Limb-Girdle Muscular Dystrophies

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Facts About Limb-Girdle Muscular Dystrophies

Updated December 2009 Dear Friends:

hen I was 4 years old, my parents administrators, a real estate professional, Wtook me to a specialist to find out a travel agency operator — all with limb- why I walked with an unusual waddle. girdle MD. Many of these bright, active, They learned I had limb-girdle muscular independent people are married, and some dystrophy. have children — and grandchildren.

Like many of you, we were shocked and Those of us with LGMD have a lot of sup- scared by this diagnosis. My parents port today. People with disabilities have wondered why I had this disease; we had more opportunities than ever before to no history of it in our family. But, as this develop and use their abilities. Federal law booklet explains, LGMD is caused by any guarantees us a public education, equal of several rare genetic defects that people employment opportunity and access to may not even know they have. That means public places. Computers and technology it wasn’t caused by anything you or your help me and other people with muscular parents did, and you didn’t catch it from dystrophy to move around, write, work anyone. and drive.

My family had to learn a lot about mus- By far, my greatest ally in living with cular dystrophy and make some major LGMD is MDA; I’m sure my parents would adjustments, both physical and psycho- say the same thing. Be sure to read “MDA logical. Our world came to include doctor is Here to Help You” on page 10! The visits, leg braces, physical therapy and Association is also the world leader in lots of questions. But gradually, muscular research on neuromuscular diseases, and Mandy Van Benthuysen dystrophy just became a part of our lives, its scientists have made many exciting and we coped with it by learning all we discoveries about LGMD in the years since could. Thanks to my determined parents, my diagnosis. We all pray for the day my devoted sister and the help of the when no one has to have a neuromuscular Muscular Dystrophy Association, I had a disease. wonderful childhood. This booklet will give you the basic facts I graduated from college, and I’m now work- about LGMD, and MDA will help you ing in L.A. in the television industry. I use a answer all your questions as they arise. wheelchair or scooter part time to help me As you face the challenges ahead, please when I work, travel and have fun with my remember two important things about friends. having LGMD: First, MDA is making rapid progress toward better treatments and a I hope you can tell from my story that cure. Second, you’re not alone. having limb-girdle muscular dystrophy doesn’t mean the end of your choices or your dreams. It isn’t easy to live with muscles that grow weaker over time, but you can have a very rewarding life with Mandy Van Benthuysen this condition. Los Angeles Not everyone with LGMD has the same experience, but most of those I’ve met have busy, fulfilling lives like mine. I know of a writer, a doctor, an air traffic control- ler, some teachers, school and college

2 LGMD • ©2009 MDA What is Limb-Girdle Muscular Dystrophy? imb-girdle muscular dystrophy When protein problems arise because one of L(LGMD) isn’t really one disease. It’s these genes is faulty, fibers in the muscles a group of disorders affecting voluntary don’t work properly. Gradually, the muscles muscles, mainly those around the hips become weak enough that people experi- and shoulders — the pelvic and shoulder ence the symptoms of limb-girdle muscular girdles, also known as the limb girdles. dystrophy. Because LGMD is progressive, the muscles continue to get weaker throughout You also may hear the term proximal used to the person’s lifetime. describe the muscles that are most affected in LGMD. The proximal muscles are those Six of the genes that, when flawed, cause closest to the center of the body; distal LGMD lead to production of proteins that are muscles are farther away from the center (for normally located in the muscle cell mem- example, in the hands and feet). The distal brane. (The membrane is a thin sheath that muscles are affected late in LGMD, if at all. surrounds each muscle cell, helping to protect it from injury during muscle contraction.) Over time (usually many years), the person If any of these proteins is missing because with LGMD loses muscle bulk and strength. the gene for it is flawed, the membrane Eventually, he may need a power wheelchair probably loses some of its “shock absorber” or scooter, especially for long distances. qualities and has a harder time protecting the LGMD can begin in childhood, adolescence, muscle cell from injury during normal con- young adulthood or even later. Both genders traction and relaxation cycles. are affected equally. When limb-girdle mus- In LGMD, the muscle membrane also may be cular dystrophy begins in childhood, some “leaky,” letting substances in or out that are physicians say, the progression is usually supposed to stay on one side of the mem- faster and the disease more disabling. When brane or the other. Membrane proteins, when the disorder begins in adolescence or adult- they’re made correctly and are in their normal hood, they say, it’s generally not as severe positions, may also perform other essential and progresses more slowly. functions in the cell; these functions may be defective when one or more of the proteins What are the forms of limb- are absent. girdle muscular dystrophy? LGMD primarily affects the muscles Not all of the muscle proteins associated with around the hips and shoulders. There are at least 19 forms of LGMD, and LGMD are in the membrane, however. For they’re classified by the genetic flaws that instance, calpain-3 is probably located in the appear to cause them (see “Known Forms main part of the muscle cell, and myotilin and of Limb-Girdle Muscular Dystrophy, page telethonin are located in the part of the mus- 7). As of 2007, 15 specific genes that lead cle cell that allows it to contract and relax. to production of muscle proteins have been implicated as definite causes of LGMD when The types of LGMD are generally classified by they’re flawed. MDA research was behind letters and numbers that indicate which gene much of the work that identified these LGMD is known or suspected to be involved and genes. whether the disorder is inherited as a dominant or recessive condition, meaning whether Genes, located on chromosomes in each cell one or two flawed genes are needed to cause in the body, are the codes, or recipes, for it. (See “Does It Run in the Family?” page 8.) production of the body’s various proteins. Some physicians classify LGMD according to The genes associated with LGMD normally which protein is missing or deficient, if this is make proteins necessary for muscle function. known. For example, one form may be called

