Coping With Central Core Disease

by Sharon Hesterlee on March 31, 1999 - 5:00pm

Central core disease occurs when the central parts (cores) of some of the muscle cells (fibers) are metabolically inactive, meaning they don't produce energy correctly. The cores lack mitochondria, the energy-producing parts of the muscle cells.

Watching Jack and Matt Tyler, 16 and 14, walk from one class to the next carrying backpacks full of books, you'd never guess how much hard work goes into these simple tasks.

Because little is known about therapy for the rare and mysterious muscle disease affecting both boys, their parents were forced to experiment with different types of physical therapy as the boys developed. Now, their mother, Kathy, along with other parents who have dealt with this challenge in their families, could give you an earful about what works and what doesn't in coping with the disorder known as "central core disease."

Central core disease (CCD) is so named because the muscle fibers of affected individuals contain strange metabolically inactive "cores." CCD primarily causes muscle weakness in the proximal regions of the body (those in and around the trunk), but it can also affect the limbs and facial muscles.

Although the disease is generally considered nonprogressive and "mild," children with CCD often have a hard time learning to walk and usually exhibit some muscle weakness throughout their lives. Jack and Matt Tyler, for instance, can walk to their classes, but they can't run, jump or climb stairs easily.

"It's like if I'm walking at school and someone pushes me down, it's sort of awkward because I have to sit there and get up while everyone watches me," Jack explains. The family lives in Paradise, Calif.

CCD differs from many of the neuromuscular diseases in MDA's program in several key ways: It's nonprogressive or only slightly progressive, meaning people don't usually get worse over time. Some people with CCD even show a degree of improvement, and physical therapy may account for this. The greatest danger posed by the disease comes not from muscle weakness but from a potentially fatal reaction to anesthesia during surgery.

Inactive Cores

Central core disease, first described in 1959, is one of a group of muscle disorders, or myopathies, named for distinguishing abnormalities seen in the muscle biopsies of people with the disease.

When muscle fibers from people with CCD are stained for various metabolic enzymes and viewed under the microscope, the central region of some fibers appears blank, as if there's no metabolic activity in this area. These blank regions are called "cores" because they extend the entire length of the muscle fiber. The cores also lack mitochondria, the muscle cells' energy-producing "power plants."

Strangely, there seems to be no correlation between the number of muscle fibers that exhibit central cores and the severity of the disease. By one estimate, over 40 percent of people with central cores in their muscle biopsies have no CCD symptoms.

The identification in 1993 of the genetic defect responsible for CCD has been an important step in understanding what causes central cores in the muscle and why the muscles of people with CCD are weak.

New research indicates that CCD may be caused by a problem in the cell's regulation of calcium. (See "The Core of the Problem".) It's still unclear whether the resulting weakness is caused by the cell's inability to regulate calcium needed for muscle contraction, or by the presence of the central core in the muscle fiber, or both.

Encouraging Prognosis

Tommy Leon, 9, underwent a series of strength tests to determine which of his muscles are affected most by CCD.

Symptoms of CCD may be noticed soon after birth. In severe cases, babies may seem "floppy" because of poor muscle tone, and congenitally dislocated hips aren't unusual.

The diagnosis of CCD is arrived at based on a muscle biopsy or a genetic test.

The outlook for children with CCD is generally good. Typically they achieve motor milestones on a delayed schedule, sitting up several months later and walking a few years later than others. Curvature of the spine (scoliosis) can also be a feature. Although children with CCD get off to a slow start, most seem to improve as they get older and live a normal life span, remaining active throughout their lives.

The description of CCD as a "mild" myopathy, however, doesn't take into account how variable the disease can be, even within the same family.

The Mallet family of Mexico City has many affected members, most of whom have mild muscle weakness. But for one member of this extended family, Tommie Leon, the word "mild" doesn't seem to apply. At 9, Tommie still doesn't walk and has much greater muscle weakness than his mother, Sofia, who also has the disease.

At the other end of the scale, it's possible for people to be so mildly affected that they don't realize they have CCD until it's diagnosed in another family member.

