Mitochondrial itochondrial Newsews - UMDF · and drive-through restaurants, 1-hour photo developing, pagers, cell phones and fax machines, the Internet and e-commerce! And you expect

U n i t e d M i t o c h o n d r i a l D i s e a s e F o u n d a t i o nMitochondrial NewsMitochondrial News

Mitochondrial medicine has become one of the fastestgrowing new disciplines in medicine (Luft 1994;

1995, Graff 1999). New mitochondrial diseases are beingdescribed every year. Nearly one hundred different muta-tions in mitochondrial DNA have been described, andnearly 500 nuclear gene defects are associated with mito-chondrial dysfunction. Not all of these genetic defectscause measurable declines in oxidative phosphorylation -the process by which food and oxygen are combined tomake energy (ATP). Nevertheless, even the mitochondri-al diseases that do not cause measurable energy failurescan be catastrophic and difficult to diagnose. Ourexpanding knowledge of the molecular, biochemical, andclinical features of mitochondrial disorders has forced achange in how scientists understand these complex dis-eases. This article will review some of the hallmarks ofthese disorders in adults, and outline some of the teststhat are required for diagnosis.

“Any disease. Any organ. Any age.” This is perhapsthe best general summary of the spectrum of mitochondr-ial disease available (Christodoulou 1999). Mitochondrial

diseases are notorious masqueraders (Kerr 1998). Theycan cause symptoms that are indistinguishable from thosecaused by common disorders. Only the behavior of themitochondrial disease over time sets it apart from itsmore common cousins. Mitochondrial dysfunction hasnow been linked to common maladies as diverse as infer-tility (Jansen 1998), cancer (Susin 1998), migraineheadaches (Welch 1995), diabetes (Damore 1999), heartdisease (Hatch 1998, DiMauro 1998), blindness (Latkany1999), deafness (Fischel 1999), kidney disease (Niaudet1996), liver disease (Treem 1998), stroke (Heales 1999), thetoxicity of AIDS drugs (Barile 1998), Parkinson disease(Kosel 1999), Alzheimer dementia (Fiskum 1999), and theaging process itself (Wallace 1997). Epidemiologic studieshave established beyond doubt that when these chronicdisorders are studied as groups, they are complex andhave multiple causes - both genetic and environmental.Mitochondrial disease does not cause a majority of anyone of the disorders listed. However, it is important toremember that mitochondrial disease can be a cause of

Adult Presentations of Mitochondrial Diseaseby Robert K. Naviaux, M.D., Ph.D.

The Mitochondrial and Metabolic Disease Center, University of California, San Diego

Continued on page 13

WHAT MITOCHONDRIA DO, AND WHAT CAN GO WRONGWhen the breakdown products of the food that we eat enter the mitochon-

dria for processing, they’re passed along a well-orchestrated assembly linemade up of hundreds of proteins, each with a specific role to play in the energyproduction process. Raw materials enter the beginning of the assembly line,and ATP energy molecules come out the other side.

The major steps in the energy extraction process are (see illustration): 1. Import and export of materials, such as fat and sugar derivatives, to and

from the mitochondria 2. The breakdown of fatty acids through beta-oxidation and the removal of

electrons in the citric acid cycle 3. The passage of electrons through the major complexes of the respiratory

chain, or electron transport chain, and 4. The manufacture of ATP by ATP synthase. When any one of these steps is blocked, usually because a genetic defect has

prevented the manufacture of a protein required for that step, mitochondrial

MITOCHONDRIAINSIDE A CELL

INSIDE THE MITOCHONDRION

FAT & SUGAR"INTERMEDIATES"

Mitochondrial DNA

BetaOxidation

CitricAcid Cycle

ATP

ATP

ATP

(Energy)

IV

V

IIIII

I

3

4

2

1

Respir

atory

Cha

inAT

P Sy

nthe

sis

Mitochondrial Myopathy:An Energy Crisis In The Cells

by Sharon Hesterlee, Quest, Volume 6, Number 4, August 1999 (Excerpts)Reprinted by permission of the Muscular Dystrophy Association

This is the first of a two-part Quest series [Excerpts] about mitochondrial

myopathy. This article covers the basic biology of mitochondria and explains

inheritance patterns and determinants ofseverity in mitochondrial diseases.

Part 2 will discuss diagnosis and treatment,including a look at new information about

mitochondrial diseases in the researchpipeline. Continued on page 5

�2Spring 2000 • Volume 5 Issue 1Mitochondrial News

United MitochondrialDisease Foundation

P.O. Box 1151Monroeville, PA 15146-1151

Phone 412-793-8077Fax 412-793-6477

email: [email protected]://www.umdf.org

Board of TrusteesChuck Mohan, Chairman

Marsha BarnettBruce H. Cohen, M.D.

John DiCeccoMark Fleming

Jane Clarke McManusLee NeffNick Rillo

Scientific AdvisorsGerard T. Berry, M.D.

Richard G. Boles, M.D.Salvatore DiMauro, M.D.

Carol Greene, M.D.Richard Haas, M.B., B. Chir.

Charles L. Hoppel, M.D.Richard Kelley, M.D., Ph.D.

Douglas S. Kerr, M.D., Ph.D.Nicholas Krawiecki, M.D.

Arnold Munnich, M.D., Ph.D.Robert K. Naviaux, M.D., Ph.D.William L. Nyhan, M.D., Ph.D.

Brian H. Robinson, Ph.D.John Shoffner, M.D.

Eric Shoubridge, Ph.D.D. M. Turnbull, M.D., Ph.D.

Rajiv R. Varma, M.D.Georgirene Vladutiu, Ph.D.Douglas C. Wallace, Ph.D.

National OfficeLeslie Boyer, Executive Director

Antoinette R. BeasleyRobert BolewitzSheryl CohenJulie Hughes

Kara Strittmatter

The opinions reported in the newsletter are not necessarily endorsed by the

United Mitochondrial Disease Foundation.Our intent is to keep you informed,

and we ask that you always discuss anydiagnoses, treatments or medications

with your personal physician.

© United Mitochondrial Disease Foundation

Chairman’s ReportWHAT CAN YOU DO?

I believe every day poses new challenges as well as new opportunities butbeing a results oriented person I sometimes have a problem waiting for my

opportunities to catch up to my challenges. Don’t we all want it yesterday?And doesn’t our society force us to expect it yesterday? Drive-through banksand drive-through restaurants, 1-hour photo developing, pagers, cell phonesand fax machines, the Internet and e-commerce! And you expect me to under-stand and accept the fact that I have been waiting six months for the results ofa muscle biopsy! And when the results finally arrive I am expected to under-stand and accept the fact that effective treatment, as well as a cure, is far off insomeone else’s immediate future!

Let’s take a deep breath and address this frustration together. That’s exactlywhat your board of directors did at the first board meeting of the UnitedMitochondrial Disease Foundation. No one said, “let’s invent a cure!” We,however, took a very important and necessary step towards a cure by definingand developing the UMDF mission: To promote research for cures and treat-ments of mitochondrial disorders and to provide support to affected families.

A few years ago, I had the opportunity to speak to a group of parents anddoctors about the goals of the UMDF. Afterwards, one of the doctorsapproached me and wanted to know who I thought I was and what medicalbackground I had qualifying me to discuss the approaches necessary to reach acure. He really got my attention when he said, “You volunteers are all alike.” Itold him I consider myself a donkey not a volunteer. A donkey harnessed to alarge wagon. I told him he shouldn’t spend any time thinking about the don-key, he should be telling this donkey what he needs to find a cure for mito-chondrial diseases. I told him I couldn’t develop the complex formulas fortreatments and cures and I certainly couldn’t design the equipment that wouldtest for the diagnosis BUT, I could get him the test tubes, the computers, thenuts and bolts that would be essential for his research. I told him to load thewagon and not worry about the donkey. When the wagon gets too heavy forme to pull alone I would find others that would push and together we couldhelp him find the cure.

UMDF has been pulling that wagon for the past 5 years and it sure has got-ten bigger and loaded with more requests than we ever expected but it hasn’tgotten any heavier because every time we look around we can see more andmore people pushing. I guess that’s volunteerism.

A very good friend of mine once told me, “If you want to solve a problem,never state it to yourself in the same terms that it is presented to you in.” Yes, Ido want a cure and I know it will come as long as I concentrate on that which Iknow I can do. I can provide the test tubes!

What can you do, or more importantly, what have you done and what willyou continue to do? Fundraising, establishing support groups or developingUMDF Chapters or just helping your friends pronounce the word mitochon-dria. Don’t be afraid to feel fear, but be sure it mobilizes you and doesn’timmobilize you.

Remember; the best time to plant an oak tree was twenty ago, the next besttime is today!

