Facts About Mitochondrial

Updated December 2009 Dear Friends:

f you are reading this booklet, it’s probably symptoms are common in the general popula- Ibecause you’ve just received a very bewil- tion, such as heart problems, and dering diagnosis: mitochondrial . . Therefore, good medical treatments What is a , and what already exist to help manage many symp- does the term mean? These are questions toms. my wife, Jennifer, and I struggled with when Always remember that researchers are con- our son, Michael, got his diagnosis in 1993. tinually moving toward better treatments, and Mitochondrial myopathies have many dif- ultimately, cures for mitochondrial . ferent faces. As you will read in this booklet, In addition, people with disabilities have great- dozens of varieties of mitochondrial diseases er opportunities than ever before to make the have been identified, with a complex array of most of their abilities, as well as legal rights symptoms. Some symptoms can be so mild to equal employment opportunity and access that they’re hardly noticeable, while others are to public places. Children with physical and life-threatening. cognitive disabilities are guaranteed by law a public education with whatever supports they Michael’s causes muscle weakness, need. muscle cramping, fatigue, lack of endurance and poor balance. You or your family member MDA has been a very valuable ally as we con- may have similar symptoms, yet each case is tinue to learn to live with mitochondrial dis- unique. ease. “MDA Is Here to Help You,” on page 14, will tell you more about MDA’s many services. When we first learned that Michael had a mitochondrial myopathy, we naturally were To us, Michael is not a victim of a disease or very frightened and uncertain about the future. a syndrome, but a happy, loving, young man The Kelly family at the MDA Labor Day Telethon. As time passed, we learned that we can do of whom we’re very proud. We’ve discovered things we didn’t think would be possible — that no one can predict exactly how Michael’s we can adapt to the uncertainty, control the or Jennifer’s cases will progress. We’ve been fear, cope with changes as they occur and still blessed to see Michael lead a normal life, have a “normal,” happy family life. earning his Boy Scout Eagle Award and being inducted into the National Honor Society. In 2004 our lives were again turned upside Michael has shown that having a mitochondri- down, when my wife, Jennifer, learned she al disease doesn’t necessarily keep you from too had a . Jennifer’s accomplishing anything you set your mind to. symptoms are more severe than Michael’s; she experiences severe muscle weakness, As we struggle to adapt to the changes in our fatigue, gastrointestinal problems, respiratory lives since Jennifer’s diagnosis, it’s reassuring problems and difficulty swallowing. to know that MDA is there for us, assisting us with equipment, clinics, continuing research, This booklet has been prepared to help you and just a friendly voice that understands understand the causes of and treatments for what we are going through. mitochondrial myopathies. We have found information to be a vital tool in managing As you face the challenges ahead, we wish Michael’s and Jennifer’s diseases and achiev- you the same blessing and the comfort of ing the best possible outcome. knowing that you are not alone.

From this booklet you’ll also learn a few Richard Kelly encouraging things. For example, although Mansfield, Massachusetts these are very rare disorders, many of their

2 Mitochondrial Myopathies • ©2011 MDA What Are Mitochondrial Diseases? ust as some diseases are named for the Because muscle cells and cells have Jpart of the body they affect (like heart dis- especially high needs, muscular and ease), mitochondrial diseases are so-named neurological problems — such as muscle because they affect a specific part of the cells weakness, , hearing loss, in the body. Specifically, mitochondrial dis- trouble with balance and coordination, sei- eases affect the mitochondria — tiny energy zures and learning deficits — are common factories found inside almost all our cells. features of mitochondrial disease. Other fre- quent complications include impaired vision, Mitochondria are responsible for producing heart defects, diabetes and stunted growth. most of the energy that’s needed for our Usually, a person with a mitochondrial dis- cells to function. In fact, they provide such ease has two or more of these conditions, an important source of energy that a typi- some of which occur together so regularly cal human contains hundreds of them. that they’re grouped into syndromes. A mitochondrial disease can shut down some or all the mitochondria, cutting off this A mitochondrial disease that causes promi- essential energy supply. nent muscular problems is called a mito- chondrial myopathy (myo means muscle, Nearly all our cells rely on mitochondria for and pathos means disease), while a mito- a steady energy supply, so a mitochondrial chondrial disease that causes both promi- disease can be a multisystem disorder affect- nent muscular and neurological problems is ing more than one type of cell, tissue or called a mitochondrial encephalomyopathy organ. The exact symptoms aren’t the same (encephalo refers to the brain). for everyone, because a person with mito- chondrial disease can have a unique mixture Despite their many potential effects, mito- of healthy and defective mitochondria, with a chondrial diseases sometimes cause little unique distribution in the body. disability. Sometimes, a person has enough healthy mitochondria to compensate for the MANY defective ones. Also, because some symp- toms of mitochondrial disease (such as diabetes or heart arrhythmia) are common in the general population, there are effective treatments for those symptoms (such as insulin or anti-arrhythmic drugs).