3 LGMD • ©2009 MDA alpha-sarcoglycan deficiency, and another is certainty, although knowing the genetic muta- known as beta-sarcoglycan deficiency. In the tion underlying your disease can be helpful. future, the term limb-girdle muscular dystrophy may become obsolete and be replaced by What happens along more specific terms. the way? How fast does LGMD Often, people with LGMD first notice a prob- progress? lem when they begin to walk with a “wad- dling” gait because of weakness of the hip It’s not yet possible to predict the course of and leg muscles. They may have trouble get- LGMD in an individual. ting out of chairs, rising from a toilet seat or climbing stairs. Some forms of the disorder progress to loss of walking ability within a few years and Weakness in the shoulder area may make cause serious disability, while others prog- reaching over the head, holding the arms out- ress very slowly over many years and cause stretched or carrying heavy objects difficult. minimal disability. At this time, progression It may become increasingly hard to keep the in each type of LGMD can’t be predicted with arms above the head for such activities as

The muscles most affected in limb-girdle muscular dystrophy (LGMD) are those surrounding the shoulders and hips, with nearby muscles in the upper legs and arms sometimes also weakening with time. Inside each muscle cell, many proteins, some of which are shown here in blue and yellow-orange, help the cell contract and protect it from the stress of contractions. When any of the proteins shown here in yellow- orange are missing or nonfunctional, LGMD is the result. At least six of these proteins are Eventual loss of walking ability is com- normally found in the muscle cell membrane, mon in LGMD, but some people walk a sheath surrounding each cell. They form longer than others. part of the structure of the membrane. Determining which proteins are missing in LGMD and what their normal functions are in the muscle cell are crucial steps in developing treatments.