Towards a Cure,

Chuck MohanChairman, UMDFBoard of Trustees

�3Spring 2000 • Volume 5 Issue 1 Mitochondrial News

Thanks To Our Contributors 9-30-99 to 2-25-00The United Mitochondrial Disease Foundation wants to thank the many people who have made contributions that will support our initiatives.

GUARDIANS ($1000+)In Honor Of All Affected by Mitochondrial Disorders

Fischer Management AssociatesIn Support of the 3rd UMDF Symposium

Mr. & Mrs. Robert M. MirvisIn Honor Of All The Children

Federation of Independent, School AlumnaeIn Honor of Dr. Bruce Cohen

Laura & Daniel LevinIn Support of the 3rd UMDF Symposium/Andrew

UhrmanLarry & Tracie Kugler

In Memory Of Avery LangfordLee Langford

In Support of the 3rd UMDF Symposium/Carly PlattCarole & Stanley Davis

In Support of the 3rd UMDF Symposium &In Memory Of Charles & Michael Barnett

Allen & Marsha BarnettIn Honor Jonah Oakes Walker

Ronald DeLucaIn Memory of Philip Neff

John & Robin RobertsLee & Matt Neff

In Memory of Cody Thomas BrackenValerie & Robert Bracken

In Honor Of David HefferonElizabeth Hefferon

In Memory Of Emma Grace MontgomeryChrist Church of the Ascension

In Honor Of The Sobeck FamilyAutomotive Booster Club of NJ

In Support of the 3rd UMDF Symposium/Gina MarieMohanSprings Blessings Fund, St. Mary of the Springs

In Memory Of Gina Marie MohanBarb & Bill Botti

In Honor Of Kelsey WrightDan & Pat Wright

In Honor Of Max DahlerbruchSidney Stern Memorial Trust

In Support of the 3rd UMDF Symposium/Philip NeffJ. Richard & Rae Hamilton

In Honor Of Taylor LagowSusan & Andrew Lagow

In Support of the 3rd UMDF Symposium March of DimesSigma Tau PharmaceuticalsVitaline CorporationMt. Sinai Health Care Foundation

SUSTAINING ($500 - $999)In Support of the 3rd UMDF Symposium

Alliance Capital Management, LPIn Honor Of All Affected by Mitochondrial Disorders

John Sheedy, IIIIn Honor Of All The Children

Dr. & Mrs. Sheldon OberfeldIn Honor Of Caitlin, Genny & Dalton Sawyer

Jeannine SawyerIn Honor Of Erik DeArce

Mr. & Mrs. Paul DeArceIn Memory Of Gina Marie Mohan

Mohan’s RestaurantIn Honor Of John Walters

Mr. & Mrs. David WaltersIn Honor Of Kyle Christopher Meyer

Mr. & Mrs. Russell MeyerIn Memory Of Lee Jordan Henrikson

Sandi & Jay HenriksonIn Memory Of Maryte “Mary” Heenan

Heenan, Althen, & RolesIn Memory Of Morgan Elizabeth Resch

Ron & Angie BjustromIn Honor Of Rachel Kindbom

Ryan HomesIn Honor of Andrew D. Garrison

Ms. Doris D. Garrison

In Honor of Heidi Marie DanielNorma Daniel Gibson

In Memory of Linda M. RiceJoseph & Patricia Rice

In Honor of all Those Affected by Mitochondrial DiseaseMarc D. Cohen

In Honor of Marisa BurnettJean Blythe

In Honor of Mary Quincy ParsonsJohn E. McFallMr.& Mrs. Robert SchellhornMr.& Mrs. William MontgomeryRandall Kent Murphy

SPONSORING ($300 - $499)In Memory Of Andrew David Bishop

Mr. & Mrs. David F. BishopIn Honor Of Chad Cooper

Bob & Linda CooperSmith-Cooper International

In Memory Of Christopher John CarracinoJoseph Zammit, Jr. and Family

In Memory Of Cody Thomas BrackenPat Moylan

In Memory Of Gina Marie MohanEvelyn & James DowneyDennis & Nancy Fantaski

In Honor Of Jessica Della ZannaTony & Karen Della Zanna

In Memory Of Morgan Elizabeth ReschCase CorporationBecky & Rick ReschEnron Foundation

In Memory Of Philip NeffMr. & Mrs. Edwin Loving

In Honor of Mary Quincy ParsonsMark & Sharon Fritz

SUPPORTING ($100 - $299)In Honor Of Adelaine “Laney” Cooper

Audrey JungClee Martin

In Honor Of Alexandra RudzitisMr. & Mrs. Dan DixonMr. & Mrs. Ray Bessick

In Honor Of All Affected by Mitochondrial DisordersChris MarinoThe Home DepotMorris & Jeannette BirSuzanne Marous

In Honor Of All The ChildrenCamille Forgues

In Honor Of Amanda Nicole PolskyPhiladelphia Insurance M.A.Mary & Anthony DiPietroAlan & Elaine Montgomery

In Honor Of Amy SchlaisQuad/GraphicsKaren & Joel Schlais

In Memory Of Brandon Glenn ThompsonRodger Homsey

In Memory Of Brian BaumLarry & Penny Baum

In Memory Of Bridget Flanagan FanoeJoanne & Dean Storkan

In Honor Of Bryan FlemingStephen & Shelley Rutty

In Memory Of Carly Ann CarieriMichele Carieri & Dan Mollnhauer

In Memory Of Casey LoughlinTina & Rich Withum

In Honor Of Christopher DickersonWillard & Amanda Dickerson

In Honor Of Claire Morris & In Memory of GertrudeShrobaJerry & Kathleen WhiteleyGregory and Susan PeylaVera Kaye LevensMary Cronin

In Memory Of Conor Philip DoerhoffBarbara De BlasiJohn & Colette Sasina

In Honor Of Cristin Murphy ZinkEileen Murphy

In Memory Of Elijah William BonneyDavid & Heather Bonney

In Honor Of Frances Anne LockwoodMark Lockwood

In Memory Of Gina Marie Mohan/John Macioce MemorialsJohn & Chris PorcoJ.J Morris & Sons, Inc.

In Memory Of Gina Marie MohanMr. & Mrs. Daniel MonacoGary BluestoneSr. Clara MohanSt. Vincent Ferrer High SchoolDr. & Mrs. Homer SnodgrassMr. & Mrs. Mark CampbellMary Ann Porco

In Honor Of Hannah & Emma BruderMarlene & Howard NovaselRichard & Pat BruderMarkowitz & Oberfeld, MD Staff

In Memory Of Jacob Lee DeMeoMr. & Mrs. Jack Williamson

In Honor Of Jenevra, Bryce & Kaylee OwenLaura & Steven Owen

In Support of the 3rd UMDF Symposium/Arielle & Jordan Cohen

Mr. & Mrs. Thomas AdlerDr. & Mrs. Richard Gold

In Honor Of Jordan & Arielle CohenMarkowitz & Oberfeld, MD StaffMarilyn & Sidney Nudelman

In Honor Of Julia ZyrollLes & Tricia Fullerton

In Honor Of Katelin & Kelsie HunterSammi Contreras

In Honor Of Katherine StewardSandy Zavrsnick & Family

In Memory Of Kayla Elizabeth NaughtonAnne M. O’SullivanAnne & John KrasnickiWilliam & Mary NaughtonWilliam & Anne Marie Naughton

In Memory Of Kevin RamseyLinda RamseyLisa Ramsey

In Memory Of Kirsten & Austin SmeltzerJulie & Tom Cullen

In Honor Of Kristen A. CharlestonAnita Koziol

In Honor Of Kyle Paul AvilaDavid StimacPaul & Monica AvilaMr. & Mrs. Robert Rice

In Memory Of Lee Jordan HenriksonDan & Amy HenriksonMichael Berman

In Honor Of Lora WasielewskiJenny Meziere

In Honor Of All Those Affected by Mitochondrial DiseaseMartha Rossi

In Honor Of Mary Quincy ParsonsMitchell & Wendi McGowanNancy Abbott FordyceMr. & Mrs. Fred HosterNancy Kemper BestWilliam V. H. ClarkeDean & Kay McGowanEddie & Sandra MelmedKatherine BerendKim JordanMedora WhiteMrs. Mary P. ClarkeMrs. Sally HoglundNancy & Charlie BahrRobert Hayes Continued on next page


UMDF Research Grant UpdateBy Mark Fleming, UMDFResearch Grant Coordinator

Exciting things are happeningwith the UMDF Research GrantProgram. The program is only threeyears old and we’ve awarded morethan $100,000 for mitochondrial dis-ease research. And, our growingresearch endowment has already sur-passed a goal originally set for 2005.The endowment will enable us tosustain research funding for years tocome through the investment incomeit generates.