INSIDE A SINGLE Each mitochondrion is an energy factory that “imports” sugars and fats, breaks them down and “exports” energy (ATP).

3 Mitochondrial Myopathies • ©2011 MDA This booklet describes general causes, mitochondria. Within each mitochondrion consequences and management of mito- (singular of mitochondria), these proteins chondrial diseases, with an emphasis on make up part of an assembly line that uses myopathies and encephalomyopathies and a fuel molecules derived from food to manu- close look at the most common syndromes. facture the energy molecule ATP. This highly These include: efficient manufacturing process requires oxygen; outside the mitochondrion, there are • Kearns-Sayre syndrome (KSS) less efficient ways of producing ATP without • oxygen.

• mitochondrial DNA depletion Proteins at the beginning of the mitochon- syndrome (MDS) drial assembly line act like cargo handlers, importing the fuel molecules — sugars and • mitochondrial encephalomyopathy, fats — into the mitochondrion. Next, other and strokelike proteins break down the sugars and fats, episodes (MELAS) extracting energy in the form of charged par- ticles called electrons. • with ragged red fibers (MERRF) Proteins toward the end of the line — orga- nized into five groups called complexes I, • mitochondrial neurogastrointestinal II, III, IV and V — harness the energy from encephalomyopathy (MNGIE) those electrons to make ATP. Complexes I Mitochondrial diseases through IV shuttle the electrons down the aren’t contagious, and • neuropathy, ataxia and line and are therefore called the electron they’re not caused by retinitis pigmentosa (NARP) transport chain, and complex V actually anything a person does. • churns out ATP, so it’s also called ATP syn- thase. • progressive external ophthalmoplegia (PEO) A deficiency in one or more of these com- plexes is the typical cause of a mitochondrial What causes mitochondrial disease. (In fact, mitochondrial diseases are diseases? sometimes named for a specific deficiency, such as complex I deficiency.) First, mitochondrial diseases aren’t conta- gious, and they aren’t caused by anything a When a cell is filled with defective mitochon- person does. They’re caused by , dria, it not only becomes deprived of ATP — or changes, in genes — the cells’ blueprints it can accumulate a backlog of unused fuel for making proteins. molecules and oxygen, with potentially disas- trous effects. Genes are responsible for building our bod- ies, and are passed from parents to children, In such cases, excess fuel molecules are along with any mutations or defects they used to make ATP by inefficient means, have. That means that mitochondrial diseas- which can generate potentially harmful es are inheritable, although they often affect byproducts such as lactic acid. (This also members of the same family in different occurs when a cell has an inadequate oxygen ways. (For more information about genetic supply, which can happen to muscle cells mutations and mitochondrial disease, see during strenuous exercise.) The buildup of “Does It Run in the Family?” on page 12.) lactic acid in the blood — called lactic aci- dosis — is associated with muscle fatigue, The genes involved in mitochondrial disease and might actually damage muscle and nerve normally make proteins that work inside the tissue.

