Matthew Denger was slow to talk as a toddler, and as he neared kindergarten age, his motor skills and coordination appeared underdeveloped. “He fell frequently and was uninterested in pedaling a tricycle,” says his father, Brian. “He wasn't keeping up physically with what you'd expect for a child his age.” Matthew's parents were concerned, but they didn't suspect a neuromuscular disease.

Around that time, the family attended a type 1 diabetes camp for Matthew's older sister, Rachel. While there, Brian and his wife, Alice, shared their observations about Matthew's development with one of the staff physical therapists. They mentioned that Matthew was “sturdy but not strong” and way behind where Rachel had been at the same age. The therapist was concerned enough to notify the camp endocrinologist, who consulted with Brian and Alice and later spoke directly with Matthew's pediatrician.

“That got the ball rolling,” Brian says. The Dengers took their son to a neurologist, who conducted genetic and muscular tests, among others. Within about three months, Matthew was diagnosed with Duchenne muscular dystrophy, a progressive neuromuscular disorder that weakens muscle cells over time, affecting walking and breathing and shortening the life span.

While doctors did not initially recommend testing Matthew's younger brother, Patrick, the Dengers had him evaluated after noticing early indications of something called Gowers' sign, which they had seen in Matthew. It often occurs in people with dystrophies, including Duchenne, and other muscle diseases. “Gowers' sign is a maneuver used by boys to get up from the ground when they have weakness in the hip girdle and quadriceps muscles,” says Peter B. Kang, MD, FAAN, a pediatric neurologist and vice chair of research in the department of neurology at the University of Minnesota Medical School in Minneapolis. The parents' worries were confirmed: 18 months after Matthew was diagnosed, Patrick received the same diagnosis, also at age 5.

When Matthew and Patrick were diagnosed, in 1997 and 1999 respectively, the future was bleak, says Brian. Since the passage of the Muscular Dystrophy CARE (Community Assistance, Research, and Education) Act in 2001, prospects for day-to-day function and survival have improved, he says.

There are many types of muscular dystrophy, all of which are caused by gene mutations that result in muscle weakness. With Duchenne, “patients are missing a critical protein in muscle called dystrophin because of a genetic mutation in the dystrophin gene,” says Paula Clemens, MD, professor of neurology at the University of Pittsburgh School of Medicine. That missing protein, she says, is right at the muscle fiber membrane, which makes muscles more fragile, breaking down easily even with normal movement. Muscle can regenerate to a point, Dr. Clemens says, “but ultimately, it fails and is replaced by fibrous connective tissue.”

Duchenne appears primarily in boys because the dystrophin gene is on the X chromosome. Since males have only one X chromosome and females have two, “boys have a complete genetic mutation, while girls have some dystrophin [from the chromosome without a mutation],” Dr. Clemens explains. In general, most girls who have the mutation are carriers and do not manifest the disease. In girls who do develop it, symptoms are typically much milder than they are in boys, who have no dystrophin.

Duchenne muscular dystrophy is a multisystem disease, which means it affects not just the skeletal muscles throughout the body but also the respiratory muscles and heart muscle. Because of that and its rapid progression early in childhood, the condition is more profoundly disabling than other dystrophies, says Tracey Willis, MD, a neuromuscular specialist at the Robert Jones and Agnes Hunt Orthopaedic Hospital in England's West Midlands region.

The first signs are weakness in the pelvic and leg muscles near the hips beginning around age 2 or 3, which affects the ability to run, jump, get off the floor, and pedal a bicycle. Boys sometimes have enlarged calves, which Dr. Willis describes as a “false-looking muscle bulk” known as pseudohypertrophy. Boys also may experience delayed speech and language development, autistic features, and learning disabilities. As the disease progresses, it can affect the heart and respiratory system, and patients may require ventilators and heart medication. Children may develop scoliosis, usually once they can no longer walk and are in wheelchairs. Historically, most people with Duchenne were unlikely to live beyond their late teen years. Now, due to increased standards of care, steroid treatments, and new therapies, many live into their thirties.