We’ve had a good response to thisyear’s grant cycle. After a review ofproposals by our Scientific AdvisoryBoard we have invited eightresearchers to submit formal propos-als. Research is occurring from themost basic level to the clinical. Wewould like to fund all of these pro-jects, but will select one or two withthe most promise.

We appreciate the support thisprogram receives from members anddonors. Thank you for making it asuccess.

Grant packets become available inJuly and can be found on the Internetat http://www.umdf.org/RESEARCH.HTMto all mitochondrial diseaseresearchers at that time. If you wouldlike to be included on the mailing listin July, please contact the UMDFmain office now with your currentpostal address, at 412-793-8077.

In Memory Of Maryte “Mary” HeenanJohn & Heidi WoodrumTilcon Connecticut Inc.Hanson Building MaterialsMr. & Mrs. S. B. ShearerUnited Safety AssociatesAnne L. & Gilles DelhommeauAlan H. YamamotoFrank D’OrsiC. Irvin McClellandRex & Susie FoughtNancy & Don KnuthJames & Dale WagenmannJackson & Kelly, PLLCMr. & Mrs. Tim RappHenry ChajetLynn M. Rausch

In Memory of Herta DahlerbruchIra Bilson

In Memory Of Michael Steven HathawaySteven & Donna Hathaway

In Honor Of Mike FalconeHarold Falcone

In Memory Of Morgan Elizabeth ReschDr. William RheadHorace Mann Choice SchoolEd and Shirl DeSmetSkip-Interdistrict EarlyBandag, IncorporatedGregg OntiverosAlbert & Elaine LestorDeanne & Ronald MirrCraig & Patty TillmanVickie & Roger ClarkCandy & Jim FranzRobert & Elizabeth MooreMary BolandJoseph & Patricia MortellLoyd & Winn TarverLisa Schafman-Nelson

In Honor Of Morgan KozuchVickki Marconi

In Honor Of Natalie SundermanNeda McGuireSteven & Maryann Montgomery

In Memory Of Nicholas CornacchiaPlasticanJohn ClementiLidia Cossi

In Honor Of Nicholas NunnoMr. & Mrs. Peter C. TedescoRosario & Anna TarabocchiaMaria & Stephen Zak

In Honor Of Nicholas Nunno/Rocco Nunno MemorialsStephen T. Boswell, Ph.D., P.E.Larry & Heni NunnoCarol & Denis RorkeLydia Nunno & FamilyGloria & Peter ColliTASC/Criminal DivisionFrank CurcioEd & Cathy KubarewiczBeverly & Angelo PerilliMr. & Mrs. Michael NunnoMr. And Mrs. Rosario Lo FasoRaymond & Pamela NunnoMary & Robert NunnoMr. & Mrs. Jim BrandenburgerThe Bergen County CourtTheresa Betar

In Memory Of Philip NeffLoren Loving VailSteven & Cathy PlumpDr. David & Kim MatthewsDaniel & Marilyn EvansDonald MostiJeff & Terry StromanMatthew & Debbie LovingMeg & Stu Allen

In Support of the 3rd UMDF Symposium/Philip NeffF.R. Huntington

In Memory Of Robin Mary WilsonBetty Friedel & FamilyRobert J. & Pauline C. McWhorterJames & Shirley McWhorter

In Memory Of Ronald Paul “RJ” Victor, IIDebra & Ron VictorDr. Marcel DeRay, M.D.Helyne K. Victor

In Memory Of Sydney SimpsonRobert Bruegger

In Memory Of Timothy M. EmeryCaroline & Joe Sigona

In Honor Of Timothy RussellAndy & Mary KenyonChuck & JoAnne Parsons

In Honor Of William “Bill” EvansDr. Joan Evans

In Honor Of Zeth UllmanKurt & Dorothy UllmanNadean AdamsLynn & Paul Ullman

In Memory of Faoileann & Seamus WebbFranz & Helga Geyling

In Honor of Graham SowersBryan & Lynn DarlingBert & Danna DuncanRonny & Tami Young

In Honor of Jason Nankivell, Jr.Matrix Absence Management, Inc

In Honor of Kerie Krystina DwyerKelley Dwyer

In Honor of Ashton B. AndersonCraig & Cheryl Anderson

In Honor of Diane DeLucaPatricia Walker

In Honor of Jacob WillisChester & Faye Gierlach

In Honor of James NemitzTom & Lori Adams

In Memory of Janine SwiftMr.& Mrs. James F. O’Connor

In Honor of Kip Dickerson & In Memory of Wil KirkpatrickMrs. Carolyn Kirkpatrick

In Honor of Kristen A. CharlestonEdwin BozekKevin & Debra WernerMr. & Mrs. Marvin CharlestonMr.& Mrs. DennisMr.& Mrs. Norman Polcyn & FamilyNadine & George Kelecich

In Honor of Kyle HughesGloria Magruder

In Honor of Kyle MartinTerri Brandetsas

In Honor of Lauren SurprenantEdward Raleigh

In Memory of Lee Jordan HenriksonMary A. Stiles

In Honor of Madisyn AldeaDonna Szenyeri

In Honor of Margo QuarrlesGregory & Andrea SmithHerbert & Lilian Radin

In Honor of Marisa BurnettMr.& Mrs. Leonard Lazar

In Honor of Meghan Shea O’ConnorJim & Tina O’Connor

In Honor of Riki KusuharaCarolyn KusuharaElaine ChristensenKaryn Alexander

In Honor of Robert Merle TuckerRobert & Leigh Ann Tucker

In Honor of Ryan BenediktAnne & Barry WallisSusan BenediktThomas & Rosemary Devine

Thanks To Our Contributors 9-30-99 to 2-25-00The United Mitochondrial Disease Foundation wants to thank the many people who have made contributions that will support our initiatives.


disease can occur. The body can’t function properlybecause the cell’s ability to make energy is reduced orstopped, and metabolic intermediates and toxic by-prod-ucts begin to build up.

The energy shortage in the tissues is the major cause ofmuscle weakness, fatigue and problems in the heart, kid-neys, eyes and endocrine system. The buildup of toxicintermediates can be responsible for liver problems, mus-cle cramps, brain dysfunction or even greater mitochondr-ial damage. Many times these two types of problems rein-force one another, each making the other worse. (Thespecific problems and symptoms that occur in mitochon-drial disorders, and their management, will be discussedin greater detail in Part 2 of this series.)

Salvatore DiMauro, a neurologist at ColumbiaUniversity in New York, says that, although there aremany different types of defects that cause mitochon-drial disorders, the term mitochondrial encephalomy-opathy has come to refer only to disorders of the res-piratory chain (numbers 3 and 4 in the illustration onpage 1). (The respiratory chain is part of the cell andhas nothing to do with a person’s breathing.)

The respiratory chain consists of four large pro-tein complexes: I, II, III and IV (cytochrome c oxi-dase, or COX), ATP synthase, and two small mole-cules that ferry around electrons, coenzyme Q10 andcytochrome c. The respiratory chain is the final stepin the energy-making process in the mitochondrionwhere most of the ATP is generated; as DiMauroputs it, it’s “the business end of mitochondrialmetabolism.” Mitochondrial encephalomyopathiesthat can be caused by deficiencies in one or more ofthe specific respiratory chain complexes includeMELAS, MERRF, Leigh’s syndrome, KSS, Pearson,PEO, NARP, MILS and MNGIE.

THE MITOCHONDRIAL GENETICS MAZEThe inheritance patterns of the mitochondrial

encephalomyopathies can be quite complicated. Themutations that cause these diseases can be in the chromo-somes; this is what’s usually meant when people talkabout a genetic or inherited disease.

But mitochondrial encephalomyopathies have a uniquesituation. People can also inherit one of these diseasesthrough mutations in the mitochondrial DNA (mtDNA),which comes from the mother only. Mitochondria are theonly parts of the cells that have their own DNA, separatefrom that of the chromosomes in the cell’s nucleus, callednuclear DNA.

This situation occurs because the mitochondrial respi-ratory chain, which is the final step in the energy-makingprocess, is made up of proteins that come from bothnuclear and mtDNA (see illustration on Page 1). Althoughonly 13 of roughly 100 respiratory chain proteins come

from the mtDNA, these 13 proteins contribute to every partof the respiratory chain except complex II, and 24 othermitochondrial genes are required just to manufacture those13 proteins. Thus, a defect in either a nuclear gene or oneof the 37 mitochondrial genes can cause the respiratorychain to break down. (This respiratory chain has nothing todo with breathing.)