4 Mitochondrial Myopathies • ©2011 MDA Meanwhile, unused oxygen in the cell can be useful. Sometimes, people with mitochon- converted into destructive compounds called drial myopathies experience loss of muscle reactive oxygen species, including so-called strength in the arms or legs, and might need free radicals. (These are the targets of so- braces or a wheelchair to get around. called antioxidant drugs and .) Exercise intolerance, also called exertional ATP derived from mitochondria provides the fatigue, refers to unusual feelings of exhaus- main source of power for muscle cell con- tion brought on by physical exertion. The traction and nerve cell firing. So, muscle cells degree of exercise intolerance varies greatly and nerve cells are especially sensitive to among individuals. Some people might only mitochondrial defects. The combined effects have trouble with athletic activities like jog- of energy deprivation and toxin accumulation ging, while others might experience prob- in these cells probably give rise to the main lems with everyday activities like walking to symptoms of mitochondrial myopathies and the mailbox or lifting a milk carton. encephalomyopathies. Sometimes, exercise intolerance is associat- What happens to someone ed with painful muscle cramps and/or injury- induced pain. The cramps are actually sharp with a mitochondrial contractions that may seem to temporarily Mitochondrial myopathies can affect disease? lock the muscles, while the injury-induced entire families. Myopathy pain is caused by a process of acute muscle breakdown called , leading to The main symptoms of mitochondrial leakage of myoglobin from the muscles into myopathy are muscle weakness and wast- the urine (myoglobinuria). Cramps or myo- ing, and exercise intolerance. It’s important globinuria usually occur when someone with to remember that the severity of any of these exercise intolerance “overdoes it,” and can symptoms varies greatly from one person to happen during the overexertion or several the next, even in the same family. hours afterward. In some individuals, weakness is most Encephalomyopathy prominent in muscles that control move- ments of the eyes and eyelids. Two common A mitochondrial encephalomyopathy typi- consequences are the gradual paralysis of cally includes some of the above-mentioned eye movements, called progressive external symptoms of myopathy plus one or more Some people with mitichondrial myopa- ophthalmoplegia (PEO), and drooping of the neurological symptoms. Again, these symp- thies lose strength in their legs and need upper eyelids, called ptosis. Often, people toms show a great deal of individual variabil- a wheelchair to get around. automatically compensate for PEO by mov- ity in both type and severity. ing their heads to look in different directions, Hearing impairment, -like and might not even notice any visual prob- and seizures are among the most common lems. Ptosis is potentially more frustrating symptoms of mitochondrial encephalomy- because it can impair vision and also cause opathy. In at least one syndrome, headaches a listless expression, but it can be corrected and seizures often are accompanied by by surgery, or by using glasses that have a -like episodes. “ptosis crutch” to lift the upper eyelids. Fortunately, there are good treatments for Mitochondrial myopathies also can cause some of these conditions. Hearing impair- weakness and wasting in other muscles of ment can be managed using hearing aids the face and neck, which can lead to slurred and alternate forms of communication. speech and difficulty with swallowing. In Often, headaches can be alleviated with med- these instances, speech therapy or changing ications, and seizures can be prevented with the diet to easier-to-swallow foods can be drugs used for epilepsy (anti-epileptics).