Risks of Anesthesia

A potentially life-threatening aspect of CCD lies not with the primary symptom of muscle weakness per se, but with the susceptibility of people who have CCD to severe reactions to certain kinds of anesthesia during surgery. When susceptible individuals are exposed to the most commonly used general anesthetic, a combination of the chemicals halothane and succinylcholine, their muscles may become rigid and their body temperatures rise to dangerous levels.

This reaction, called malignant hyperthermia (MH), can be fatal within minutes if not treated. Fortunately, a compound called dantrolene can stop the symptoms of MH if they're recognized in time.

Not everyone who is susceptible to MH has CCD, but most people with CCD seem to be susceptible to MH. However, even susceptible people don't experience an episode of MH each time they undergo anesthesia.

MDA grantee David MacLennan suggests that anyone with a CCD diagnosis wear a MedicAlert bracelet that warns of MH susceptibility.

"They should absolutely be concerned," MacLennan says. "The thing about MH is that the typical person who reacts to anesthesia does so on about their fourth visit to the operating room." Males in the 10-to-40-year age range seem to be most susceptible.

Anyone with a diagnosis of CCD should alert his anesthesiologist to this fact before undergoing surgery. People who test positive for malignant hyperthermia should use alternative anesthetics during surgery. However, local anesthesia for dental work is generally considered safe. If you have CCD and anyone in your extended family has ever had an MH reaction, then you should consult your physician about seeking the advice of a neurologist or anesthesiologist before surgery.

'Mild' Disability?

As a baby Jack enjoyed a doorway jumper, which his parents believe helped build his leg strength.

Because the symptoms of CCD can be so mild and the disorder is so little known, people with CCD may not get a proper diagnosis for many years.

In the past, it wasn't uncommon for symptoms of this rare disease to be misdiagnosed as limb-girdle muscular dystrophy or some other muscle problem. This was the case for Kathy Tyler, the mother of Jack and Matt.

She now uses a wheelchair because of surgeries she underwent as a child for frequent hip dislocations. The reason for the problem with her hips remained undiagnosed for many years.

"Doctors couldn't understand why my hips kept coming out of the socket. They finally decided to keep me in a body cast for three years to make my hips stay in the sockets, and boy did they -- it was a natural fusion," she said.

When Tyler's son Jack was born, he had low muscle tone and dislocated hips. Before he was a year old he was given a diagnosis of CCD.

Tyler told her doctors she suspected she had the same disorder. A muscle biopsy later showed that she did indeed have CCD.

Some people with sporadic CCD (no one else in the family has it) are told there's nothing wrong with them at all.

This happened to Lisa Brooks of Elon College, N.C., and her identical twin sister, who weren't diagnosed with CCD until they were 33. The very mildness of their symptoms contributed to years of psychological suffering because they didn't know that their inability to run or go up stairs was due to a medical condition.

"In school we got laughed at, and I couldn't put a name to anything so I grew up thinking that I was just a weird person. All I kept hearing was, 'It's all in your head, there isn't anything wrong with you,'" says Brooks, now 37.

The condition of Lisa and her twin was finally diagnosed as CCD four years ago. "That was such a relief," Brooks says. "We could finally put a name to it."

Even when a person has a proper diagnosis of CCD, the very mildness of the disorder may prevent others from understanding that each day has special challenges.

"My kids are in a real gray area," Tyler says. "They look like average kids. They are intelligent, they are articulate -- they just aren't strong and they can't run or jump or walk fast. So they fall into this gray area where a lot of kids and people don't really believe that they have a disability, but they do."

Exercise and Theraphy

Elliott Etheridge, 11, has CCD and walks with the help of braces.

The question of exercise comes up again and again when dealing with neuromuscular disorders: When muscles aren't working the way they should, can working them harder cause more harm?

In some neuromuscular disorders, there's a logical rationale for worrying about the potentially harmful effects of exercise. In Duchenne muscular dystrophy, for instance, the loss of a key structural protein may leave muscle cells more susceptible to damage during the repetitive muscle contraction that occurs with exercise. In other neuromuscular disorders, such as some of the metabolic diseases, strenuous exercise may trigger a buildup of toxic byproducts or the breakdown of the muscle cells themselves.