When mitochondrial disease is caused by defects in thenuclear DNA, the inheritance follows a “Mendelian” pat-tern, just as other inherited disorders do (named for GregorMendel, the 19th-century scientist who first explainedinheritance). These inheritance patterns include autosomaldominant, autosomal recessive and X-linked. Leigh syn-drome (caused by defects in complexes I and IV) is one ofthe most common forms of mitochondrial encephalomy-opathy inherited in this fashion. It’s usually autosomalrecessive, meaning that two copies of the defective gene,one from each parent, are required to produce the disease.

Mitochondrial MyopathyContinued from page 1

Continued on next page

70% mutantmitochondria

= severe symptoms?

30% mutantmitochondria

= mild symptoms?

Nucleus

Most healthy people have homoplasmic cells - that is, each cell has normal mitochondrial DNA. People with mitochondrial DNA mutations haveheteroplasmic cells. Each cell has a mixture of good and bad mitochondria.

“Homoplasmic Cell”

all normalmitochondria

“Heteroplasmic Cells”

some mutant and some normal mitochondria

Normalmitochondria withnormal DNA

Mitochondriawithmutant DNA

HETEROPLASMY

Although nuclear DNA defects are relatively straight-forward, when a disease is caused by defects in themtDNA, it gets more complex. Mitochondrial genetics aremade thornier by the fact that, instead of inheriting twocopies of each mitochondrial gene (one from the father andone from the mother) in the way that nuclear genes areinherited, you inherit from your mother literally hundredsof thousands of copies of the 37 mitochondrial genes,while you inherit no mtDNA from your father. (Each of theroughly 100,000 mitochondria in the mother’s egg cell maycontain between two and 10 copies of the mtDNA genes.)

Also, when a mutation occurs in the mtDNA, onlysome of the many copies of mtDNA distributed within themitochondria of each cell will carry the mutation — a situ-ation known as heteroplasmy (see illustration above). The


ratio of mutant to normal mtDNA in each tissue, alongwith other factors, may determine the severity of the dis-ease in an individual.

Most healthy people have homoplasmic cells — thatis, each cell has normal mitochondrial DNA. People withmitochondrial DNA mutations have heteroplasmic cells.Each cell has a mixture of good and bad mitochondria.

“And therefore the nice rules that Mendel introducedover a century ago to explain autosomal recessive, domi-nant and X-linked inheritance do not apply,” says

Salvatore DiMauro, an MDA researcher at ColumbiaUniversity in New York, who has studied mitochondrialdisorders for over 30 years.

The only “rules” for inheritance of mtDNA mutationsthat can be counted on are that a father can’t pass onmtDNA mutations and a mother will pass on mtDNAmutations to 100 percent of her offspring. This pattern isknown as maternal inheritance.

But, even though all of a woman’s children will inherither mtDNA mutations, that doesn’t make it easy to pre-dict how severe the disease will be in each child. This isbecause the ratio of mutant to normal mtDNA passedfrom mother to child can vary dramatically and unpre-dictably with each pregnancy. Thus a mother with verymild symptoms of mitochondrial disease, perhaps not

Mitochondrial MyopathyContinued from page 5

even diagnosed as such, may give birth to one child witha very severe disease and a second child with no diseasesymptoms at all. Some researchers believe this is causedby a “bottleneck” effect during the maturation of themother’s egg cells (see chart).

MATERNAL INHERITANCE OF MITOCHONDRIAL DNA MUTATIONS

Some mitochondrial encephalomyopathies that may becaused by mtDNA mutations and are subject to the rulesof maternal inheritance are MERRF, MELAS, NARP, PEOand MILS.

In some syndromes, mtDNA mutations tend to occurspontaneously — that is, themutation isn’t present in themother or the father but has,instead, occurred very early inthe development of theembryo. This is often the casefor KSS, PEO and Pearson,three diseases that result froma type of mtDNA mutationcalled a deletion (specific por-tions of the DNA are missing)or mtDNA depletion (a gener-al shortage of mtDNA). Thesetypes of spontaneouslyacquired mutations aren’t usu-ally passed to the next genera-tion.

A third kind of mito-chondrial disease inheritanceis a combination of nuclearand mtDNA defects. This typeof disease is inherited in aMendelian fashion, indicatingthe involvement of a nucleargene, but is also characterizedby mtDNA deletions. In thiscase, the mtDNA deletionsoccur because there’s a “break-down in communication”

between the nuclear and mitochondrial DNA.An example of this type of disease is MNGIE. Editor’s

Note: We would like to thank the Muscular DystrophyAssociation (MDA) for sharing portions of their August1999 article. Although some UMDF members may havealready read this article, we found it very informativeand a reprint would give those who have not read it achance to see it.

To read the complete articles (Part 1 and Part 2) by Sharon Hesterlee, please visit the MDA website at

http://mdausa.org/publications/Quest/q64mito.html or you may call the UMDF office for other contact information.

child with= severe

disease?

child with = mild

disease?

child with = no

disease?

80% mutant +

50% mutant +

20% mutant +

number of mitochondria

increases

“Bottleneck Effect”

cells that willbecome egg cells

mature egg cells

sperm cells(no mitochondria)

mother’s cellsmay have 20%

mutant mitochondria

small number ofmother’s

mitochondriaselected randomly

goes into eachearly egg cell

contributionfrom

mother

contributionfromfather

possibleoutcome

mother withmild or nosymptoms

MATERNAL INHERITANCE OF MITOCHONDRIAL DNA MUTATIONS


Mohan ReceivesPrestigious JeffersonAward

Chuck Mohan, Chairman of theUMDF Board, was honored as arecipient of the Jefferson Award onJanuary 20, 2000. He received theaward for founding UMDF, for thecountless hours he spent talking withfamilies devastated by a mito diag-nosis, and for his unselfish commit-ment to raising research money for adisease that had already claimed thelife of his daughter.

Two hundred people in the south-western Pennsylvania area werenominated for the award. Of thisgroup, forty-six were given the“Community Champion” designa-tion. From forty-six CommunityChampions, 11 judges chose six win-ners of the 1999 Jefferson Award.Chuck was one of the six.

Chuck and his story appeared inthe January 13, 2000, edition of thePittsburgh Post Gazette. The two-page story detailed Chuck’s personalstory as well as information on mito-chondrial disease. As a result of thearticle, UMDF received many calls,and one person hand-delivered a siz-able donation, “because [he] wasinspired by the work of one man.”

Chuck was also honored at areception and ceremony on January20 at the Pittsburgh Carnegie ScienceCenter. As he accepted the award, hegave a heartfelt speech that movedmost of the audience to tears.

This is the second member ofUMDF’s Board of Trustees to receivea Jefferson Award. In 1997, MarshaBarnett received the award for herefforts in establishing the Michaeland Charles Barnett Center for thestudy of Mitochondrial Disorders.

UMDF Mission Statement

To promote research for cures andtreatments of Mitochondrial Disorders

and to provide support to affected families

COMMON MITOCHONDRIAL DISEASES AFFECTING MUSCLE

(also part of MDA Quest Excerpt)

The terminology used in describing mitochondrial disorders can be confusing. Asingle syndrome (combination of symptoms) may have many different causes, whilemore than one syndrome may have the same cause.

In most cases, the underlying causes of these syndromes are deficiencies in therespiratory chain of the mitochondria (see “What Mitochondria Do” page 1). You maybe given a diagnosis named for the cause, such as COX deficiency or complex I andIV deficiency. The following have names based on the symptoms of the disease, butare caused by respiratory chain deficiencies.

■ Mendelian Inheritance

● Maternal Inheritance

▼ Sporadic

KSS: Kearns-Sayre syndrome ▼Onset: Before age 20Disease characteristics: May cause blindness, eye muscle paralysis, severe heart problems, coordination problems, mental retardation and coma.

Leigh’s syndrome: Subacute necrotizing encephalomyopathy ■Onset: Infancy; progression can be fast or slow.Disease characteristics: May cause brain abnormalities, vomiting, seizures, feeding difficulties, heart problems, epilepsy, speech difficulties and muscle weakness.

MELAS: Mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes. ●This is the most common type of mitochondrial encephalomyopathy. Onset: Before age 20Disease characteristics: May cause exercise intolerance, seizures, dementia, muscle weakness, heart problems.

MERRF: Myoclonus epilepsy with ragged-red fibers ● ▼Onset: Usually before adolescence; variable progression.Disease characteristics: May cause epilepsy, coordination loss, dementia and muscle weakness.

MILS: Maternally inherited Leigh’s syndrome ●Disease characteristics: Same as Leigh’s syndrome

MNGIE: Myogastrointestinal encephalomyopathy ■Onset: Before age 20Disease characteristics: May cause eye muscle paralysis, muscle weakness, digestive tract disorders, loss of coordination and brain abnormalities.

NARP: Neuropathy, ataxia and retinitis pigmentosa ●Onset: Infancy or childhoodDisease characteristics: May cause vision problems, lack of coordination and mental retardation. This syndrome may represent a less severe form of MILS.