lamin A/C cell nucleus

POMT1 FKRP fukutin

4 LGMD • ©2009 MDA combing your hair or arranging things on a muscle soreness and aching joints. Exercises high shelf. Some people find it harder to type to keep joints limber, moving around as on a computer or other keyboard and may much as possible, warm baths and, if need- even have trouble feeding themselves. ed, medication can keep this kind of discom- fort to a minimum. Assistive devices, such as a cane or a long- handled reacher, can make things easier as The brain, the intellect and the senses are weakness progresses. unaffected in LGMD. People with LGMD can think, see, hear and feel sensations as well as A power wheelchair or scooter becomes con- those without muscular dystrophy. venient when weakness in the pelvic girdle and upper legs causes frequent falls. People What tests are used to whose LGMD has reached this stage often find that a great deal of their independence diagnose LGMD? returns, and they’re much less fatigued, when In diagnosing any form of muscular dys- they begin using this type of vehicle. trophy, a doctor usually begins by taking a patient and family history and performing a The heart can be affected in LGMD, but this physical examination. Much can be learned doesn’t occur as often as it does in some A wheelchair or scooter, such as the from these, including the pattern of weak- other forms of muscular dystrophy. Heart one this physician with LGMD uses, ness. The history and physical go a long way becomes convenient when weakness in problems can take two forms — weak- toward making the diagnosis, even before the pelvic girdle and upper legs causes ness of the heart muscle (cardiomyopathy) frequent falls. any laboratory tests are done. and abnormal transmission of signals that regulate the heartbeat (conduction abnormali- The doctor also wants to determine whether ties or arrhythmias). The heart should be the patient’s weakness results from a prob- monitored for these complications. When lem in the muscles themselves or in the necessary, medications or devices (such as nerves that control them. Problems with pacemakers) can be used to treat them. muscle-controlling nerves, or motor nerves, originating in the spinal cord and reaching Respiratory (breathing) function can decline out to all the muscles, can cause weakness over time, and this, too, should be monitored that looks like a muscle problem but really regularly. There are devices that can help isn’t. sustain respiratory function. Usually, the origin of the weakness can be What’s not affected in LGMD? pinpointed by a physical exam. Occasionally, special testing called electromyography is LGMD, like other muscular dystrophies, is done. In this kind of test, the electrical activ- primarily a disorder of voluntary muscles. LGMD doesn’t impair the intellect, the ity of the muscles is measured and nerves senses or the desire for a challenge. These are the muscles you use to move the stimulated to see where the problem lies. limbs, neck, trunk and other parts of the body Electromyography is uncomfortable but not that are under voluntary control. usually very painful. The involuntary muscles, except for the A nerve conduction study also may be done. heart (which is a special type of involuntary This too is uncomfortable, but not seriously muscle), aren’t affected in LGMD. painful. Digestion, bowel and bladder functions and Early in the diagnostic process, doctors often sexual function, which are carried out by order a special blood test called a CK level. involuntary muscles, remain normal. CK stands for creatine kinase, an enzyme that Severe pain isn’t a major part of LGMD, leaks out of damaged muscle. When elevated although limited mobility sometimes leads to CK levels are found in a blood sample, it

5 LGMD • ©2009 MDA usually means muscle is being destroyed by biopsy findings or symptoms clearly associ- some abnormal process, such as a muscular ated with one or two types of LGMD), it may dystrophy or inflammation. Therefore, a high be practical to do DNA testing to pinpoint the CK level suggests that the muscles them- gene defect. However, if there are no such selves are the likely cause of the weakness, clues, testing for more than a dozen genetic but it doesn’t tell exactly what the muscle defects is available but extremely expensive. disorder might be. Understanding your inheritance pattern may, Today, DNA testing to look for genetic flaws however, be important for family planning. that are known to cause LGMD is available Your family history can help determine the for several forms of the disease and is rapidly inheritance pattern of your disorder. expanding. If a particular type of LGMD is suspected, DNA testing, using a blood sam- Treatment for LGMD, mainly involving physi- ple, may be undertaken relatively early in the cal and occupational therapy, assistive devic- diagnostic process, often before the doctor es, and monitoring for heart and breathing considers a more invasive procedure. complications, is essentially the same in all forms of the disease. An individual’s precise In some cases it is necessary for a doctor to genetic defect makes little difference in these order a muscle biopsy, the surgical removal interventions. of a small sample of muscle from the patient. By examining this sample, doctors can tell Can special diets help a great deal about what’s actually happen- An echocardiogram (ultrasound imag- in LGMD? ing of the heart) can be used to moni- ing inside the muscles. Using a variety of tor heart function in LGMD. techniques, muscular dystrophies can be At this time, no special dietary restrictions or distinguished from inflammatory and other additions are known to help in LGMD. disorders. Specific testing of the biopsy also Many people, when they hear the words “lack may distinguish among different forms of of a protein,” logically ask, “Should I eat muscular dystrophy. more protein?” Unfortunately, eating more Tests on the biopsy sample also can provide protein than your normal requirement has information about which muscle proteins no effect on any of the proteins missing in are present in the muscle cells, and whether LGMD. It’s true that when you eat a steak, they’re present in the normal amounts and you’re ingesting many muscle proteins (from the cow). Your body then breaks down these The diagnostic process usually begins in the right locations. This can tell the doc- with a history and physical examina- tor and patient what’s wrong with the cells’ proteins into their component parts and uses tion. proteins and provide likely candidates as to them to build its own proteins. But a person which genes are responsible for the problem. who lacks the genetic instructions to make The correlation between missing proteins these new proteins won’t be able to make on the muscle biopsy and genetic flaws isn’t them no matter how much protein he eats. perfect, however. A doctor may advise a weight reduction or weight stabilization diet for some people Is it important to find out with LGMD. Being markedly overweight puts what genetic type of LGMD greater stress on already weakened muscles. a person has? At this time, genetic testing to determine an Are there special exercises individual’s exact type of LGMD is commer- that can help? cially available for only some LGMD forms. A physical therapy program is usually part If there are clues as to what gene is involved of the treatment for LGMD. Your MDA clinic (from previously tested family members, physician may refer you to the physical

