INSIDE.Winter Seasonand Exercise

.PROGENlln Print OGENI News.In memoriam:CliffordShults,M.D. NEWSLETTERFORPARKINSON'SRESEARCH:

THE ORGANIZEDGENETICSINITIATIVE Volume9 . November2007

GENETICTESTINGIN PARKINSONDISEASEBy Tatiana Foroud, Ph.D., Indiana University

During the past decade, there has been a revolution inour understanding of the genetics of Parkinson disease(PD). Five genes have now been identified which playan important role in the development of PD.These genesare called alpha synuclein (SNCA), parkin (PRKN), PINK1,DJ-l and LRRK2. Studies of many families, includingmany of our PROGENI families, have helped us to betterunderstand how each of these genes contributes to therisk of PD.

To understand the genetics of PD, it is important to firstunderstand the basics of genetics. Each cell in our body,with a few exceptions, contains deoxyribonucleic acid(DNA), which is the genetic building block. DNA isorganized into 23 pairs of chromosomes, with onemember of each chromosome pair inherited from thefather and the other member of the chromosome pairinherited from the mother. In this way, each individualinherits an equal amount of their genetic material fromtheir mother and father. The pairs of chromosomes arenumbered sequentially by size, with the chromosome1 pair having the most DNA and being the longest.The 23rd pair of chromosomes determines whetheran 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 theirmother and a Y chromosome from their father. We cannot

know if an individual will develop PD by simply viewingthe gross structure of chromosomes (termed aKaryotype, see Figure 1).

Along each chromosome are many genes. Each genecodes for a protein, enzyme or other importantcompound in our body. For example, there are geneswhich code for eye color or hair color. .Each gene comesin two copies, with one copy inherited on the

chromosome from the mother and the other copyinherited on the chromosome from the mother. Each

gene consists of a sequence of DNA which is used tocode for an amino acid, which is the building block used

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Figure 1, Thiskaryotype, with two X chromosomes and no Y chromosome,is from a female,

to make a protein. When the normal DNA sequence of agene is varied, the production of an altered protein mayresult, or in some cases no protein is made and this lackof a normal protein contributes to the symptoms of PD.

The genetics of PD is quite ,complex. The genes whichhave been identified for PD act in different ways. In somecases, only one of the two copies of a gene must bedefective in order to result in PD.This type of inheritanceis termed autosomal dominant (see Figure 2). This patternof inheritance typically results in a family history inwhich multiple members of a family ,

report symptoms of thedisease and theseindividuals are in

multiple generations.When an individualhas PD due to a

change in a genethat acts in anautosomal dominant

pattern, the offspring> continuedonpage2

10 11

" II, II'15 16 17

.. .'. II21 22 X

Genetic Testingin Parkilof the individual with PD have a 50% risk of inheriting the

change in the gene and potentially developing PD.Thereare two genes which are important in PD and which actin an autosomal dominant pattern: SNCA and LRRK2.Individuals with a change in the SNCA gene that causes

II II

II IIFigure 2. A simplified example of autosomal dominant inheritance,

where the red gene is defective.

PD typically onset with PD at a younger age, often priorto age 40 or 50. These individuals will often report anextensive family history of PD, with multiple membersalso having a younger onset of disease: Several typesof changes in DNA sequence changes in SNCA havebeen reported. Some families have been identified witha single change in the DNA sequence in this gene (calleda mutation), which results in the formation of an abnormalform of the protein produced by the SNCA gene. Therehave 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 has been duplicated or triplicated. That means thatpotentially too much SNCA is being made and this resultsin PD. SNCA was the first gene identified to be importantin PD; however, only a small number of families have beenidentified in which DNA sequence changes in SNCA causePD.

