age appear to carry mutations in the PINK1 gene. Genetic testing for the PARK7, SNCA and LRRK2 genes is also available.
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Risk Factors Of Intermediate Strength In Pd
Heterozygous mutations in the gene for glucocerebrosidase , which cause Gaucher’s disease in the homozygous or compound heterozygous state, have been identified as a relatively frequent risk factor for PD . GBA mutation carriers have an increased risk to develop PD by a factor of ?5, compared to the general population (corresponding to a reduced age-dependent penetrance of about 30% by the age of 70 . Some mutations are particularly prevalent in specific ethnic groups, such as the N370S mutation amongst Ashkenazi Jewish, where GBA mutations are found in 15 to 30% of sporadic PD cases. Clinically, patients with GBA mutations have typical PD with a slightly earlier on set age, and a higher prevalence of autonomic and other non-motor manifestations and cognitive impairment . The LRRK2 G2019S variant discussed above can also be considered to be a risk factor of this category, rather than a high penetrance mutation.
Genetic Testing In Pd In A Clinical Setting
Genetic testing in an affected individual or at-risk person in a clinical setting can serve several purposes. If a causal treatment results from the molecular confirmation of a diagnosis, ideally even before development of overt symptoms, as can be the case in Wilson’s disease, the motivation to pursue genetic testing is obvious. However, also in the absence of clear therapeutic consequences, a patient or an at-risk relative may have well justified reasons to ask for genetic testing. The patient may simply look for a definitive diagnosis, a final explanation of his or her symptoms and complaints. This is often particularly true for young patients, who struggle with the diagnosis of a neurodegenerative disorder usually considered adisease of late life. In such a case, a genetic diagnosis may end an odyssey of hospital visits and costly, sometimes invasive or risky clinical tests.
Life or family planning may be another reason, usually in the setting of a strong dominant family history. A study exploring the attitudes of patients and their families towards genetic diagnosis indicates a high level of interest, but a lack of knowledge about genetic testing , clearly indicating an unmet need of patient and caretaker education.
New Dna Diagnostics For Parkinson’s Disease
14 December 2014
Research at UCL into the genetic causes ofParkinson’s disease led to the development of a new genetic test, now availableto patients and their families.It also provided insights into patterns of Parkinson’s disease in particularethnic groups and generated industry research leading to new drug candidates.
Approximately 200,000 people in the UK suffer from Parkinson’s disease , a neurodegenerative condition affectingmultiple areas of the brain. The lifetime risk of developing PD in the UK is now4%, making it the second most common neurodegenerative disease in the country.
Huge improvements over the last 15 years in the understandingof PD have been driven largely by findings in genetics research. In 2004,researchers led by Professor Nicholas Wood were anintegral part of the group that first described mutations in the gene LRRK2. Thisrepresented a significant shift in understanding of a condition that had, formany years, had been taught to medical students as the prime example of anon-genetic disease. Furthermore, the team’s discovery in 2005 of the so-calledcommon mutation in this gene showed for the first time that arelatively rare genetic variant could not only cause familial PD, but couldalso play a significant role in sporadic PD.
The test gives patients a precise diagnosis, andunderstanding of the risk of disease to relatives. Prenatal testing is also apossibility. To a lesser degree, an understanding of the mutation may help theprognosis of the disease.
Bioinformatics And Clinical Interpretation
Bioinformatics
Clinical interpretation
We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.
Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.
The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic and variants of uncertain significance are confirmed using bi-directional Sanger sequencing by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.
When Should A Person Seek Genetic Testing
Genetic testing is available for some genes related to Parkinson’s disease, but testing may not provide useful information to individuals.
For one thing, a wide range of genes may play a role, and it is not possible to test them all. A person may also have a relevant feature but not go on to develop Parkinson’s disease.
For example, only around 0.7% of people with symptoms of Parkinson’s disease have changes in the LRRK2 gene, and around 0.3% have changes in the PRKN gene, according to a 2020 review.
Finding out in advance if a young person has the gene may help them prepare for the future if there is strong evidence of a family history of the condition. However, the results are unlikely to be conclusive and may cause unnecessary anxiety.
Anyone who is interested in genetic testing should discuss the pros and cons with a doctor and consider genetic counseling if they decide to go ahead.
The Parkinson’s Foundation notes that testing is often hard to access. It can also be costly, and health insurance may not cover it. Genetic counseling can be an additional cost.
Autosomal Dominant Forms Of Mendelian Pd
The exchange of a single basepair in the ?-synuclein gene leading to an alteration of the amino-acid sequence of the endoded protein was the first disease-causing PD mutation found in a large family of Italian origin with an autosomal dominant pattern of inheritance . Later, a few additional missense mutations were recognized , but the results of large screening studies of several thousands of patients suggest that the overall frequency of SNCA-mutations is below 0.1% . Since 2003 , duplications and triplications of the SNCA gene are also recognized as a rare cause of autosomal-dominant PD .
A more common form of monogenic PD with dominant inheritance is caused by mutations in the gene for leucine-rich repeat kinase 2 . The pathogenicity of several rare point mutations is supported by co-segregation in large families , but a specific and much more common variant, p.G2019S, also occurs in 2 to 7% of sporadic Caucasian PD patients, and, due to a founder effect, even in up to 25% of patients from Ashkenazi Jewish or North African Berber ancestry. Due to reduced age-related penetrance, estimated between 25 and 70% , many of those patients do not have a very clear family history of the disease.
Overall, LRRK2 mutations account for 5 – 15% of dominant familial , and 1– 3% of sporadic PD cases , whilst another mutation, the R1441G variant, is a Basque founder mutation with a prevalence of 15% in patients with PD from this region .