6 LGMD • ©2009 MDA therapy department at your medical center for cles as toned as possible without causing a thorough evaluation and an individualized undue stress on them. The buoyancy of the exercise program. water helps protect against certain kinds of muscle strain and injury. Before undertaking The primary goals of physical therapy are an exercise program, make sure you’ve had a to allow greater motion in the joints and to cardiac evaluation. And don’t swim alone. prevent contractures (freezing of the joints). These problems can arise when movement Occupational therapy focuses more on specif- is limited, and it’s important for the patient’s ic activities and functions, particularly use of comfort and function to avoid them. the hands, while physical therapy emphasizes mobility and (where possible) strengthening Doctors and therapists have somewhat differ- of large muscle groups. Your MDA clinic also ent opinions on the relative value or danger can refer you to the occupational therapy of various exercise regimens in people with department, where you can receive help with muscular dystrophy. In LGMD, certain kinds tasks related to your job, recreation or daily of stress-causing exercises may actually has- living. For example, arm supports can make ten muscle damage. tasks such as using a computer or fixing your Some experts recommend swimming and hair less tiring. Some experts recommend swimming water exercises as a good way to keep mus- and water exercises to keep muscles toned. Known Forms of Limb-Girdle Muscular Dystrophy Type Pattern of Inheritance Gene or Chromosome LGMD1A Autosomal dominant Myotilin gene LGMD1B Autosomal dominant Lamin A/C gene LGMD1C Autosomal dominant Caveolin gene LGMD1D Autosomal dominant Chromosome 7 LGMD1E Autosomal dominant Chromosome 6 An important goal of physical therapy LGMD1F Autosomal dominant Chromosome 7 is to allow greater motion in the joints. LGMD1G Autosomal dominant Chromosome 4 LGMD2A Autosomal recessive Calpain-3 gene LGMD2B Autosomal recessive Dysferlin gene LGMD2C Autosomal recessive Gamma-sarcoglycan gene LGMD2D Autosomal recessive Alpha-sarcoglycan gene LGMD2E Autosomal recessive Beta-sarcoglycan gene LGMD2F Autosomal recessive Delta-sarcoglycan gene LGMD2G Autosomal recessive Telethonin gene LGMD2H Autosomal recessive TRIM32 LGMD2I Autosomal recessive FKRP gene LGMD2J Autosomal recessive Titin gene LGMD2K Autosomal recessive POMT1 gene LGMD2L Autosomal recessive Fukutin gene These forms of LGMD have been identified since the early 1990s. More forms will undoubtedly be discovered as research continues.

7 LGMD • ©2009 MDA Does it Run in the Family? n being told they have a genetic have to start somewhere), so there may Odisorder such as LGMD, bewildered really be no family history or even carri- patients often ask, “But it doesn’t run in ers of the disorder in the family. However, the family, so how could it be genetic?” once someone develops a genetic disease, even if the mutation is spontaneous (new) LGMD can run in a family, even if only one with that person, he or she can then pass person in the biological family has it. This on the mutation to any offspring, thereby is because of the ways in which genetic introducing the gene for the disease into diseases are inherited. the family.

LGMD can be inherited in one of two basic The details of inheritance risks for any ways, known as the autosomal dominant particular form of LGMD depend on many pattern and the autosomal recessive pat- circumstances, including exactly which tern. “Known Forms of LGMD” on page 7 type of LGMD has been diagnosed. A good shows which types follow each pattern. way to find out more is to talk to your The word autosomal means that the genes MDA clinic physician or ask to see the involved aren’t on the X or Y chromosome genetic counselor at the MDA clinic. You and, therefore, don’t have a preference for also can read MDA’s booklet “Facts About either men or women. Genetics and Neuromuscular Diseases.”

LGMD can run in a family, In diseases with dominant inheritance even if only one person in patterns, a person who inherits a flawed the biological family has it. gene from one parent will have disease symptoms. That parent would also have the disease.

In diseases with recessive inheritance, a person must inherit two flawed genes — one from each parent — to have disease symptoms. The parents don’t have symptoms.