PEO: Progressive external ophthalmoplegia ▼ ● ■Onset: Usually in adolescence or early adulthood; slow progression.Disease characteristics: May cause paralysis of eye muscles, drooping eyelids, muscle weakness and fatigue.

Pearson syndrome: ▼Onset: ChildhoodDisease characteristics: Severe anemia and pancreas malfunction; children who survive the disease may develop KSS as adolescents.

THE SCHEDULE:

FRIDAY, JUNE 2, 2000

9:00-12:00 Hospitality Suite hosted by the Ohio Support Group12:00-1:30 Registration and Box Lunch1:30-2:00 Welcoming Remarks

Chuck Mohan, Chairman, UMDFLeslie Boyer, Executive Director, UMDFSheryl Cohen, LISW, Support Coordinator

2:00-3:00 Introduction and Overview of Energy MetabolismBruce H. Cohen, M.D., Chief, Section of Child Neurology, Cleveland Clinic Foundation

3:00-3:30 Beverage Break3:30-4:30 Issues in Adults with Mitochondrial Diseases

Robert K. Naviaux, M.D., Ph.D., Assistant Professor, Biochemical Genetics and Metabolism, Mitochondrial and Metabolic Disease Center, UCSD School of Medicine

5:00-5:45 Keynote AddressBernadine P. Healy, M.D., President and Chief Executive Officer, American Red Cross

5:45 Break6:30-7:00 Reception (Cash Bar)

7:00-10:00 Banquet

SATURDAY, JUNE 3, 2000

8:00-9:00 Continental Breakfast9:00-9:45 Breakout Session A

“End of Life Care” - Sarah Friebert, M.D., Pediatric Medical Director, Hospice of the Western Reserve; Mary Kay Tyler, RN. PNP, Pediatric Team Leader, Hospice of the Western Reserve

10:00-10:45 Breakout Session B“Families Dealing With Chronic Illness” -Sheryl Cohen, LISW, Clinical Social Worker

11:00-11:45 Breakout Session C“Nutritional Support” - Phyllis Acosta, Ph.D., Director of Metabolic Disease, Ross Product Division, Abbott Laboratories; Najeebah Shine, Registered Licensed Dietician, Cuyahoga County Board of Health

12:00-1:30 Luncheon with PhysiciansA panel of six clinicians will field questions from the audience

1:30-2:30 Genetics of Mitochondrial DiseasesJohn Shoffner, M.D., Director Molecular Medicine, Children’s Healthcare of Atlanta

2:30-3:00 Beverage Break

3:00-4:00 Treatment for Mitochondrial DiseasesRichard Haas, M.D., Professor of Neuroscience and Pediatrics, Mitochondrial and Metabolic Disease Center, UCSD School of Medicine

4:00-5:00 Review of the Medical Meeting - Bruce H. Cohen, M.D.will review the proceedings of the June 1-2 Scientific Meeting and will summarize important information

5:00-5:30 Business MeetingA general membership business meeting will be held.UMDF Bylaws Amendments and other business will be covered at this time.

HOTEL RESERVATION INFORMATIONA block of rooms has been reserved at the Marriott Airport Hotel atthe special rate of $85.00/night. Please call 800-228-9290 or 440-542-2312 to make reservations. Be sure to say that you are part of the“UMDF” meeting in order to get the special rate.Reservations must be booked by May 4, 2000. After that date, thespecial rate may not apply. However, space is limited, so please makeyour reservations early! Any advance deposit is refundable if thereservation is cancelled at least 48 hours in advance.

IMPORTANT INFORMATION

CANCELLATION POLICYIf cancellations are received in writing by May 15, 2000, the reserva-tion fee will be refunded. There will be no refunds after May 15, 2000.If you wish to send an alternate attendee, please notify us. Refundswill be mailed after the conference.

CHILD ATTENDANCE POLICYChildren will not be permitted at conference sessions. The conferenceis intended as a professional and educational weekend for adult partic-ipants. Please make other child-care arrangements. Additionally, thoughthe doctors have generously agreed to participate in the family meet-ing, there will be no doctor appointments taken during the conference.

The 2000 International Conference on Mitochondrial DiseasesUMDF is pleased to invite you to attend the third international symposium on mitochondrial diseases. This intensivetwo-day conference will provide you an opportunity to learn more about the latest developments in the study of the

disorder as well as treatments, psycho-social issues, and other concerns related to this illness.We want to you to come away from the conference armed with a better understanding of how to help yourself and other

affected family members. We have invited experts in the field to speak - from researchers and clinicians to dieticians and social workers. Whether you are “new” to mitochondrial disorder, or have been dealing with it for a while, you

will find information of value at the symposium.

STOP BY THE HOSPITALITY SUITE!Symposium registrants are encouraged to visit a hospitality

suite that will be hosted by the Ohio Support Group on Friday,June 2, from 9:00 a.m. to noon, at the Marriott Airport Hotel.Signs will direct registrants to the hospitality area.

Participants that arrive the night before or get in earlier in the morning will be able to meet other families over acup of coffee. It will also be a time to share itineraries or gettogether with old friends.

UMDF thanks the Ohio group for its generosity and time inhosting this event!


ORGAN SYMPTOMS

Brain Migraine

Gastrointestinal Gastroesphageal reflux, bowel pseudo-obstruction

Muscle Cramping and aching

Nerve Burning or knife-like

Before discussing pain assessmenttechniques, we must briefly

address the fact that pain myths stillexist in society—-even today. Manymisconceptions surround the notionthat children do not experience pain.Perhaps the most blatant manifesta-tion of these beliefs is the continuedpractice of performing circumcisionswithout analgesia (pain medication).Here is some simply stated data tostore for when you encounter indi-viduals who think this way.

Early in the gestational period,fetal peripheral nerve endings arepresent and functional. An intrinsicopioid analgesic system (similar tocirculating endorphins) is also inplace. It is not totally clear what thissystem does for the fetus. It isthought that the analgesic systemprotects the fetus from asphyxia (lackof oxygen) and acidosis (low pH)during the labor and deliveryprocess.

Two types of nerve fibers exist thatare capable of pain impulse transmis-sion - A delta fibers and C polymodalfibers. The former are myelinated(coated with a protein sheath) andtend to predominate in more superfi-cial structures. These fibers are mostlikely responsible for quick with-drawal of a body part away from ahot iron, for example. C polymodalfibers tend to predominate in deeperstructures and are unmyelinated.Contrary to what some believe,myelin is not necessary for painimpulse transmission. Though chil-dren’s nerves are not completelymyelinated until approximatelyschool age, this does not mean theycannot feel pain. Myelin enhances thesmoothness and rapidity of painimpulse transmission-it does not needto be there for impulse transmissionto occur. If you watch a baby closelywho is experiencing a heel stick, forexample, you will observe that thebaby has a delayed response to the

pain stimulus. He cannot react imme-diately because the impulses are tak-ing a bit longer to reach his cerebralcortex or brain. This delayed trans-mission time is balanced by the short-er distance impulses have to travel ina small infant or young child.

Another goal to achieve beforebecoming an expert in assessing yourchild’s pain is understanding your“pain prejudices.” We all have themand they are not always as overt asbelieving people of certain cultures“are stoic when they are hurting” orbelieving that “adolescent boys are

boo” making it challenging to man-age the pain without a clear, detaileddescription. Pre-verbal or nonverbalchildren present an entirely differentset of challenges.

BEHAVIORBabies can anticipate negative

stimuli as early as 6 months of age.Behavioral pain responses in verysick or compromised infants (birth to1 year) may be subtle. Research hasdemonstrated some of the followingbehaviors as being indicative of painin infants: lip smacking, facial grimac-

Is Your Child in Pain? Basic Assessment Tips for Parents By Tracy Pasek, RN, MSN, CCRN

Advanced Practice RN, PICU, Children’s Hospital of Pittsburgh

Continued on page 12

Pain Syndromes In Mitochondrial Disease

Provided by Bruce H. Cohen, M.D., The Cleveland Clinic Foundation

babies if they cry when they arehurt.” Pain prejudices may be asseemingly insignificant as pridingyourself in not being a “pill taker” orboasting that you did not require anepidural during labor. Get in touchwith what you really think aboutpain-it will influence how you pro-ceed with pain assessment. Also,consider moving suspicion of painmore to the forefront of yourthoughts. Instead of assuming that asick baby is crying because he is hun-gry, ask yourself “Is there any reasonwhy he might be in pain?” Is some-thing about the disease process caus-ing pain?

How does one know when a childis in pain? Pain responses are notalways as obvious as writhing andcrying intensely. Children with lim-ited vocabulary may only be able todescribe pain as an “owie” or “boo

ing, yawning & eyebrow furrowing.Neonates and premature neonatesmay simply lie still with their eyesclosed when they are in pain.Though they appear to be sleeping,they may be totally overwhelmedwith stimulation and cannot tolerateany more environmental input. Theydon’t have the reserve to cry, kick orwithdraw like a healthy infant can.