Mutations in LRRK2 have now been shown to be the most

common cause of PD. LRRK2 codes for a protein calleddardarin. The most common change in LRRK2 that resultsin PD is called the G2019S mutation. G2019S means that

at position 2,019 of the dardarin protein the amino acidglycine (G) replaces the usual amino acid called serine (S).Among individuals with PD who also have a family historyof the disease, particularly one that is consistent withautosomal dominant inheritance, this DNA sequencechange (mutation) occurs at a frequency of about 5%.Thismutation occurs at a lower frequency, only 1-2%,amongindividuals with PD who do not have another familymember with the disease. Individuals with this LRRK2

.

son 0 isease > continued from page 1

mutation typically develop PD in their 50's or 60's.However, researchers have found some individualswho have inherited this mutation and who have not

yet developed PD even in their 70's. This observationsuggests that it is possible that some people whohave the G2019S mutation may never develop PD.

Another group of families have a different typeof family history of PD. In these PI) subjects, mostaffected individuals are siblings and there are noother affected members in the family. In this case,we describe the pattern of inheritance as autosomalrecessive and believe that both copies of a particulargene must be defective in order to result in PD (seeFigure 3). There are three genes which are importantin PD and which act in an autosomal recessive

pattern: PRKN, PINK1, and DJ-l. In each case,individuals who have inherited a mutation in both

copies of the gene have early onset PD, typicallyprior to age 40.

I I I I

Figure 3. A simplified example of autosomal recessive inheritance,

where the red gene has a mutation.

The first of these three genes to be identified wasPRKN, which codes for the protein called parkin.Over 100 mutations in PRKN have been reportedin patients with PD. These mutations include changesin the DNA sequence that result in the change in anamino acid of the resulting parkin protein. There arealso some PD patients who have more complexmutations in the PRKN gene. In some cases, an entireregion of the PRKN gene is either deleted (missing)or duplicated (doubled). Such changes result in afaulty parkin protein and can result in PD. Mutationsin PRKN are the most common cause of early onsetPD. Perhaps as many as 10-20% of PD patients whodevelop PD prior to age 40 have mutations in the

PRKN gene. Mutations in PINKI and D]-I typicallyoccur in patients with early onset PD, as well, thoughmutations in these genes are far less common.

DNA testing is now available for all five of thesegenes. However, it is important to weigh what wouldbe learned from DNA testing. There _arereally twosituations when considering DNA testing for genesimportant in PD. In some cases, the individual isalready diagnosed with PD. DNA testing can provideinformation that may help understand why theindividual has developed PD. However, at this time,treatment for PD symptoms is not altered if anindividual is known to have a mutation in one of

these 5 genes. There are important implications toother family members if an individual is tested forone of these genes. For example, if an individual isknown to have a mutation in the LRRK2 gene, thenthe offspring of that individual are at 50% risk of alsoinheriting that mutation. This information can haveimportant health insurance implications for theoffspring of the person being tested.

I I

DNA testing may also be considered by individualswith a family history of PD, but who are themselvesnot diagnosed with PD. In this case, DNA testing istermed presymptomatic. While some individuals maywish to know if they have inherited a mutation inone of these 5 genes, such information is difficultto interpret. For example, a growing number ofindividuals have been identified who have inherited

one or two mutations in one of these 5 genes andyet that person does not have PD.This is describedas reduced penetrance. The implication is that wecannot predict with certainty from a DNA testwhether an individual will develop PD. Importantly,there is no treatment which can be initiated thatwould then decrease the risk or onset of PD.

Therefore, most neurologists and geneticists agreethat pre symptomatic testing of individuals for anyof these 5 genes is not warranted and should notbe undertaken.

We have learned a great deal about PD. However, itshould also be clear that we have a great deal yet tolearn. The PROGENI Study participants, both thosewith PD and those without PD, are an absolutelycritical piece for future research. By studying theDNA of those with PD, those at risk for PD who donot show symptoms, and those without PD who donot have a family history of PD, we will improve ourunderstanding of the factors which determine whysome individuals develop PD. It is our hope that thisunderstanding will then translate to bettertreatments.

e

Winter Season and Exercise ByCherylA. Halter,MS,CCRC,IndianaUniversity

It is well documented that we can

all benefit from regular exercise.

