The Brain in Duchenne Muscular Dystrophy

Are learning disabilities part of the picture?

By the early 1990s, researchers began to see more than they had expected. The dystrophin gene wasn't just a muscle protein gene. There was also a brain form of dystrophin, made from the same gene, but in a slightly different way.

Not surprisingly, scientists began to speculate that, if this brain protein were also flawed in Duchenne muscular dystrophy (DMD), it might account for the cognitive problems seen in the disease. And, if different people had different flaws in the same gene, it might account for some of the variation seen with these problems.

This theory, with some modifications, is what most doctors and scientists believe today, though few would deny that social and emotional factors also play a role in intelligence and behavior.

Retardation is rare

"The vast majority of patients with Duchenne are not mentally retarded," says Dr. Mark Mehler, a professor of neurology and neuroscience at Albert Einstein College of Medicine in New York.

Instead, he says, they may have subtle and complex cognitive and behavioral deficits, or learning disabilities, which can be accounted for by dystrophin abnormalities. Mehler, an MDA grantee, is a neurologist who practices medicine and studies the brain.

Much of Mehler's research is based on what is now known about the dystrophin gene, work done by MDA-sponsored molecular geneticists Louis Kunkel at Boston Children's Hospital, Jeffrey Chamberlain at the University of Michigan, and Uri Nudel at the Weizmann Institute of Science in Rehovot, Israel.

The dystrophin gene is the largest gene ever found, and is among the most complex. It has at least eight start sites, known as promoters, meaning there are eight places in the gene where the recipe for a protein can begin. So far, four of these start sites have been found to begin recipes for brain forms of dystrophin — for two long and two short forms of the protein. Only one site has been found that starts the muscle dystrophin recipe.

A lot of the variation in cognitive functioning in children with Duchenne, Mehler says, can be explained by the differing locations of their mutations (abnormalities) in the dystrophin gene. Some children probably make some of the brain forms of dystrophin, while others may not make any, or may make some imperfectly. Mehler believes few children make the two long forms of brain dystrophin, because these two forms are almost the same as the muscle form, and a genetic mutation that affects the muscle protein recipe would very likely also affect these brain forms.

Children and adults with Becker haven't been well studied with regard to cognitive functioning, but Mehler suspects that, because of their dystrophin abnormalities, they too probably have more learning disabilities than the general population.

Flawed interactions

"The vast majority of children with Duchenne don't have classical intellectual deterioration," Mehler says. "What they have is an inability to communicate what they know and to interact effectively with the outside world."

Mehler says they can't communicate what they know because of flaws in the way they receive information and retrieve it from their brain's storage areas.

Standard IQ tests rely heavily on input-output functions when they attempt to measure "intelligence." If, for example, a child is so distracted by a fly in the room that he can't pay attention to the test, his score will be significantly lower on a standard IQ evaluation.

Inability to focus is common to almost all the Duchenne patients Mehler has tested, and he thinks it's responsible for a lot of misunderstanding about IQ.

"I can guarantee you that most of the IQ difference in Duchenne is due to the attentional problem and not due to intrinsic problems in intellectual attainment," Mehler says.

He has found that children with Duchenne have problems in three main areas, all of them hampering their interactions with the world and its information: attention focusing, verbal learning and memory, and, to a lesser extent, emotional interaction.

A Duchenne profile?

Among the questions researchers have set out to answer is whether there are cognitive and behavioral abnormalities common to many Duchenne patients, even if they differ in severity. If there are, doctors would call that a "Duchenne profile," and its existence would certainly point to biological causes closely associated with this disorder.

Mehler believes that, so far, the evidence points to a Duchenne profile of brain-associated deficits.

The first, and most common, is an attention deficit disorder, although Mehler cautions that this term is both overused and misused today. Children with attentional difficulties don't just have trouble focusing attention; they also have trouble letting go of attention.

"We'll have Duchenne kids that will focus on an object like it's a holy totem, and then two seconds later, they're doing seven other things that they'll attend to for three seconds and be gone," he says. "They can't modulate [regulate] their attention."

Another misunderstanding is confusion of attention deficit with hyperactivity. In young children, he says, attention deficits show up as hyperactivity; but, as they get older, they change to inattention without hyperactivity, even in children without muscle disease.

The second area of difficulty is more subtle and harder to explain, but it underlies several of the learning and language disabilities often seen with Duchenne. The problem, Mehler says, is with a brain process known as the "phonological code."

The phonological code is a system the brain uses to break down language into its smallest units of sound (known as "phonemes"). Normally, when people hear or read words, the brain processes and stores the words in a code of "sound bites," or phonemes, and probably later retrieves them the same way, before recoding them back into words.

If the phonological code isn't working properly, processing spoken language becomes very difficult, and what hasn't been processed correctly in the first place becomes difficult or impossible to retrieve, or remember. If the phonological code is essential for reading, and there are defects in one's phonological code, then learning to read and remembering what has been read also become daunting tasks.

Fortunately, as with most learning disabilities, deficits in the phonological code can be gotten around, at least to some extent, with special education that helps children use pathways other than phonology for learning, memory and language processing.

The third area in which Duchenne patients have shown abnormalities is perhaps the least clear, and the most controversial. At least some boys have difficulty with emotional interaction that suggests a lack of "connectedness," making a child appear immature or "off" in some way that's hard to define.