Toddlers exhibit unique behaviorswhen they are in pain. Unfortunately,they are often described as beingaggressive in a painful threateningsituation. Toddlers are particularlyvulnerable because they have verylimited vocabulary and little to noconcept of time. They may be forcedto express themselves motorically.Kicking, punching and attempts atbiting are not uncommon. It is partic-ularly important with this age group


Mom Runs Race of Her LifeAs is so often the case with families dealing with mito-

chondrial disease, Becky Resch was a mom who felt thatshe wanted to do more for her child, Morgan. “Morgie”as she was affectionately known, was threeyears old before her symptoms beganto occur. She developed tremors, herbalance and walk deteriorated, andher energy level became low. Aftermonths of doctor visits, she was diag-nosed with Leigh’s Disease andCytochrome C-Oxidase Deficiency.

Becky and her husband were desper-ate to find help, but they were told thatthe most they could hope for was atmost - two more years with their child.Morgie was only four years old.

But Morgie was full of strength anddetermination. She battled and overcamethe odds. She attended school and playedregularly with her friends. She was aninspiration to others, and while her body sometimes gaveway, her spirit endured. She was a delight to be aroundand she brightened everyone’s day.

While Becky was giving Morgie supplements anddoing everything possible to slow the progression of herdisease, she wanted to do more. She got the word out toher local community and began to raise awareness aboutmitochondrial disorders.

This summer, Becky and her friend, StephanieFreeman, decided to train for and run in the Quad CityMarathon. A 26.2 mile race is grueling by any standard,but Becky turned this race into an opportunity to raisemoney and raise awareness of mitochondrial disease. Shedecided to get people to pledge money to UMDF for eachmile she completed in the race.

“I was amazed at the outpouring of love and generosi-

ty from family, friends and other acquaintances, but alsofrom total strangers,” remarked Becky. “It seemed likepeople were grateful to be asked to help.”

On September 24, 1999, Becky and Stephanie ran therace. It was a metaphor for life - the race was difficult, butlike any challenge, it was rewarding. They completed all26.2 miles. Becky was able to get media coverage for hercause, and raised an astounding $15,000! UMDF is grate-ful for the Resch’s unselfish support and work on behalfof all those who suffer from mitochondrial disorders.

Morgan Elizabeth Resch passed away on October 15,1999. Becky wanted to tell us that, “knowing what I know now, that I would not have Morgie more than 8years, would I go through it all again?” “ Yes,” she said, “in a heartbeat.”

The UMDF National Office receives numerous callsfrom persons interested in organizing a fundraiser (whichis GREAT). The staff will provide them with materials,which will hopefully help them get started. Fundraisingcan be fun, but it can also be challenging. “First timers”are often surprised by their success.

Mr. William Webbe, of England, decided to givefundraising a try. In May of 1999, Mr. Webbe emailed methat he planned to cycle in the Etape du Tour De France.He asked for a layman description of mitochondrial dis-ease and a pledge form. I immediately emailed him backwith an easy to understand description of mitochondrialdisease, a pledge form (tailored for cyclists), and then

mailed hard copies along with 15 UMDF brochures. Mr. Webbe obtained sponsorships for his cycle ride in

the Etape du Tour, which was held in July. The Etape is anopportunity for amateur cyclists to participate in one ofthe stages of the Tour De France, the most prestigious raceof the cycling world. Mr. Webbe was one of 5,500 riderswho tackled a 125-mile course through the Massif Centralregion of France. On November 11th, the office received acheck (made out in U.S. currency) for $7,056.56. Mr. Webbesingle handedly raised this money by obtaining pledgesfor his ride.

When that fundraising call comes in, “you just neverknow” how it will turn out!! Thanks again Mr. Webbe!

You Just Never Know by Kara Strittmatter

Fundraisers


Chairman of Rutherford Elks Club, Joseph Europa, presents$1,000 to Angela & David Nunno

Support UMDF -Win a Weekend in New York City

Joe Rice, of St. James, New York, is holding a raffle to benefit UMDF as amemorial to his wife, Linda Rice. “A Weekend in New York”, May 19th and20th, will include a luxury hotel suite, dinner for two and a Broadway showfor two. Cost for one chance is $5 or six chances for $25. Drawing date is April30, 2000, 9:00am, at the Café Testarossa, Syosset, New York. Winners do nothave to be present to win. Anyone interested in purchasing tickets should con-tact Joe at 516-236-3998.

We thank Joe for his unique and generous idea! Joe has already brought inover $1,000 and we hope to print the final tally in the next newsletter as well asthe WINNERS! Thank you in advance to all who participate in the raffle andwe wish the winner a great time in NYC!!

First Annual Nicholas NunnoDinner to Benefit Mitochondrial

Disease Research

Fundraisers

Halligan’s Pub Hosts Another Successful You Go Girl Golf Outing

Airline InformationThe National Patient Travel Center(formerly National Patient Air TransportHelpline)4620 Haygood Road, Suite 1Virginia Beach, VA 23455Email: [email protected] or 1-800-325-8908www.patienttravel.org or 1-800-296-1217

Miles for Kids in NeedAmerican Airlines offers one flight perpatient, must be referred by a non-profitorganization, based on financial need.Phone: 817-963-8118

Continental Care ForceContinental Airlines offers free flight certificates for patients. Run by a volunteer - Bob Jack.Phone: 281-261-6626

AirLife LineA national network of volunteer pilots whodonate free air transport for ambulatorypatients and time critical cargo. Goesstrictly on basis of need. Limited to 800-900 miles one way.Phone: 916-641-7800 (PST)Phone: 800-446-1231

Angela and David Nunno are not new to the outstand-ing fundraising efforts accomplished by UMDF members.In the past few years, they have brought in over $30,000including their most recent endeavor on September 25,1999! The Nunnos held their First Annual Benefit Dinnerin honor of their five-year-old son, Nicholas. The Dinnerraised $15,010 and now the Nunno’s hope to continue thisevent on an annual basis. Angela and David noted thefollowing in their dinner program:

On January 12, 1998, after months of testing, Nicholaswas diagnosed with Mitochondrial Encephalomyopathy,an incurable neuromuscular disease. From that moment,our lives changed forever. The future of our son’s lifebecame very uncertain. But through everything, the peo-ple that love Nicholas have worked very hard to keep himas healthy and happy as possible.

We, Nicholas’ parents, would like to thank everyonewho has helped with this dinner. We would also like tothank everyone who has purchased a ticket, donated a giftor sent in money directly to the UMDF. We must work tofind a cure now, and this dinner is a step towards a cure.

Angela & David Nunno

UMDF gratefully acknowledges Angela and David’s efforts.Their hard work and generosity will help pave the way to that

“path to a cure!”

On October 6, 1999, Halligan’s raised over $6,500 to benefit UMDF and local newspaper coverage was great! Chairperson for the event, Jane Jacquinto, organizes the annual event in honor of the Shelly Family - Maripat, Pat, Kevin, Brendan and Maili. This unique women’s golf outing offers nine holes of golf, refreshments, course contests, great prizes and a buffet lunch at Halligan’s Pub. What more can a golfer ask for!!!!Thank you for your continued support!


to NOT use the words “good” and“bad” during painful situations.Rather, they should be rewarded forsurviving a painful procedure bybeing told they are brave. Lying still isnot “good” nor is crying “bad.”

At this time, it is necessary to dis-cuss pain assessment scales or tools.Many pain scales exist. None are ideal.Pain scale development has been theresult of many a doctoral dissertation.They are often useful for childrenbetween the ages of 3 and 7 (preschooland early school age.) Children in thisage span have difficulty quantifying.They may have a hard time using anumeric scale (1-10) because they maynot understand that “5” means worsepain than “2.” Obviously, this agegroup cannot use scales with words onthem—these should be reserved foruse with children who can read. Painscales for this age group are oftencomprised of faces. A child can choosewhich face “looks” like the degree ofpain he is having.

School-age children are rule-orient-ed. They may cope with pain by“behaving” and being “good patients”similar to being “good students.”They may not want to complain orcause trouble. These kids may evendeny pain to avoid getting a “shot.” Infact, many children-regardless of age-will go to great lengths to avoid nee-dles. This age on through adolescenceis where a new set of challenges withpain assessment begins. Typically,people think that unless there areovert signs of pain-crying, screaming,etc.-a child is not experiencing pain.Adolescents may also cope with painthrough activity and may even playcomputer games in the presence ofpain. Both school-agers and teens maybegin to be able to use more sophisti-cated pain scales due to their advanc-ing cognitive level. However, this isnot a given.

