Muscle weakness that starts in infancy can leave parents, and sometimes pediatricians, groping for answers
by Sharon Hesterlee

[Sam Talerico photo]
Sam Talerico

When Sam Talerico was an infant, his mother thought he was the world's most content baby. "Sam was my first," explains Julia Talerico of Des Moines, Iowa. "He wasn't moving around in the crib much, but I just thought he was happy where he was. Then I started wondering. He was a little behind in his motor skills and, at 9 months, he still lost his balance easily when he was in a sitting position."

Marilyn McCollum describes a similar experience with her daughter Maggie McCollum Wilson, who, at 17 months, still didn't walk and wasn't able to grip her mother's waist with her legs when carried.

Both children were eventually found to have a rare and often misunderstood type of muscular dystrophy known as congenital muscular dystrophy (CMD). Difficulties in diagnosing the disease, combined with changing terminology, contribute to the confusion surrounding CMD.

Beginning at the Beginning

The word congenital means "existing at birth"; muscular dystrophies are progressive disorders that cause muscle wasting and weakness. But the term congenital muscular dystrophy can be a bit misleading.

The genetic defects that cause all forms of muscular dystrophy are present at birth, so you could say all muscular dystrophies are congenital. But in CMD, significant muscle weakness is usually detectable in newborns or infants, whereas muscle weakness in most other forms of childhood muscular dystrophy takes at least three or four years to become noticeable.

To complicate matters, the diagnosis of CMD was used for many years as a "catchall" category to describe conditions that looked like Duchenne muscular dystrophy (DMD), but began in infancy and affected both sexes. Doctors didn't know whether this type of muscle weakness represented more severe or earlier-onset versions of other muscular dystrophies, or whether the congenital MDs were disorders in their own right, with their own genetic causes. As it turns out, people who received diagnoses of CMD probably fell into both categories.

CMD Categories

Originally, the congenital muscular dystrophies were divided into two categories: classical CMD, a relatively mild form and the type seen most often in the United States; and several types of severe CMD involving mental retardation, which are more common in Japan and Europe. It's now known that most people with classical CMD have some anatomical brain abnormalities, but these only rarely cause cognitive deficits.

Classical CMD is characterized by slowly progressive muscle weakness and changes in the white matter of the brain (where nerve tracts are located) that can be seen with a technique called MRI, or magnetic resonance imaging. Many children with CMD are able to walk, and subsequently remain ambulatory for varying amounts of time. Although the disease typically progresses slowly, the severity of this form of CMD can vary dramatically from one child to the next.

Classical CMD was further subdivided in 1994, when MDA grantees Kevin Campbell of the University of Iowa in Iowa City and Ferdinand Tome of the National Institute of Health and Medical Research in France discovered that, in half of these cases, the muscle protein merosin (also known as laminin 2) was deficient. The subsequent discovery of the genetic defect for this form of classical CMD soon led researchers to recognize a milder type of CMD with a later onset that was caused by a partial deficiency of merosin. Thus, some people may technically have a CMD that didn't begin in infancy.

Now, doctors divide classical CMD cases into those with merosin deficiency and those without. It isn't yet known what causes classical CMD without merosin deficiency, or even if this form of CMD has only one genetic cause.

The severe types of CMD, which typically have extensive brain involvement with mental retardation in addition to muscle weakness, include Fukuyama CMD, Walker-Warburg disease and muscle-eye-brain disease (MEB).

Fukuyama CMD usually causes severe progressive muscle weakness and mental retardation. While it's almost nonexistent in the United States, in Japan it's second only to DMD in frequency. Researchers have identified defects in the gene for a protein called fukutin as the culprit, but the normal role of this protein isn't yet known.

Walker-Warburg disease and MEB are very rare CMDs, both of which involve severe abnormalities of the eyes and central nervous system as well as muscle weakness. Researchers don't yet know if these two disorders are variations of a single disorder, or if they have different genetic causes.

Difficulties With Diagnosis

Because of its rarity, CMD often remains undiagnosed or misdiagnosed for many years, keeping parents on an emotional roller coaster ride.

By the time Sam Talerico was a year old, his parents had become concerned enough about his lack of motor skills to have some tests done. Their pediatrician found that Sam had elevated blood levels of an enzyme called creatine kinase (CK ), and said that he probably had DMD.

[Maggie McCollum Wilson photo]
Maggie McCollum Wilson

"My heart went down to my feet," Julia Talerico says. What the Talericos didn't know then was that DMD was to be the first of two incorrect diagnoses (the second was spinal muscular atrophy) that Sam would receive before he was finally found to have CMD of the merosin-deficient type.

When Marilyn McCollum brought her concerns about her daughter to a pediatrician, the doctor broke the news that Maggie probably had cerebral palsy. Further testing soon yielded a finding of congenital myopathy and, finally, a diagnosis of CMD.

"We're still looking for the subtype of congenital muscular dystrophy that Maggie has," McCollum says. "Right now, they're calling it 'congenital MD, subtype unknown.'"

Neurologist Valerie Cwik isn't surprised by these tales.

"The congenital muscular dystrophies are often unrecognized among general pediatricians, and probably even some general pediatric neurologists," says Cwik, a physician at the MDA clinic at the University of Arizona Health Sciences Center in Tucson.