5 Mitochondrial Myopathies • ©2011 MDA In addition to affecting the musculature of Though dangerous, this condition is treatable the eye, a mitochondrial encephalomyopa- with a pacemaker, which stimulates normal thy can affect the eye itself and parts of the beating of the heart. Cardiac muscle damage brain involved in vision. For instance, vision also may occur. People with mitochondrial loss due to optic atrophy (shrinkage of the disorders may need to have regular examina- optic nerve) or (degeneration of tions by a cardiologist. some of the cells that line the back of the eye) is a common symptom of mitochondrial Other potential health issues encephalomyopathy. Compared to muscle Some people with mitochondrial disease problems, these effects are more likely to experience serious kidney problems, gastro- cause serious visual impairment. intestinal problems and/or diabetes. Some of these problems are direct effects of mito- Often, mitochondrial encephalomyopathy chondrial defects in the kidneys, digestive causes ataxia, or trouble with balance and system or pancreas (in diabetes), and others coordination. People with ataxia are usually are indirect effects of mitochondrial defects prone to falls. One can partly avoid these in other tissues. problems through physical and occupational therapy, and the use of supportive aids such For example, rhabdomyolysis can lead to as railings, a walker or — in severe cases — kidney problems by causing a protein called a wheelchair. myoglobin to leak from ruptured muscle cells into the urine. This condition, myoglo- Occupational therapy is important for Special issues in binuria, stresses the kidneys’ ability to filter children with mitochondrial myopathies. waste from the blood, and can cause kidney mitochondrial myopathies damage. and encephalomyopathies Special issues in children Respiratory care Vision: Though PEO and ptosis typically Sometimes, these diseases can cause signifi- cause only mild visual impairment in adults, cant weakness in the muscles that support they’re potentially more harmful in children breathing. with mitochondrial myopathies. Also, mitochondrial encephalomyopathies Because the development of the brain is sen- sometimes cause brain abnormalities that sitive to childhood experiences, PEO or pto- alter the brain’s control over breathing. sis during childhood can sometimes cause Mitochondrial myopathy can lead to respiratory problems that require sup- A person with mild respiratory problems permanent damage to the brain’s visual port from a ventilator. might require occasional respiratory sup- system. For this reason, it’s important for port, such as pressurized air, while someone children with signs of PEO or ptosis to have with more severe problems might require their vision checked by a specialist. permanent support from a ventilator. Those Developmental delays: Due to muscle weak- with mitochondrial disorders should watch ness, brain abnormalities or a combination for signs of respiratory insufficiency (such as of both, children with mitochondrial diseases shortness of breath or morning headaches), may have difficulty developing certain skills. and have their breathing checked regularly by For example, they might take an unusually a specialist. long time to reach motor milestones such Cardiac care as sitting, crawling and walking. As they get Sometimes, mitochondrial diseases directly older, they may be unable to get around as affect the heart. In these cases, the usual easily as other children their age, and may cause is an interruption in the rhythmic beat- have speech problems and/or learning dis- ing of the heart, called a conduction block. abilities. Children who are severely affected by these problems may benefit from services

6 Mitochondrial Myopathies • ©2011 MDA such as physical therapy, speech therapy and Another substance, carnitine, generally possibly an individualized education program improves the efficiency of ATP production (IEP) at school. by helping import certain fuel molecules into mitochondria, and cleaning up some How are mitochondrial of the toxic byproducts of ATP production. diseases treated? Carnitine is available as an over-the-counter supplement called L-carnitine. While mitochondrial myopathies and enceph- alomyopathies are relatively rare, some of Finally, coenzyme Q10, or coQ10, is a their potential manifestations are common in component of the , the general population. Consequently, those which uses oxygen to manufacture ATP. complications (including heart problems, Some mitochondrial diseases are caused by stroke, seizures, , deafness and coQ10 deficiency, and there’s good evidence diabetes) have highly effective treatments that coQ10 supplementation is beneficial in (including medications, dietary modifications these cases. Some doctors think that coQ10 and lifestyle changes). (See “Special issues supplementation also might alleviate other in children,” page 6.) mitochondrial diseases.

It’s fortunate that these treatable symptoms Creatine, L-carnitine and coQ10 supplements are often the most life-threatening complica- often are combined into a “cocktail” for treat- tions of mitochondrial disease. With that ing mitochondrial disease. Although there’s The brain’s visual system can be affected in children with mitochondrial in mind, people affected by mitochondrial little scientific evidence that this treatment myopathy. diseases can do a great deal to take care of works, many people with mitochondrial themselves by monitoring their health and disease have reported modest benefits. You scheduling regular medical exams. should consult your doctor or MDA clinic director before taking any medication or Instead of focusing on specific complications supplement. of mitochondrial disease, some newer, less- proven treatments aim at fixing or bypassing What syndromes occur with the defective mitochondria. These treatments are dietary supplements based on three natu- mitochondrial disease? ral substances involved in ATP production in Note: Typically, these syndromes are inher- our cells. ited in either a maternal pattern or a so-called Mendelian pattern, and/or they’re sporadic, Although they don’t work for everyone, they which means occurring with no family his- do help some people. (Always check with tory. For more information about inheritance, your physician to see what’s best for your see “Does It Run in the Family?” page 12. condition.) KSS: Kearns-Sayre syndrome One substance, creatine, normally acts as Inheritance pattern: a reserve for ATP by forming a compound sporadic Some children with mitochondrial called creatine phosphate. When a cell’s Onset: myopathies experience developmental demand for ATP exceeds the amount its delays. before age 20 mitochondria can produce, creatine can Features: release phosphate (the “P” in ATP) to rapidly This disorder is defined by PEO (usually as enhance the ATP supply. In fact, creatine the initial symptom) and pigmentary reti- phosphate (also called phosphocreatine) nopathy, a “salt-and-pepper” pigmentation typically provides the initial burst of ATP in the retina that can affect vision, but often required for strenuous muscle activity. leaves it intact. Other common symptoms include conduction block (in the heart) and