In the case of central core disease, the potential negative effects of exercise aren't as clear-cut. Some doctors worry that because excess calcium in the muscle cell may be a problem for people with CCD, anything more than mild exercise should be avoided because muscle contraction requires calcium release in the muscle cells.

At the same time, some researchers speculate that exercise may actually stimulate the muscle cells to develop better strategies for removing the extra calcium that leaks into the main part of the cell.

Parents report mixed results with exercise in CCD. Tyler doesn't think her son Jack would have ever been able to walk without the physical therapy that he had as a child.

When Jack was a baby, the Tylers helped build his leg strength by letting him bounce in a Johnny Jump-Up that attached to the doorframe with a bungee cord. Later, they let Jack color at a standing table that held him upright in a supported position several times each day.

Now teen-agers, Jack and his brother, Matt, who is less severely affected by CCD, walk to class unassisted and carry their own books. The boys still work out and swim as part of their physical therapy routines.

Kathryn and Bill Etheridge of Raleigh, N.C., have tried some physical therapy with their son Elliott and have found the progress "slow, but worth the effort."

"There's no doubt," Kathryn Etheridge says, "that the more he exercises, the more he gains in strength, but there are certain exercises that are almost impossible for him to do." Elliott, 11, uses leg braces to walk indoors and a wheelchair to get around outside the house.

Finally, the Leon family of Austin, Texas, recently discovered that their son, Tommie, who is 9 years old and still doesn't walk unattended, may be experiencing a phenomenon called "disuse atrophy" on top of the fairly severe muscle weakness caused by his CCD. Although Tommie has received regular physical therapy from a very young age, some of his muscles are much weaker than others.

Recently, MDA grantee Susan Hamilton of Baylor College of Medicine in Houston, who is interested in the relationship of CCD and exercise, arranged for a team of researchers, including exercise physiologists, basic researchers and a neurologist, to examine Tommie. After a day of rigorous testing, it was determined that, although all of Tommie's muscles were weaker than those of an average boy his age, his weakest muscles had the same potential as his strongest muscles.

These experts concluded that, in his efforts to move as efficiently as possible, Tommie had learned to "cheat" by moving only the stronger muscle groups. Thus, the muscles that Tommie avoided using tended to become even weaker through disuse.

Tommie's parents, Tomas and Sofia Leon, are trying to find equipment that will allow their son to isolate and exercise specific muscle groups. In the meantime, because some of Tommie's torso muscles were so weak that he couldn't contract them at all, the Leons started him on a regimen of mild electrical stimulation to force the muscles to contract and gradually grow strong.

After two weeks of electrical stimulation, Tommie was able to contract these muscles without the stimulation.

"It's progress already," says Sofia Leon, who has mild CCD herself. "Of course, we need to get him a lot stronger than that. You can hardly see the squeeze, but you can see something."

Where does this "anecdotal evidence" leave people with CCD on the question of exercise? It seems that more research is required to determine the benefits versus harm of exercise in CCD.

One of the few studies on this topic found a 50 percent increase in exercise capacity in a man with CCD who underwent endurance training on a stationary bicycle for nine months. The main author of the study, Michael Brooke, director of the Muscle Research Center of the University of Alberta in Canada, says he knows of no good study indicating a direct negative effect of exercise in CCD.

Hamilton is interested in taking a closer look at the effects of exercise in an animal model of CCD. More research is required before doctors will feel comfortable with recommending anything beyond very moderate exercise to their patients with CCD.

One thing that medical doctors, parents and researchers all agree on is that swimming seems to provide excellent non-weight-bearing exercise. Because so little is known about the effects of exercise in this disorder, people with CCD should exercise only under the supervision of a physician.

The Core of the Problem: Too Much Calcium in the Muscle Cell

When central core disease was first described in 1959, almost nothing was known about the molecular problems that cause the disease. Now, 40 years later, we're getting a handle on the causes of this elusive neuromuscular disorder.