This is especially true for peoplewith Parkinson disease. Regularexercise can help preserve flexibility

and improve posture. It can helpmaintain strength, increase appetiteand improve circulation. Regularexercise has also been shown to

reduce stress and improve overallfeelings of well being and control.

With winter approaching andtemperatures turning colder, weathermay limit our ability to get outdoorsfor regular exercise. Snow and ice

can make it treacherous to keep updaily walking and other forms ofoutdoor exercise routines. Even

though the weather is changing,

exercise is still an important aspectin the well being for people withParkinsons disease. If you live in anarea of the country where wintertime makes it difficult to get outsideand exercise you may need to lookfor alternative forms of exercise such

as swimming or aquatic exercise.Exercising in water has a much lower

impact on joints, but some peoplefind it difficult to tolerate the heat

of a pool. For those, no-impactYoga may be an appealing way tostretch and increase. flexibility.

If you are unable to get out of thehouse for regular exercise, it is still

possible to have a regular exerciseprogram. There are stretching andflexibility exercises that can beperformed indoors and many can beperformed while sitting. There havebeen a number of books writtenabout exercise and PD. One

reference that received a glowingreview from the Parkinson's Action

Network (PAN) is Parkinson's

Disease & the Art of Moving, a bookand companion video series by John

Argue. Boththe book and videosprovide clear, well paced instructionsfor exercises specifically developed

or modified for people with PD.The lessons are aimed at improvingflexibility, balance, and coordination.This is just one resource available,a quick internet search will revealother possibilities. Many may beavailable from your local supportgroup or library.

General Tips aboutExercise.Even small amounts of exercise arebetter than no exercise at all. It is

not necessary to perform 60 minuteworkouts in a gym each day. Even15 minutes of daily exercise canbe beneficial.

.Make sure to include thoroughstretching and a warm up and cooldown period.

.Try to perform each exercise to thebest of your ability. If you are unableto raise your arms above your head,raise them as high as you are able.Include rest periods in your routine,over exertion can make yoursymptoms worse.

. Exercising in groups may makeexercising more fun and mayincrease your commitment to the

0

program. Organizing small groupswithin an assisted living community,support group or neighborhoodmay provide needed motivationto maintain a program.

.Include everyday activities in yourexercise program. Raising your armsover your head, or stretching canhelp maintain flexibility for activitiessuch as dressing, personal hygieneand eating.

.Remember to exercise your face.Looking into a mirror or at anotherperson and practice smiling,frowning, raising your eyebrowsin surprise, etc.

If you are interested in exerciseoptions that may be available inyour area, contact your local supportgroup. But remember, beforebeginning any new exerciseprogram, it is best to contactyour local healthcare providerfor help in determining the bestprogram for you. She or he mightrecommend a consultation with

a Physical Therapist or athletictrainer who could tailor an exercise

program to your needs and lifestyle.

PROGENIin PrintPROGENI was recently featured in two publications. The

Parkinson Report, the official quarterly journal of theNational Parkinson Foundation (NPF), included an article

on PROGENI in the Research Reports section of the Spring2007 edition. Past and current issues of The Parkinson

Report can be downloaded for free from NPF's website,www.parkinson.org.

Tatiana Foroud, PROGENI's Principal Investigator, wasinterviewed for an article entitled "The Hunt for Genes

and Cures;' which was published in the Marchi April

2007 y?lume of Neurology Now. Neurology Now ispublished by the American Academy of Neurology(AAN), and it is available free to neurology patients,

their families, and caregivers.

If you would like to subscribe to Neurology Now,

you can visit their website, www.neurologynow.com.or call 1-800-422-2681. Past issues of Neurology Nowcan be downloaded at the website listed above.