7 Mitochondrial Myopathies • ©2011 MDA ataxia. Less typical symptoms are mental cise intolerance, hearing loss, diabetes and retardation or deterioration, delayed sexual short stature. maturation and short stature. MERRF: myoclonus epilepsy with Leigh syndrome: subacute necrotizing ragged red fibers encephalomyopathy Inheritance pattern: (MILS = maternally maternal inherited Leigh syndrome) Onset: Inheritance pattern: late childhood to adolescence maternal, Mendelian Features: Onset: The most prominent symptoms are myoclo- infancy nus (muscle jerks), seizures, ataxia and mus- Features: cle weakness. The disease also can cause Leigh syndrome causes brain abnormalities hearing impairment and short stature. that can result in ataxia, seizures, impaired vision and hearing, developmental delays and MNGIE: mitochondrial altered control over breathing. neurogastrointestinal encephalomyopathy It also causes muscle weakness, with promi- Inheritance pattern: nent effects on swallowing, speech and eye Mendelian movements. Onset: usually before age 20 MDS: mitochondrial DNA depletion Features: syndrome This disorder causes PEO, ptosis, limb Inheritance pattern: weakness and gastrointestinal (digestive) Mendelian problems, including chronic diarrhea and Onset: abdominal pain. Another common symptom infancy is (a malfunction of Mitochondrial myopathies can be Features: the that can lead to sensory impair- inherited, and severity can vary within This disorder typically causes muscle weak- a family. ment and muscle weakness). ness and/or liver failure, and more rarely, brain abnormalities. “Floppiness,” feeding NARP: neuropathy, ataxia and difficulties, and developmental delays are retinitis pigmentosa common symptoms; PEO and seizures are Inheritance pattern: less common. maternal Onset: MELAS: mitochondrial infancy to adulthood encephalomyopathy, lactic acidosis Features: and strokelike episodes NARP causes neuropathy (see above), ataxia Inheritance pattern: and retinitis pigmentosa (degeneration of maternal the retina in the eye, with resulting loss of Onset: vision). It also can cause developmental childhood to early adulthood delay, seizures and . Features: MELAS causes recurrent stroke-like episodes Pearson syndrome in the brain, migraine-like headaches, vomit- Inheritance pattern: ing and seizures, and can lead to permanent sporadic brain damage. Other common symptoms Onset: include PEO, general muscle weakness, exer- infancy