OTHER SIGNS OF PAINThe autonomic nervous system

(ANS) responds to pain. Increasedheart rate (tachycardia), sweating,

decreased oxygen levels, increasedblood pressure are a few nonspecificpain responses. They are called non-specific because these things can hap-pen as a result of stressors other thanpain like anxiety or fear, for example.

HOW CAN YOU ADVOCATE FORYOUR CHILD?

Take an active role in assessingyour child’s pain. Keep a diary. Trackpain responses at home, at the doc-tor’s office and in the hospital.Observe for trends and similaritiesduring different situations. Recordwhat works and what doesn’t workfor your child. Review your findingswith your child’s nurses and doctors.Work with your healthcare providersto secure a pain assessment scale thatsuits your child’s needs. Numerousones are available and the literatureon this topic is vast. Laminating willallow you to wipe your pain scalesclean. Scales should match yourchild’s cognitive level. Partner withyour healthcare providers to learnhow to use the tool so that there isconsistency. Using pain scales takespractice for both the parents and thechild. Though this may be awkwardat first, perseverance will pay off.Never introduce a pain scale to yourchild the first time during an acuteepisode of pain. Learning will notoccur. Practice using it when yourchild is comfortable.

You can play a significant role inyour child’s ability to cope during

painful times. Your presence is vital.If you can manage to stay with yourchild during painful situations (someparents may get sick or faint), thendo so! Being in the room with yourchild can greatly reduce his anxietywhich will, in turn, decrease his per-ception of pain and make it seem bet-ter or more tolerable. Remember,you know your child better than any-one. Ask questions and provideinput. Healthcare providers willvalue your expertise and your childwill benefit.

The following are some valuableresources with accompanying refer-ence lists that will assist you withlearning more about pediatric pain.

1. Schechter, N.L., Berde, C.B. &Yaster, M. Pain in Infants, Childrenand Adolescents. 1993. Williams &Wilkins, Baltimore, Maryland. (book)

2. Kuttner, L. No fears, no tears:children with cancer coping withpain. Vancouver, BC: CanadianCancer Society, 1986. (video)

3. Walker, ME, Wong, DL. A battleplan for patients in pain. AmericanJournal of Nursing (1991);91:32-36.

You can also subscribe to the fol-lowing quarterly newsletter for thelatest research pertaining to pediatricpain:

Pediatric Pain LetterPsychology DepartmentJill Hatchette, Managing EditorDalhousie UniversityHalifax, Nova Scotia, BeH4J1email: [email protected]

Is Your Child in Pain?Continued from page 9

If you are looking to start or add to your art collectionUMDF may have something of interest

UMDF would like to thank Mr. & Mrs. Richard Perry for their generous donation of Red Skelton Lithographs (the Perrys donated the lithographs in honor of Heidi Marie Daniels). Mr. & Mrs. Perry graciously donated a total of

12 Red Skelton Canvas Transfer Lithographs; each print is framed and has a certificate of authenticity signed & thumbprinted by Mr. Skelton. He personally

autographed them only after they were sold and all issues are sold out. Many of the images did not reach their full edition quantities before his death and this fact

makes some scarce, which affects value.

UMDF may already have a buyer for the entire collection. Interested parties may still contact the UMDF office at 412-793-8077 to check status of the lithographs.


any of these disorders, because mito-chondrial disease tends to extend toother organ systems, progress withage, and respond poorly to currenttherapy. A comprehensive listing ofsigns and symptoms of mitochondri-al disease is beyond the scope of thisarticle. This is true in part becausethe general statement quoted at thebeginning of this paragraph is a clini-cal fact. The more patients we evalu-ate with proven mitochondrialdisease, the broader the spectrumof signs and symptoms becomesthat we normally associate withany particular disease. A fewexamples will be reviewed belowto clarify this point.

Even a single point mutation inmitochondrial DNA can producemany different diseases. Perhapsthe best studied example of this isthe A3243G mutation first linkedto the disease called MELAS(mitochondrial encephalomyopa-thy, lactic acidemia, stroke-likeepisodes). In our experience at theMitochondrial and MetabolicDisease Center (MMDC), adultsbearing this mutation in mito-chondrial DNA frequently pre-sented with diabetes years beforeonset of brain disease. Somepatients first suffered psychiatricdisease and hearing loss fordecades before the onset of recur-rent stroke-like episodes and dia-betes led to the correct diagnosis.Other patients had early onsetdementia in their 30s that wasundiagnosed until the occurrenceof a seizure and stroke-like episode.In still other patients, the single man-ifestation of this mutation was anunexplained cardiomyopathy andmildly elevated lactate. Nearly athird of the patients who carry theA3243G mutation had near normalblood lactic acid levels. In thesepatients, only the cerebrospinal fluidlactic acid was elevated. In 10-15%,lactic acid was elevated neither in theblood nor spinal fluid. The message

slow progression before all thesesymptoms are present together. Mostoften in adults, the symptoms willappear one by one over severalyears. When progression is relativelyslow, adult patients will typically bereferred to a new medical specialistevery few years, to take care of eachnew symptom as it appears. Often itis a medical student trying to makesense of the multisystem disease whoprompts a referral to a mitochondrialand metabolic disease center wherethe final diagnosis is made.

If mitochondrial disorders are socomplex and protean, how cangeneral physicians make the diag-nosis? A systematic approach isessential. It would be wrong to saythat everyone with diabetes orheart disease should be checkedfor mitochondrial disease. Table 1lists three rules of thumb that canhelp guide anyone who suspectsmitochondrial disease. If theanswer to any two of the threerules of thumb is yes, and the rea-sons for these affirmative answersare not explained by the patient’spresent diagnosis, then a mito-chondrial work-up is justified.Table 2 lists the standard tests thatare required in the evaluation ofsuspected mitochondrial disease. Icall this the “5 + 2” evaluation.Frequently, the results of thesetests will suggest other studiesthat may need to be performed,but these 7 tests will provide asolid database upon which therational selection of additionalstudies can be based. The first fivetests listed (omitting brain spec-troscopy for the moment) are rela-tively non-invasive and can usual-

ly be performed for about $1500. Thelast two tests are more costly, but areconsidered by many specialists to bethe most informative. The brain MRIand muscle biopsy, along with theassociated respiratory chain assays,and mtDNA testing may cost about$5000. When the results of theseseven studies are combined withcareful medical history, family histo-ry, and serial physical examinations,

Adult PresentationsContinued from page 1

Continued on next page

is that not all patients with theA3243G mutation have MELAS.Similarly, most adult patients whocarry the T8993G mutation, oftenreferred to as the NARP mutation, donot have the “neuropathy or neuro-genic muscular weakness, ataxia, orretinitis pigmentosa”, for which theacronym was coined. These factsillustrate that the name of a mito-chondrial disease can be misleading.Physicians and patients who rely onan acronym like MELAS or NARP toguide them in making a diagnosiswill be wrong more often than not.

Even classical mitochondrial diseaseslike Kearns-Sayre syndrome can bedifficult to diagnose when the firstsymptoms appear. Neither the onsetnor the rate of progression to otherorgan systems is stereotyped. Whenptosis, ophthalmoplegia, retinopathy,ataxia, weakness, exertional fatigue,cardiac conduction block, elevatedcerebrospinal fluid protein, andragged red fibers are all presenttogether, the diagnosis is simple.However, it may take decades of

TABLE 1. RULES OF THUMB

Think mitochondria when:1. A “common disease” has atypical features

that set it apart from the pack.2. Three or more organ systems are involved.3. Recurrent setbacks or flares in a chronic

disease occur with infections.

TABLE 2. DIAGNOSTIC TESTING FOR MITOCHONDRIAL DISEASE

1. Blood for mtDNA (PCR and Southern)

2. Blood and CSF for Lactate and Pyruvate, or Brain MR Spectroscopy

3. Urine Organic Acids (by GC/MS)4. Plasma and Urine Amino Acids5. Blood and Urine Carnitine6. Brain MRI7. Muscle Biopsy

Neuropathology and Electron MicroscopyMitochondrial Electron Transport StudiesFresh (coupled) mitochondrial PolarographyMuscle mtDNA (PCR and Southern)


and assembled by a metabolic special-ist with expertise in neurometabolicdisease and mitochondrial medicine,an accurate diagnosis can be reachedin about 50% of the adult patientsreferred for suspicion of mitochondri-al disease. Among children, the yieldis higher. These studies permit anaccurate diagnosis in about 75% of thechildren referred for evaluation ofsuspected mitochondrial disease.