Over the years, the Dengers witnessed the different ways the disease can manifest. By the time he was 8, Matthew could no longer walk. When he was a teenager, he couldn't dress, bathe, or use the toilet. He also needed breathing support and couldn't turn himself in bed on his own. In 2013, Matthew died of heart failure at age 20.

Patrick, on the other hand, was able to walk until he was 13. Now 27, he is a college graduate and can feed himself and drive a car. “Once he's up in his powered wheelchair, Patrick enjoys a level of independence many don't,” says Brian.

Evolving Options

When Matthew and Patrick were diagnosed, the only treatment was prednisone, a steroid that seems to slow progression. “We think it reduces inflammation,” says Dr. Clemens.

It is standard to put boys on steroids, says Dr. Kang. “They can prolong a child's ambulatory phase by one to three years,” he says. But side effects, including weight gain, poor growth, behavioral changes, and bone demineralization, cause significant long-term problems. For years, the only other treatments available were those that address complications: for example, breathing devices for respiratory difficulty, medications for cardiac complications, and surgeries for scoliosis.

In 2016, however, the US Food and Drug Administration (FDA) approved eteplirsen for patients who have specific mutation types within the dystrophin gene—about 13 percent of boys who have Duchenne. The brand name is Exondys 51, after the exon that contains the mutation. (An exon is an RNA-coding part of a gene.) Known as an exon-skipping therapy, eteplirsen prevents exon 51 from being included in the final messenger RNA, which then allows the body to produce more functional dystrophin protein and slow progression of the disease. Dr. Kang compares the process to removing a letter from a sentence that contains only three-letter words—such as “Red cat ate the rug”—with each letter representing a nucleotide and each word representing an amino acid in an RNA code. If you remove the t in “cat” and move each subsequent letter one space forward, the sentence is rendered nonsensical: Red caa tet her ug. Exon-skipping removes more letters from the code (ca, for example), with the result that the words make at least partial sense: Red ate the rug.

Four additional drugs have been approved by the FDA, although there has been some controversy over cost. “They all potentially can improve the course of the disease,” says Dr. Kang. “But there is room for additional treatments since none of the current ones are cures, and the approved exon-skipping drugs benefit only around 30 percent of Duchenne patients.”

Developing effective treatments is difficult because Duchenne muscular dystrophy affects so many parts of the body, says Dr. Clemens. “Skeletal muscle is around 40 percent of body mass—it's everywhere and governs everything from respiration to movement. The challenge is getting treatments efficiently to the places they need to be.”

In the United Kingdom (UK), where Dr. Willis practices, trials for gene therapy and other investigative disease-modifying drugs have begun. Currently, ataluren (Translarna) is approved for use in the UK for Duchenne, as are steroids. While hopeful about long-term outcomes of gene therapies and other trials, Dr. Willis says it's vital to focus on treating complications and symptoms. “We especially focus on maintaining mobility, preventing contractures, addressing bone health and scoliosis, assessing for cardiac and respiratory muscle weakness, and intervening before a problem develops,” she says. “We used to wait and then treat, but we now know that being proactive is much better than being reactive. A high standard of care is still the main thing we've got that seems to improve quality of life and longevity.”

Dr. Kang is optimistic about a cure or something close to it. “In the next decade, I think we'll have further improvements for these boys so that they walk longer and live longer and have a higher quality of life in general.”

Ripple Effect

“Duchenne affects every system of the person with the disease, but it also affects the family in ways that you don't anticipate,” says Brian Denger. Scenarios that could develop, he says, include the parents focusing so much on the child that they ignore their own needs and their relationship, and the emotional needs of their other children.

In addition, providing long-term caregiving, feeling guilty about the genetic link, and seeing a loved one struggle take a tremendous toll. Brian says that long-distance running has been therapeutic for him and that his family sought professional counseling to address their depression and heartache. They also reached out to the Duchenne muscular dystrophy community.