8 Mitochondrial Myopathies • ©2011 MDA Features: might proceed with more specialized tests This syndrome causes severe and that can detect abnormalities in muscles, malfunction of the pancreas. Children who brain and other organs. survive the disease usually go on to develop KSS. The most important of these tests is the muscle biopsy, which involves removing a PEO: progressive external small sample of muscle tissue to examine. ophthalmoplegia When treated with a dye that stains mito- Inheritance pattern: chondria red, muscles affected by mitochon- maternal, Mendelian, sporadic drial disease often show ragged red fibers — Onset: muscle cells (fibers) that have excessive Usually in adolescence or early adulthood mitochondria. Other stains can detect the Features: absence of essential mitochondrial enzymes As noted above, PEO is often a symptom in the muscle. It’s also possible to extract of mitochondrial disease, but sometimes it mitochondrial proteins from the muscle and stands out as a distinct syndrome. Often, it’s measure their activity. associated with exercise intolerance. In addition to the muscle biopsy, noninvasive How are mitochondrial techniques can be used to examine muscle without taking a tissue sample. For instance, diseases diagnosed? a technique called muscle phosphorus mag- None of the hallmark symptoms of mitochon- netic resonance spectroscopy (MRS) can drial disease — muscle weakness, exercise measure levels of phosphocreatine and ATP intolerance, hearing impairment, ataxia, (which are often depleted in muscles affected seizures, learning disabilities, cataracts, heart by mitochondrial disease). defects, diabetes and stunted growth — are CT scans and MRI scans can be used to unique to mitochondrial disease. However, a visually inspect the brain for signs of dam- combination of three or more of these symp- age, and surface electrodes placed on the toms in one person strongly points to mito- scalp can be used to produce a record of the chondrial disease, especially when the symp- brain’s activity called an electroencephalo- toms involve more than one organ system. gram (EEG). To evaluate the extent of these symptoms, Similar techniques might be used to examine a physician usually begins by taking the the functions of other organs and tissues in patient’s personal medical history, and then the body. For example, an electrocardiogram proceeds with physical and neurological (EKG) can monitor the heart’s activity, and exams. a blood test can detect signs of kidney mal- Diagnostic tests in function. mitochondrial diseases Finally, a genetic test can determine whether The physical exam typically includes tests of someone has a genetic that causes strength and endurance, such as an exercise mitochondrial disease. Ideally, the test is test, which can involve activities like repeat- done using genetic material extracted from edly making a fist, or climbing up and down blood or from a muscle biopsy. It’s impor- a small flight of stairs. The neurological exam tant to realize that, although a positive test can include tests of reflexes, vision, speech result can confirm diagnosis, a negative test and basic cognitive (thinking) skills. result isn’t necessarily meaningful. Depending on information found during the medical history and exams, the physician

9 Mitochondrial Myopathies • ©2011 MDA Diagnostic Tests in Mitochondrial Diseases

Type Test What it shows Family Clinical exam or Can sometimes indicate inheritance pattern by noting history oral history of “soft signs” in unaffected relatives. These include deaf- family members ness, short stature, migraine headaches and PEO.

Muscle 1. Histochemistry 1. Detects abnormal proliferation of mitochondria and biopsy deficiencies in (COX, which is 2. Immuno- complex IV in the electron transport chain). histochemistry 2. Detects presence or absence of specific proteins. Can 3. Biochemistry rule out other diseases or confirm loss of electron trans- 4. Electron port chain proteins. microscopy 3. Measures activities of specific enzymes. A special test called polarography measures oxygen consumption in mitochondria.

4. May confirm abnormal appearance of mitochondria. Not used much today.

Blood 1. Lactate and 1. If elevated, may indicate deficiency in electron trans- enzyme pyruvate levels port chain; abnormal ratios of the two may help identify test the part of the chain that is blocked. 2. Serum creatine kinase 2. May be slightly elevated in mitochondrial disease but usually only high in cases of mitochondrial DNA depletion.

Genetic 1. Known 1. Uses blood sample or muscle sample to screen for test mutations known mutations, looking for common mutations first.

2. Rare or 2. Also can look for rare or unknown mutations but may unknown require samples from family members; this is more mutations expensive and time-consuming.

10 Mitochondrial Myopathies • ©2011 MDA Mitochondrial Disease: An Inside Look

Nervous system: Seizures, spasms, developmental Eyes: delays, deafness, dementia, stroke Drooping eyelids (pto- (often before age 40), visual system sis), inability to move defects, poor balance, problems with eyes (external ophthal- peripheral nerves moplegia), blindness (retinitis pigmentosa, optic atrophy), cataracts Heart Cardiomyopathy: (cardiac muscle weakness), conduction block : Muscle weakness, exercise intolerance, cramps, Liver: excretion of muscle pro- Liver failure (uncom- tein myoglobin in urine mon except in babies (myoglobinuria) with mtDNA depletion syndrome), fatty liver (hepatic steatosis) Digestive tract: Difficulty swallow- ing, vomiting, feeling Kidneys: of being full, chronic Fanconi’s syndrome diarrhea, symptoms of (loss of essential metabolites intestinal obstruction in urine), nephrotic syndrome (uncommon except for infants with coenzyme Q10 Pancreas: deficiency) Diabetes

he main problems associated with mito- This diagram depicts common symptoms Tchondrial disease — low energy, free of mitochondrial disease, of which most radical production and lactic acidosis — affected people have a specific subset. can result in a variety of symptoms in many Many of these symptoms are treatable. different organs of the body.