The figures quoted in the para-graph above are influenced by thecurrent state of the art, and by thenature of the patients referred to aspecialty center for diagnosis.Research is being conducted todaythat will change these figures signifi-cantly. New diseases are being discov-ered. New methods of diagnosis arebeing developed. New experimentalsystems and animal models of mito-chondrial disease are being construct-ed, and new treatments are being test-ed. Both clinical and basic researchare absolutely essential for thisprogress. The history of scientificprogress has taught us that the mostmonumental discoveries are not pre-dictable. We cannot foresee what thenext five years will be like for mito-chondrial medicine, but based on thecurrent rate of growth, it is safe to saythat there are still a number of sur-prises in store, that many cherishedbeliefs will fall, and new ideas aboutthe role and function of mitochondriain human disease will be expandeddramatically.

References1. Barile, M; Valenti, D; Quagliariello,

E; Passarella, S. Mitochondria as cell tar-gets of AZT (zidovudine). GeneralPharmacology, 1998 Oct, 31(4):531-8.

2. Christodoulou J. Somatic cell mito-chondrial mutations and respiratorychain disorders. Presented at TheBottleneck Serono Symposium, SydneyAustralia, 7-8 May 1999.

3. Damore, ME; Speiser, PW; Slonim,AE; New, MI; Shanske, S; Xia, W;Santorelli, FM; DiMauro, S. Early onset ofdiabetes mellitus associated with the

mitochondrial DNA T14709C point muta-tion: patient report and literature review.Journal of Pediatric Endocrinology andMetabolism, 1999 Mar-Apr, 12(2):207-13.

4. DiMauro, S; Hirano, M.Mitochondria and heart disease. CurrentOpinion in Cardiology, 1998 May,13(3):190-7.

5. Fischel-Ghodsian, N. Mitochondrialdeafness mutations reviewed. HumanMutation, 1999, 13(4):261-70.

6. Fiskum, G; Murphy, AN; Beal, MF.Mitochondria in neurodegeneration:acute ischemia and chronic neurodegen-erative diseases. Journal of CerebralBlood Flow and Metabolism, 1999 Apr,19(4):351-69.

7. Graff C, Clayton DA, Larsson N-G.Mitochondrial medicine—recentadvances. J Internal Med 1999; 246:11-23.

8. Hatch, GM. Cardiolipin: biosynthe-sis, remodeling and trafficking in theheart and mammalian cells (Review).International Journal of MolecularMedicine, 1998 Jan, 1(1):33-41.

9. Heales, SJ; Bola-os, JP; Stewart, VC;Brookes, PS; Land, JM; Clark, JB. Nitricoxide, mitochondria and neurological dis-ease. Biochimica et Biophysica Acta, 1999Feb 9, 1410(2):215-28.

10. Jansen, RP; de Boer, K. The bottle-neck: mitochondrial imperatives in ooge-nesis and ovarian follicular fate.Molecular and Cellular Endocrinology,1998 Oct 25, 145(1-2):81-8.

11. Kerr, DS. Protean manifestations ofmitochondrial diseases: a minireview.Journal of PediatricHematology/Oncology, 1997 Jul-Aug,19(4):279-86.

12. Kösel, S; Hofhaus, G; Maassen, A;Vieregge, P; Graeber, MB. Role of mito-chondria in Parkinson disease. BiologicalChemistry, 1999 Jul-Aug, 380(7-8):865-70.

13. Latkany P, Ciulla TA, Cacchillo PF,Malkoff MD. Mitochondrial maculopa-thy: geographic atrophy of the macula inMELAS associated Q to G 3243 mitochon-drial DNA point mutation. Am JOphthalmol 128:112-114, 1999.

14. Luft, R. The development of mito-chondrial medicine. Proceedings of theNational Academy of Sciences of theUnited States of America, 1994 Sep 13,91(19):8731-8.

15. Luft, R; Landau, BR. Mitochondrialmedicine. Journal of Internal Medicine,1995 Nov, 238(5):405-21.

16. Niaudet, P; Rötig, A. Renalinvolvement in mitochondrial

Adult Presentations Continued from page 13

cytopathies. Pediatric Nephrology, 1996Jun, 10(3):368-73.

17. Susin, SA; Zamzami, N; Kroemer,G. Mitochondria as regulators of apopto-sis: doubt no more. Biochimica etBiophysica Acta, 1998 Aug 10, 1366(1-2):151-65.

18. Treem, WR; Sokol, RJ. Disorders ofthe mitochondria. Seminars in LiverDisease, 1998, 18(3):237-53.

19. Wallace D. Mitochondrial DNA inaging and disease. Sci Am 8(Aug):40-47,1997.

20. Welch, KM; Ramadan, NM.Mitochondria, magnesium and migraine.Journal of the Neurological Sciences,1995.

SUPPORT GROUPSArizona Support Group, the Desert AngelsLeader: Cathleen KanePhone: 480-807-8271 or 480-807-3201Delaware Valley MitochondrialSupport Group, Pennsylvania (meetings in Philadelphia area)Leaders: Maria and Dave Chuisano Email: [email protected] Mitochondrial SupportGroup, FloridaLeaders: Kathy McElhinny and Christine Golden Email: [email protected] [email protected] Support GroupLeaders: Eileen Mitchell, Bill Shea &Deb SheaEmail: [email protected] Mitochondrial Support Group(provisional status of becoming aUMDF Chapter)Leaders: Jennifer & Marty LymanEmail: [email protected] California MitochondrialSupport GroupLeader: Lissa Mirand Email: [email protected] PennsylvaniaLeader: Chuck MohanEmail: [email protected]

For more information on Support Groups, call the UMDF office

at 412-793-8077 or email at [email protected]

UNITED MITOCHONDRIAL DISEASE FOUNDATION

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■■ Enclosed are my $35 Annual Membership Dues (Outside U. S. $50 in U. S. Currency )

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IF YOU WANT TO NETWORK,please fill out this form and send to UMDF even if you are already a member

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given the doctor’s name. Under no circumstanceswill any member’s name be released to anyone

but another member, and only if you haveapproved such release by indicating above.

UMDF assumes no responsibility for the protection of the data except as described

specifically in this release. At anytime, you mayrevoke your approval by delivering a writtenrequest to UMDF. Confidentiality is of utmost

importance to UMDF and is essential to encourage networking among members.


NONPROFIT ORG.U.S. POSTAGE

PAIDPittsburgh, PA

Permit No. 4899

Volume 5 • Issue 1 • Spring 2000

In This Issue:Chairman’s Report . . . . . . . . . . . . . 2Contributors . . . . . . . . . . . . . . . . . . 3Mitochondrial Myopathy . . . . . . . . . 1Symposium 2000 Schedule . . . . . . . 8Child Pain Assesment . . . . . . . . . . . . 9Fundraisers . . . . . . . . . . . . . . . . . 10Adult Presentations of Disease . . . . . 1Membership Form . . . . . . . . . . . . . 15Symposium Registration . . Back Cover

P.O. Box 1151Monroeville, PA 15146-1151

Phone 412-793-8077Fax 412-793-6477email: [email protected]://www.umdf.org

SYMPOSIUM 2000 REGISTRATION FORM (Tear off and return this portion) (Please duplicate this form for additional registrants)

Please Print : (Name will appear on your badge as you indicate here)

Name: First _____________________________________ Last _______________________________________________________ Mr., Mrs., Ms. ____________

Mailing Address _______________________________ City _________________ State ____ Province ________ Postal Code ____________ Country ______

Daytime Phone (with area code) ( _____ ) _____________________ Fax ( _____ ) ______________________ E-mail ___________________________________

FEES: (Please mark the appropriate boxes)

■■ $150 Conference fee (per person)* Fee includes all meals, refreshment breaks, access to all sessions, printed program materials and gala banquet

All meals are included. However, we need an accurate count for the following:■■ I will attend the Friday lunch ■■ I will attend the Friday banquet ■■ I require vegetarian meals

■■ I will attend the Saturday lunch ■■ I will attend the Saturday breakfast ■■ I require Kosher meals

■■ I require handicapped assistance. (Note: a few hotel rooms are equipped for people with disabilities. Please indicate your needs with the hotel.Please contact us should you require further assistance.)

PAYMENT OPTIONS:

■■ Make check payable to UMDF ■■ Credit card payment: ■■ VISA ■■ MasterCard

Card Number ___________________________________ Expiration Date: ___________

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For credit card payees only: To expedite your registration, please fax your form to: UMDF, 412-793-6477. Once faxed, DO NOT mail in original registration form.

Mail check and registration form to: UMDF, P.O. Box 1151, Pittsburgh, PA 15146-1151

Questions? Call 412-793-8077.

* A limited number of funds to offset part of the cost of attending the symposium are available for those experiencing financial hardship. To receive the applicationform for a partial scholarship, please call 412-793-8077. Our sincere thanks to Allen and Marsha Barnett for underwriting the cost of the scholarships.

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