New research from MDA grantee David MacLennan of the University of Toronto and collaborator Tommie McCarthy of the University of Cork, Ireland, suggests that too much calcium in the wrong part of the muscle cell could be the problem.

1. NORMAL MUSCLE CONTRACTION

When the nervous system signals the muscle cell to contract, an electrical signal is sent from the surface of the muscle cell to the inner part of the cell through the T-tubule.

2. A CLOSER VIEW OF THE T-TUBULE AND SARCOPLASMIC RETICULUM

The electrical signal traveling through the T-tubule activates the ryaodine receptor to release calcium from the sarcoplasmic reticulum. The calcium washes over the actin and myosin filaments and makes them squeeze together. Calcium is then pumped back into the sarcoplasmic reticulum through a special pump.

We all know that calcium is required for strong bones, but you might not know that calcium also plays an important role in all of our cells. Muscle cells respond to messages from the brain with a burst of calcium. This increase in calcium in the main part of the muscle cell allows filaments in the cell to slide past one another and make the cell shorter. When thousands of muscle cells become shorter, the end result is muscle contraction.

Exposure to too much calcium for too long is actually harmful to a muscle cell. High calcium levels are especially damaging to the mitochondria, the cells' "power plants." The muscle cell gets around this problem by storing high concentrations of calcium in a special compartment, the sarcoplasmic reticulum, which is separate from the rest of the cell.

When the nervous system signals the muscle cell to contract, a short burst of calcium is allowed to flood out of the sarcoplasmic reticulum through a special "pore" called the ryanodine receptor. The calcium stays in the main part of the cell just long enough to start the contraction process, and is then pumped back into the sarcoplasmic reticulum by a calcium pump.

Researchers have found that many people with CCD have genetic mutations in the DNA that codes for the ryanodine receptor. MacLennan wondered if the mutations in this receptor might affect the way calcium is contained in the sarcoplasmic reticulum.

To study this question, he cloned the faulty ryanodine receptor gene from members of one large family in which cases of CCD are particularly severe. He then put the DNA for the mutated ryanodine receptor into cells in a culture dish and allowed these "host" cells to manufacture the mutated ryanodine receptor.

MacLennan found that the cells expressing the CCD-causing ryanodine receptor had higher levels of calcium in the main part of the cell than cells without the mutant receptor. Based on this and other observations, MacLennan concluded that the ryanodine receptor from this family with CCD is "leaky" -- that is, calcium is able to leak out of the sarcoplasmic reticulum even when the nervous system isn't signaling the muscle.

MacLennan suspects that the constant leak of calcium from the sarcoplasmic reticulum in the muscle cells of people with CCD may cause two types of problems.

First, because calcium isn't properly contained in the sarcoplasmic reticulum, when the nervous system signals the muscle cell to contract, there's less calcium available to create the calcium "burst" required for contraction. This problem is akin to a telegraph operator who, instead of tapping out a message, holds the button down lightly all the time.

The second problem that can occur is that the constant high levels of calcium may destroy mitochondria in the center of the muscle cell. MacLennan suspects that the remainder of the cell may be able to expel excess calcium, but extra calcium in the center of the cell is taken up by the mitochondria, destroying them.

The metabolically inactive "cores" in the muscle fibers of people with CCD may represent the cell's attempt to "wall off" areas of the cell that aren't able to deal with the extra calcium.

It isn't known which of these two problems might be the primary cause of muscle weakness in CCD. MacLennan is currently funded by MDA to study the proteins involved in calcium regulation in muscle cells, and he intends to compare the calcium-regulating proteins and their activity from people with mild CCD to those from people who do not have CCD or have severe CCD.

MacLennan suspects that the muscle cells of some people may be better at coping with the calcium leak than others. He hopes that learning how some muscle cells are able to deal with extra calcium may pave the way for developing treatments for people with CCD whose muscle cells don't seem to have these coping mechanisms.

NOTE: The problem of the muscle cell's regulation of calcium has nothing to do with the calcium in your diet. You still need dietary calcium for strong bones, and cutting down on your intake of calcium won't have any effect on what goes on in the muscle cells.

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