When Matthew was diagnosed, resources on the internet were modest, but Brian and Alice found a few families through parent-run sites who helped them deal with the disease and things like the school system and Medicaid waivers. “Those families provided guidance on how to look for resources locally, and we could then pass along the same information to other families.”

The Denger family misses Matthew deeply but celebrates the higher quality of life that Patrick is able to enjoy, Brian says. He is proud of his family and of his children as individuals. “People sometimes come up and say we do well as parents,” he says. “I always respond, ‘We have great kids; why wouldn't we?’ That's how we've always looked at it.”

Four Common Forms of Dystrophy

There are dozens of different genetic subtypes of muscular dystrophy. Duchenne muscular dystrophy is among the most severe, says Peter B. Kang, MD, FAAN, a pediatric neurologist and vice chair of research in the department of neurology at the University of Minnesota Medical School in Minneapolis. The condition is considered rare, with a prevalence in North America and Europe of about six per 100,000 individuals, according to the Muscular Dystrophy Association. Dr. Kang describes the three other common types after Duchenne, all of which affect males and females equally.

Myotonic (type 1 and 2)

Type 1 of this dystrophy, also known as Steinert disease, is generally more severe than type 2 and begins earlier in life. While both forms cause weakness of the voluntary muscles as well as myotonia—the inability to relax muscles—type 1 also can affect involuntary muscles. The prevalence rate is about 10 per 100,000 individuals.

Facioscapulohumeral dystrophy (FSHD)

FSHD symptoms usually begin during young adulthood, but they sometimes appear earlier. Muscle weakness in the face, shoulders, and upper arms is usually most severe, but other muscles are commonly affected, such as in the lower legs and abdomen. About four in 100,000 people have this type.

Limb-girdle

There are multiple, diverse types of limb-girdle, each defined by disease gene and inheritance. In all of them, weakness usually begins first in the muscles around the hips and shoulders. The estimated prevalence is two in every 100,000 individuals.

Clinical Trials

Families of youngsters with Duchenne muscular dystrophy should stay informed and engaged, advocate for research development, and participate in clinical trials, says Paula Clemens, MD, FAAN, professor of neurology at the University of Pittsburgh School of Medicine. “There's a tremendous need for families to participate in research. It will take involvement from patients, families, researchers, academics, and industry sponsors to move the needle forward on this condition.”

For information about trials, visit clinicaltrials.gov and type “Duchenne” in the search field. Here are two sample trials.

• What: The Children's National Research Institute is recruiting boys older than 2 for an investigation of the safety and efficacy of canakinumab on muscle inflammation, as demonstrated by short-term changes in select biomarkers.
• Where: Washington, DC
• For more information: Email Christopher F. Spurney, MD, at cspurney@childrensnational.org or call 202-476-2020.
  
  
• What: Stanford University is recruiting males between the ages of 7 and 21 for a study aimed at better understanding changes in heart health caused by Duchenne muscular dystrophy. MRI scans will be performed on healthy volunteers and those with the disease to help researchers identify and validate cardiac MRI biomarkers.
• Where: Palo Alto, CA
• For more information: Email Kifle Yohannes, MPH, at kifley@stanford.edu or call 650-724-4661.

Duchenne Muscular Dystrophy Resources

• American Academy of Neurology: BrainandLife.org/MuscularDystrophy
• Cure Duchenne: cureduchenne.org; 949-872-2552
• Jett Foundation: jettfoundation.org; 781-585-5566
• Muscular Dystrophy Association: mda.org; 800-572-1717
• National Institute of Neurological Disorders and Stroke: ninds.nih.gov; 800-352-9424
• National Organization for Rare Disorders: rarediseases.org; 617-249-7300
• Parent Project Muscular Dystrophy: parentprojectmd.org; 800-714-5437