11 Mitochondrial Myopathies • ©2011 MDA Does It Run in the Family? itochondrial genetics are complex, and often, a mito- Another unique feature of mtDNA diseases arises from the Mchondrial disease can be difficult to trace through a fact that a typical human cell — including the egg cell — family tree. But since they’re caused by defective genes, contains only one nucleus, but hundreds of mitochondria. mitochondrial diseases do run in families. A single cell can contain both mutant mitochondria and normal mitochondria, and the balance between the two will To understand how mitochondrial diseases are passed on determine the cell’s health. through families, it’s important to know that there are two types of genes essential to mitochondria. The first type This helps explain why the symptoms of mitochondrial dis- is housed within the nucleus — the part of our cells that ease can vary so much from person to person, even within contains most of our genetic material, or DNA. The second the same family. type resides exclusively within DNA contained inside the mitochondria themselves. Imagine that a woman’s egg cells (and other cells in her body) contain both normal and mutant mitochondria, and Mutations in either nuclear DNA (nDNA) or mitochondrial that some have just a few mutant mitochondria, while oth- DNA (mtDNA) can cause mitochondrial disease. ers have many. A child conceived from a “mostly healthy” egg cell probably won’t develop disease, and a child con- Most nDNA (along with any mutations it has) is inherited in ceived from a “mostly mutant” egg cell probably will. a Mendelian pattern, loosely meaning that one copy of each gene comes from each parent. Also, most mitochondrial Also, the woman may or may not have symptoms of mito- diseases caused by nDNA mutations (including Leigh syn- chondrial disease herself. drome, MNGIE and even MDS) are autosomal recessive, meaning that it takes mutations in both copies of a gene to The risk of passing on a mitochondrial disease to your cause disease. children depends on many factors, including whether the disease is caused by mutations in nDNA or mtDNA. Unlike nDNA, mtDNA passes only from mother to child. That’s because during conception, when the sperm A good way to find out more about these risks is to fuses with the egg, the sperm’s mitochondria — and its talk to a doctor or genetic counselor at your local MDA mtDNA — are destroyed. Thus, mitochondrial diseases clinic. Also, see MDA’s booklet “Facts About Genetics and caused by mtDNA mutations are unique because they’re Neuromuscular Diseases.” inherited in a maternal pattern (see illustration).

normal mitochondrion abnormal mitochondrion The severity of a mitochondrial disease in a child depends on the percentage of abnormal (mutant) mitochondria in the egg cell that formed him or her.

egg-cell progenitor

12 Mitochondrial Myopathies • ©2011 MDA MDA’s Search for Treatments and Cures he MDA website is constantly updated biochemical processes that go on inside Twith the latest information about the mitochondria, with the goal of correct- neuromuscular diseases in its program. ing or working around these to treat See the latest research news at www.mda. mitochondrial abnormalities, whether or org. not new genes are added. Still others are studying the behavior of mitochondria as With MDA’s support, scientists continue they exist inside cells as miniature organs to make significant progress in their quest (“”), interacting with each other to fully understand and treat mitochondrial and with other cellular components. diseases.

Unique progress has been made in MNGIE, a disease in which a flaw in a gene in the nucleus indirectly causes a mitochondrial problem. MDA-funded researchers are experimenting with infus- ing donor stem cells into patients with MNGIE to restore normal metabolic condi- tions and halt damage to the mitochon- dria.

In addition, MDA-funded scientists have identified many of the genetic defects that cause mitochondrial diseases. They’ve used knowledge of those genetic defects to create animal models of mitochondrial disease, which can be used to investi- gate potential treatments. They’ve also designed genetic tests that allow accurate diagnosis of mitochondrial defects and provide valuable information for family planning.

Perhaps most important, knowing the genetic defects that cause mitochondrial disease opens up the possibility of devel- oping treatments that target them.