"When kids are weak and they don't have Duchenne, CMD is not the first thing that comes to mind," Cwik says. "Disorders like spinal muscular atrophy are more common causes of weakness in infants. It's usually not until someone thinks to order a creatine kinase test that a diagnosis of muscular dystrophy is even considered."

CK and Other Tests

Cwik explains that low muscle tone in infants tends to be caused by either a problem with the muscles or a problem with the nervous system. The test for elevated CK levels in the blood is a simple first step in determining where the primary problem lies.

[Dr. Valerie Cwik photo]
Dr. Valerie Cwik

Creatine kinase is a muscle enzyme that's released into the blood when muscle is degenerating; thus, elevated levels of CK tend to indicate that the primary problem is in the muscle. CK levels may be elevated in several types of muscle disorders, including metabolic muscle disorders and inflammatory muscle disorders, but high CK levels are also a hallmark of the muscular dystrophies.

"If the CK levels are elevated and my suspicion is high for any sort of muscle problem," Cwik says, "I'll go straight for a muscle biopsy."

The biopsy involves removing a small piece of muscle and sending it to a pathology lab for evaluation. An experienced neurologist can look at a section of the muscle and determine whether it most closely resembles muscle in muscular dystrophy or that in other muscle disorders.

In addition to the standard evaluation of the muscle biopsy, antibodies can be used to determine if the sample shows deficiencies of specific muscle proteins. For instance, a deficiency in the protein dystrophin may indicate Duchenne or Becker muscular dystrophy.

In a suspected case of classical CMD, a doctor would examine the muscle specimen for the absence of the merosin protein. In some cases, if the results are still unclear, a genetic test could be done to determine if there are defects in the gene for merosin.

If all the tests for muscle proteins are normal, yet a child still seems to fit the pattern of classical CMD, the diagnosis may be "CMD, merosin-positive" or "CMD, subtype unknown."

One further clue that a child may have classical CMD, rather than an unusually early onset of some other type of muscular dystrophy, is that this disorder is often associated with dramatic changes in the white matter of the brain. The white matter is the portion of the brain that contains tracts of nerve fibers. These abnormalities can be seen with an MRI, a noninvasive technique for seeing the anatomical structure of the brain.

Despite these brain abnormalities, most children with classical CMD have normal intelligence. Cognitive deficits, when they do occur, tend to be more common in the "merosin-positive" subtype of classical CMD.

"Unfortunately," says Cwik, "we can't give everyone a specific diagnosis. Some kids [with muscular weakness] aren't merosin-deficient or dystrophin-deficient. There are some of them out there that we just don't know yet, and I know that it's frustrating for a lot of parents."

Fear of the Future

Because the course of CMD is so variable, and it isn't always possible to get a specific diagnosis for the disorder, parents worry about what to expect down the road for their children.

Sam Talerico, 10, whose diagnosis is partial merosin deficiency, serves as the 1999 MDA Goodwill Ambassador for Iowa. Sam loves golf, basketball and MDA summer camp. He also plays the piano. "He told me recently that he'd like to start playing another instrument," his mother says.

Sam now walks unassisted at home and uses a wheelchair at school. "He just does whatever he needs to do keep going," Talerico says.

"As Sam got older, it was hard for his muscles to keep up with the growth. He started putting his hands behind his back to help him walk. Now he walks with his hands behind his head to give his neck more support. It amazes the doctors. They have never seen a kid do that!"

Talerico admits to having a certain fear of the future. "We just have no clue what to expect," she says, but cites a strong religious faith as a steadying factor.

Maggie McCollum Wilson, whose CMD subtype is listed as "unknown," may also have merosin deficiency. Now 5, Maggie has mild weakness in her legs and weak muscle tone in her abdomen.

"Maggie is really giggly and happy," says her mother. "She loves to be with other kids. She's very sociable, but she gets tired easily and she just sort of curls up and sucks her thumb."

McCollum plans to have some genetic testing done soon to try to determine the specific cause of Maggie's CMD. If Maggie doesn't test positive for merosin deficiency, or any of the known genetic defects that cause other forms of muscular dystrophy, she'll fall into the category of "CMD without merosin deficiency."

"It's kind of hard not to know," McCollum says. "You gear yourself up to becoming educated and being able to know what to expect so that you have the right knowledge to help her. I hope for those reasons to find out the specific cause of Maggie's CMD, but it's a scary thing. In a way, it's a blessing, too, about not knowing."

From a physician's perspective, Cwik says identifying the cause of CMD is useful because it helps her give parents a prognosis when they ask, "Is my kid going to stay strong? Is he going to be in a wheelchair in a year or two or five years?"

Cwik also points out that a specific diagnosis for a childhood muscular dystrophy can be important for young families considering having more children. The inheritance patterns for various types of muscular dystrophy differ.

"What I also tell parents," Cwik says, "is that, although we may not have treatments at this point, that might not be true in five years.

"A little over 10 years ago, we didn't even know where dystrophin was, and in that period of time many of the genetic defects that cause muscular dystrophies have been identified," she adds. "And research isn't stopping just because we know about these. I try to leave it open with all that is going on in gene therapy." .

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