Sadie’s short-term but severe leg pain didn’t change over the 5 ½ years she and her family searched for a diagnosis. But the world of genetics did. A new test, facilitated by the Roberts Individualized Medicine Genetics Center (IMGC) at Children’s Hospital of Philadelphia (CHOP), was the key to unlocking the mystery. 

Her health odyssey started when Sadie was 7. She had brief periods when her legs hurt, especially during or after activities like soccer or skiing. The pain didn’t last long and went away as quickly as it started. She continued to be active and enjoyed being a big sister to her new brother, Cameron.

Right before Christmas break, the school nurse called Sadie’s parents, Melissa and Kevin, to say Sadie had complained of severe groin pain. Sadie’s pediatrician ordered a blood test. The test revealed Sadie’s creatine kinase (CK) level was sky-high at 31,000 units per liter. A normal CK range for a child is up to 250 U/L. Creatine kinase, an enzyme in the heart, brain and skeletal muscles, leaks into the bloodstream when muscle tissue is damaged or undergoes stress. The results surprised their pediatrician so much that he suggested redoing the blood work. The second test’s results: 34,000 U/L.

Off to CHOP Neurology

He told the family that Sadie needed to see a pediatric neurologist ASAP. Her family chose Children’s Hospital of Philadelphia, even though it was three hours from their Lycoming County home. Melissa says:

“I had always heard wonderful things about CHOP, and we knew that was where we wanted to take Sadie.”

It was Dec. 27, 2012, when Sadie saw Brenda Banwell, MD, Chief of the Division of Neurology, and other members of CHOP’s Neuromuscular Program for the first time. Given Sadie’s symptoms, Dr. Banwell ordered extensive blood work to check for the leading causes of high CK levels: muscle disease, genetic metabolic disorders, or viruses. Everything came back normal.

“Over the next six months, Sadie’s symptoms increased in frequency and intensity,” Melissa says. “Most days, she had pain. Sometimes it was severe, but it never lasted more than an hour. It usually occurred in one leg at a time and didn’t favor one leg or specific area.”

Determining what it was not

Sadie made more trips to CHOP to make sure the high CK levels weren’t disrupting her heart and kidney functions. She had an electromyography/nerve conduction velocity test to look for muscle or nerve damage. She had two muscle biopsies to see what was going on at the cellular level. Normal all around. “We were ruling out a lot of ‘bad’ diagnoses,” Kevin says, “but we still didn’t know why Sadie was having these episodes.” Carsten G. Bönnemann, MD, a former CHOP physician now at the National Institutes of Health who returns to consult on tough cases in the Undiagnosed Neuromuscular Disease Clinic, was stumped as targeted genetic tests were negative.

To help relieve the symptoms, Sadie, then 8, started on prednisone, a steroid that did help with the pain but caused GI problems, weight gain, and affected her mood. “It was a lot for anyone to deal with, let alone an 8-year-old girl,” Melissa says.

The hunt continued, with an AMPS detour

Since prednisone helped, it pointed to inflammation. Perhaps her pain was triggered by some sort of autoimmune disease? Rheumatologist Melissa Lerman, MD, PhD, MSCE, joined Sadie’s team. “We tried many different meds — immunosuppressants, infusions of IVIG and Rituxan^® — hoping that we could get her off steroids, but nothing seemed to work,” Sadie’s mother says.

Normally an upbeat kid, Sadie was getting discouraged. “As the years passed, I felt scared and frustrated,” she says. “Even though I had great doctors and nurses, I was scared that I wouldn’t be able to walk because of the pain. I worried I would never get a diagnosis.”

Then, she started having severe and constant pain in her stomach that got worse when she ate. She missed 52 days of sixth grade and lost 12 pounds in five weeks because she only ate soup. Nothing helped; she was miserable. The complete GI workup at CHOP came back — what else? — normal.

But this time, Drs. Lerman and Banwell suspected a cause: amplified musculoskeletal pain syndrome, or AMPS, a medical condition that causes intense episodes of pain. Of the several causes for AMPS — stress, illness, injury, age and genetics — Sadie checked the box on a few. David D. Sherry, MD, who started the Center for Amplified Musculoskeletal Pain Syndrome at CHOP, outlined the intense treatment program of occupational and physical therapy Sadie would need to do to “break” the pain cycle.

She accepted the challenge, diligently did her exercises at home — with her family doing them along with her for motivation — and her AMPS gut pain went away. Her leg pain persisted, however. It was time to look again for a genetic cause.

Looking to genetics for answers

Because Sadie was adopted from China, it wasn’t possible for doctors to review a typical family medical history for clues. Genetic counselor Līvija Medne, MS, LCGC, Co-director of the Roberts IMGC, who first met Sadie in 2012, explained that a broad-scale approach with an exome 7 newly available genetic tests led to a rare genetic diagnosis for Sadie, 13, much to the relief of her parents, Melissa and Kevin, and brother, Cameron. Sequencing test — a more recently available test where all the approximately 20,000 human genes are analyzed at once — might provide an answer for Sadie’s unique symptoms.

The Roberts IMGC team cleared several hurdles to help the family obtain insurance coverage for exome sequencing. Sadie gave more blood; then they waited. “Dr. Banwell called on the Saturday of Labor Day weekend and asked if we could come Tuesday to meet with her and Liv,” Melissa says. “Could we meet with them? Of course!”

Sadie had a rare genetic muscle condition the neuromuscular community was just starting to learn about. It is caused by two identical mutations in the MLIP gene, expressed in the cardiac and skeletal muscle. Sadie is the first person on record in the United States with this disorder and the third recorded patient in the world; the others are in United Arab Emirates (diagnosed through the Roberts IMGC) and Japan. The condition is so rare, it doesn’t have a clever name yet, and information on it is very limited. The two other patients are faring well; the muscle symptoms aren’t progressing. Banwell recommended Sadie abstain from strenuous, endurance sports, like soccer, and stay well hydrated. She continues on a low dose of prednisone for now, and it’s helping.

“Once I got my diagnosis, I felt pretty lucky,” says Sadie, now 13.

“I have so many people who care about me and want to help me. Now that we know what’s causing my pain, I hope they can find a cure. And if they do, I hope that I can play soccer again!”