PROGENIAutopsyCoordinatorSusanFox is the autopsy coordinator

for PROGENI. Susan joined theDepartment of Medical andMolecular Genetics at Indiana

University in 1984, where she

worked as part of the MedicalGenetics clinic for two years. Shethen moved to the Division of

Hereditary Genomics and worked

on the Huntington Disease ResearchRoster until 1998. From thereshe moved to the National Cell

Repository for Alzheimer's Diseasewhere she worked until her

retirement in September of 2001.Susan returned to work part-time

in 2002, and based on her experienceplanning autopsies for Alzheimer's

disease patients, she became theautopsy coordinator for the PROGENI

project. She arranges for the tissue tobe shipped to Indiana University forthe neuropathological examinationor makes arrangements for the tissue

removal and the neuropathologicalexamination to be done at the

removal facility.

If you have any questions about

autopsy for PROGENI, please feel freeto contact Susan at (317) 278-9683

or toll-free at (888) 830-6299 or by

email.safox@iupui.edu.

You'rein GoodCompany!By Claire EWegel, MPH, Indiana University

As a PROGENIparticipant, you areamong a large group of people fromall over the world, spanning severalcontinents, taking part in this vital

project. Over 2,200 people haveparticipated in the PROGENI and

PROGENI Cares studies by undergoing

Study Visits or providing blood samples,and these numbers continue to grow.Of that total, 85% have Parkinson

disease, and the other 15% are family,friends, and other unrelated volunteers

willing to help with this important research. While the

majorityof participantsare between the agesof 60 and80 years old, we have participants as young as 25 years

,,

... /i-

old, and our oldest participants are looking forward

to their lOOth birthday. We're grateful to all of youfor your continued support of the PROGENI study.

.

In memoriam:CliffordW. Shults,M.D.Dr.CliffordW.Shultsdied of

complications of cancer inFebruary of this year. Manyof you may not have knownDr. Shults, however, he wasinstrumental in the success

of the PROGENI study. Dr.Shults was the leader of

the PROGENI Steering

Committee for the pastfive years, and he providedcritical guidance and inputto the research ongoing in

the PROGENI Study. Hewas a co-author on 13 recent

PROGENI Study publications in addition to his workinvestigating Multiple System Atrophy as well as theeffectiveness of Co Q 10 for the treatmentof PD.

Dr. Shults was a professor of neurosciences at the

University of California, San Diego School of Medicineand a neurologist at the Veterans Mfairs San DiegoHealthcare System. He was instrumental in establishingthe Veterans Mfairs San Diego Medical Center as partof the national network of Parkinson's Disease Research,

Education and Clinical Centers (PADRECC), dedicated

to caring for veterans with the disease.

He was a PROGENI neurologist who, along withhis nurse coordinator Deborah Fontaine, saw

many PROGENI subjects. He was dedicated to thedevelopment of new treatments for Parkinson'sdisease and served on the Michael J. Fox Foundationfor Parkinson Research.

Dr. Shults was a great researcher and a compassionatedoctor. His work on the PROGENI Study is greatlyappreciated and Dr. Shults will be deeply missed by all.

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The American Parkinson DiseaseAssociation (APDA)

http://www.apdaparkinson.orgTel: 718-981-8001 or 800-223-2732

The Michael J. Fox Foundationfor Parkinson'sResearch

http://www.michaeljfox.orgTel: 800-708-7644

National Parkinson Foundation

http://www.parkinson.org/Tel: 305-547-6666 or 800-327-4544

Parkinson'sDisease Foundation (PDF)

http://www.pdf.orgTel: 212-923-4700 or 800-457-6676

Parkinson Disease information and Resources

www.pslgroup.comIPARKINSON.HTM

The ParkinsonStudy Group (PSG)http://www.parkinson-study-group.org/

World ParkinsonDiseaseAssociation

http://www.wpda.org/

Tel: [39] 02667.13.111 (Italy)

Parkinson'sAction Network (PAN)

info@parkinsonsaction.org

http://www.parkinsonsaction.orgTel:800-850-4726 or 202-842-4101

Calif:707-544-1994.Fax: 202-842-4105

PROGENIDepartmentofMedicalandMolecularGenetics

DivisionofHerditaryGenomics.410WestTenthStreet. Suite4000. Indianapolis,IN46202-3002