A recessive form of LGMD can show up in one person when there’s no family history. Other family members may have been carriers, having no disease symptoms. Carriers have the genetic flaw (mutation) on a chromosome and can have a child with the disease, but only if the child’s other parent is also a carrier. So it isn’t unusual for carriers of a rare recessive disease not to know they’re carriers until someone in the family develops the disease.

Just to make things a little more compli- cated, a person with LGMD may have a brand new genetic mutation (after all, they

8 LGMD • ©2009 MDA MDA’s Search for Treatments and Cures he MDA Web site is constantly updated regions (“exon skipping”); this research Twith the latest information about the also may have relevance for LGMD treat- neuromuscular diseases in its program. ment. See the latest research news at www.mda. org/whatsnew. Another avenue of investigation is blocking a natural protein called myostatin, Throughout the 1990s and the first decade which puts a brake on muscle growth. of the 21st century, MDA-supported This strategy has the potential to treat researchers identified dozens of genes a variety of conditions in which muscle that, when defective, cause LGMD. growth or maintenance is insufficient.

This gene identification work continues Still another strategy is to use stem cells to the present day, along with research to to help ailing muscles regain strength. determine the precise function of these Stem cells are early-stage, flexible cells genes so that missing functions can be that can give rise to mature muscle fibers. compensated for and toxic functions can They’re found in muscle tissue and other be inhibited. places in the body, and scientists are working to determine which cells are the In the recessive forms of LGMD, it may be safest and most effective to test in people possible to insert a new gene to compensate with LGMD and other diseases. for one that isn’t working properly. This type of intervention — gene therapy — has MDA-supported researchers worldwide shown promise in a pilot trial in people with continue to pursue every avenue that the alpha-sarcoglycan-deficient form of might lead to potential treatments for LGMD. LGMD.

In the dominant forms of LGMD, blocking a toxic function using strategies such as “antisense,” which keep cells from inter- preting genetic information, may become a treatment in the future.

Some genetic mutations, known as “pre- mature stop codons,” cause cells to stop reading genetic instructions before a fully functional protein has been synthesized. A drug that causes cells to “read through” these stop codons is being tested in another form of muscular dystrophy (Duchenne) and may have some applica- tion in LGMD.

Some genetic mutations add or remove DNA and change the way cells interpret the information in a gene. In Duchenne muscular dystrophy, clinical trials are under way of compounds that coax cells to snip out these error-containing DNA

he Muscular Dystrophy 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 LGMD. ning quarterly magazine. Quest publishes The staff at your local MDA office is detailed articles about research findings, there to assist you in many ways. The medical and day-to-day care, helpful 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 neuromuscular disease 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 obtaining durable medical copies of other publications. equipment through its national equipment loan program If you have any questions about LGMD, someone at MDA will help you find the • financial assistance with repairs to all answer. To reach your local MDA office, types of durable medical equipment call (800) 572-1717.

• annual occupational, physical, respiratory and speech therapy consultations

• annual flu shots

• support groups for those affected, On the cover: spouses, parents or other caregivers Amy Dunaway-Haney of South Padre Island, Texas, was found to have limb- • online support services through the girdle MD at age 8 and began using a wheelchair in her teens. Now married, e-community myMDA and through she teaches high school Spanish and myMuscleTeam, a program that helps has been nationally honored for her recruit and coordinate in-home help teaching and as the 2003 recipient of the MDA National Personal Achievment Award. 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 Web site at www.mda.org contains thousands of pages of valuable information, including disease specifics, research findings, clinical trials and past magazine articles.

10 LGMD • ©2009 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) Myotonic dystrophy (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 spinal muscular atrophy Other Myopathies (Type 1, Werdnig-Hoffmann disease) Myotonia congenita Intermediate spinal muscular atrophy Paramyotonia congenita (Type 2) Central core disease Juvenile spinal muscular atrophy Nemaline myopathy (Type 3, Kugelberg-Welander disease) Myotubular myopathy Adult spinal muscular atrophy (Type 4) Periodic paralysis Spinal-bulbar muscular atrophy (Kennedy disease) Inflammatory Myopathies Polymyositis Dermatomyositis Inclusion-body myositis Diseases of Neuromuscular Junction Myasthenia gravis MDA’s Web site is constantly Lambert-Eaton (myasthenic) syndrome updated with the latest information Congenital myasthenic syndromes about the diseases in its program. Diseases of Peripheral Nerve Go to www.mda.org. Charcot-Marie-Tooth disease Friedreich’s ataxia Jerry Lewis, National Chairman Dejerine-Sottas disease www.mda.org • (800) 572-1717