As of late 2009, some MDA-supported researchers are working on ways to add therapeutic genes to mitochondria. Others are concentrating on understanding the

13 Mitochondrial Myopathies • ©2011 MDA MDA Is Here to Help You he Association Everyone registered with MDA automati- Toffers a vast array of services to help cally receives Quest, MDA’s award-win- you and your family deal with mitochon- ning quarterly magazine. Quest publishes drial myopathy. The staff at your local detailed articles about research findings, MDA office is there to assist you in many medical and day-to-day care, helpful ways. The Association’s services include: products and devices, social and family issues, and much more. Other MDA pub- • nationwide network of clinics staffed by lications can be found at www.mda.org/ top specialists publications; many booklets are available • MDA summer camps for kids with neu- in Spanish. Ask your local office for “MDA romuscular diseases Services for the Individual, Family and Community” and for help with obtaining • help with locating durable medical copies of other publications. equipment through its national equip- ment program If you have any questions about mitochon- drial myopathy, someone at MDA will help • financial assistance with repairs or you find the answer. To reach your local modifications to all types of durable MDA office, call (800) 572-1717. medical equipment

• annual occupational, physical, respira- tory or speech therapy consultations

• annual flu shots

On the cover: • support groups for those affected, Mattie was MDA’s National Goodwill spouses, parents or other caregivers Ambassador from 2002 through 2004, and became a best-selling poet who touched millions of lives with his mes- • online support services through the sages of peace and hope. Mattie had e-community myMDA and through mitochondrial myopathy and lost his life myMuscleTeam, a program that helps just before turning 14. His siblings also had the disease, and his mother, Jeni, has recruit and coordinate in-home help an adult form of the disease. MDA’s public health education program helps you stay abreast of research news, medical findings and disability information through magazines, publications, edu- cational speakers, seminars, videos and newsletters.

MDA’s website at www.mda.org contains thousands of pages of valuable informa- tion, including disease specifics, research findings, clinical trials and past magazine articles.

14 Mitochondrial Myopathies • ©2011 MDA MDA’s Purpose and Programs he Muscular Dystrophy Association Metabolic Diseases of Muscle Tfights neuromuscular diseases through Phosphorylase deficiency (McArdle disease) an unparalleled worldwide research effort. Acid maltase deficiency (Pompe disease) The following diseases are included in Phosphofructokinase deficiency MDA’s program: (Tarui disease) Debrancher enzyme deficiency Muscular Dystrophies (Cori or Forbes disease) (Steinert disease) Mitochondrial myopathy Duchenne muscular dystrophy Carnitine deficiency Becker muscular dystrophy Carnitine palmityl transferase deficiency Limb-girdle muscular dystrophy Phosphoglycerate kinase deficiency Facioscapulohumeral muscular dystrophy Phosphoglycerate mutase deficiency Congenital muscular dystrophy Lactate dehydrogenase deficiency Oculopharyngeal muscular dystrophy Myoadenylate deaminase deficiency Distal muscular dystrophy Emery-Dreifuss muscular dystrophy Myopathies Due to Endocrine Abnormalities Motor Neuron Diseases Hyperthyroid myopathy Amyotrophic lateral sclerosis (ALS) Hypothyroid myopathy Infantile progressive Other Myopathies (Type 1, Werdnig-Hoffmann disease) congenita Intermediate spinal muscular atrophy (Type 2) Juvenile spinal muscular atrophy (Type 3, Kugelberg-Welander disease) Myotubular myopathy Adult spinal muscular atrophy (Type 4) Spinal-bulbar muscular atrophy (Kennedy disease) Inflammatory Myopathies Polymyositis MDA’s website, mda.org, is Dermatomyositis constantly updated with the latest Inclusion-body myositis research news and information Diseases of Neuromuscular about the diseases in its program. Junction Follow MDA on Facebook, Twitter and YouTube. Lambert-Eaton (myasthenic) syndrome Congenital myasthenic syndromes Diseases of Peripheral Nerve mda.org • (800) 572-1717 Charcot-Marie-Tooth disease Friedreich’s ataxia Dejerine-Sottas disease ©2009, 2011, Muscular Dystrophy Association Inc.

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