The three parts of the brain in which the most dystrophin would normally be found roughly correspond to the functional areas where Duchenne children tend to have difficulties, Mehler says. It's found in the cortex, where attention is regulated and signals from the rest of the brain are integrated; the hippocampus, where short-term memories are processed and prepared for storage as long-term memories elsewhere in the brain; and the cerebellum, where complex motor (movement-related) functions, such as walking, playing an instrument or writing, are learned and fine-tuned.

According to Mehler, recent evidence suggests the cerebellum may also be involved in other kinds of information processing and perhaps in social connectedness.

Getting around the deficits

Telling parents that their child's cognitive differences may be due to a brain abnormality isn't meant to be frightening, but to encourage and help parents to get the kinds of intervention needed for their children, Mehler says.

He recommends an evaluation by a developmental or pediatric neuropsychologist as soon as a child receives a diagnosis of Duchenne, so that educational and psychological interventions can begin right away. (Many parents have found the psychologists and educators in their own school systems to be very effective, and most MDA clinics are located at major medical centers that can make referrals to a neuropsychologist if a parent requests one.)

Often, Mehler says, parents of children with Duchenne feel that they are helpless, passive partners in their child's care and development. But parents can make a difference by following exercises and ways of interacting with the child prescribed by a neuropsychologist. Such prescriptions should begin as soon after diagnosis as possible, Mehler says.

Special education

Wyatt Moore, Wesley Rehse and Joseph Cohan are in special education now, and all have made progress. The precise solutions differ for each, but there are some common threads.

Wyatt, now 7, has moved from his regular public school to a public school for students with special needs, part of the New York state BOCES (Board of Cooperative Educational Services) program. Instead of a class of 15 children, he's now in a class of five, and, his mother says, "is doing wonderfully."

Like all children in special education, Wyatt has an Individualized Education Program (or Plan), which sets specific educational objectives for a child, the means to reach them and the methods for evaluating whether they've been reached. 

He's beginning to put things together in reading, his mother says, using a visual processing method specified in his IEP. He still has great difficulty writing, which may be due to poor hand-eye coordination or to weakness in his hands. It took him a year to learn to write his name, but now he can do it.

Wyatt is also developing some social skills, his mother says. "Before, he just could not figure out what to do," she says. Vicki Moore isn't sure Wyatt can yet interpret other people's feelings, but she says he's doing better and treats animals, such as his grandfather's cats, with more understanding.

Reports from school now say "good" and "excellent," while last year they were coming back with comments like "poor" and "fair." And, he doesn't dread going to school anymore.

When Wesley Rehse started first grade 10 years ago, he, like Wyatt Moore, was placed in a BOCES program in a special school. But his mother doesn't think it was the best situation for him, because the other children were mostly from very troubled families. In fourth grade, he switched to a special education class in a regular public school, where, she says, "he flowered."

Wesley also has an IEP. He physically can't write and has a classroom aide do some of the writing for him. (He can still use his fingers to do art work, including painting Ukrainian Easter eggs.) Math is one of Wesley's stronger subjects, but reading is very hard for him. Learning to read with phonics proved impossible, but, with a sight reading method known as "whole word reading," he's been able to read at about third-grade level. "Books on tape did nothing for him," his mother says, explaining that learning for Wesley has to be visual.

Social life in school is still a problem, Wesley says. He says he's the only child with physical disabilities in his present class, and the other kids don't have the same problems he has. As in his first school, some of his current classmates come from unstable homes, and their attitudes toward school aren't the same as his. Wesley describes himself as "sort of obsessive-compulsive," and he doesn't like it when the less committed students interrupt or distract him.

Wesley enjoys video games and exploring the Internet, but his greatest enjoyment comes from tending his two dogs and eight lizards.

"Tiffany always stays with me," he says of one of his dogs. "I like animals, because they comfort me. I'd like to work at a zoo with lizards, snakes and alligators, and help people understand not to be afraid of them."

"We don't let the disease control us," says his mother, Diane. "We adapt to it. Our quality of life is above average."

Joseph Cohan is receiving special education services and classroom modifications in his regular third-grade class in Stratham, N.H. He started his special education services in first grade, after testing revealed specific learning disabilities, despite an average IQ.

He has a classroom aide 20 hours a week. He can write, but not very well, and is using some assistive technology in this area. He can read at a fourth-grade level, and, unlike many children with Duchenne, reads phonetically, his mother says. Math has been very difficult, and his mother attributes this to his poor memory.

Joseph is still highly distractible, but a swimming class has helped enormously with attention focusing. He also receives physical, occupational and speech therapy, as well as psychological counseling, all through the public school system.

Margaret Cohan is extremely involved in her son's education and has become an advocate for other parents in her school system and at the state level.

Lately she's found that some teachers feel overly sorry for her son because of his prognosis and they worry only about how he feels. A colleague even compared her to the "wicked stepmother" in fairy tales for pushing her son too hard in school. But, Cohan says, "He deserves an education. I want them to push him, not brutalize him."

Mehler wants all children to get the attention they need. "There are ways of helping these children to adapt, to act upon what they know," he says.

"What we need to impart to families is that there's this other area besides the motor disability that they really need to pay attention to. And we're not just talking about doing well in school or being smart. We're talking about maximizing their ability to interact in ways that are constructive for them — to communicate, to derive a measure of comfort from interacting with other people, to enjoy reading. As we learn more about some of the deficits, we can improve how they function. It's really important to maximize what they can do intellectually and emotionally."