Scientists find possible treatment for muscle contractures in childhood paralysis

October 29, 2019

When children experience brachial plexus injury at birth, or are born with cerebral palsy, some of the most disabling problems that follow are muscle contractures, or tightness of muscles, that severely restrict limb function.

Over time, these muscle contractures disrupt skeletal growth, leading to pain, loss of mobility, and heavy reliance on costly health care and supportive services. Many affected children require surgeries and other treatments that can temporarily relieve symptoms but do not cure the contractures. This lack of effective treatments results from doctors not knowing how muscle contractures form in childhood paralysis. Until now.

Experts at Cincinnati Children's report that, in mice, a drug called bortezomib helped re-balance disrupted muscle growth and prevented the contractures that untreated mice displayed. This early-stage success suggests that future generations of children facing these conditions may be treated in new and far more effective ways.

The study was published online Oct. 29, 2019, in JCI Insight.

"After four weeks of treatment shortly after birth, our study found that bortezomib significantly reduced shoulder and elbow contractures in a mouse model that mimics these common childhood conditions," says Roger Cornwall, MD, Division of Pediatric Orthopaedics. "Future studies confirming the efficacy of this approach could ultimately render obsolete the destructive surgeries currently required to alleviate contractures in a variety of conditions."

Conditions affect 1 in every 200 newborns

The brachial plexus is a bundle of intertwined nerves running from the neck that control movement and sensation in the arm and hand. In some cases, these nerves can be damaged during childbirth, leading to weakness or even complete paralysis of an arm. While about two thirds of such injuries heal on their own, the rest can require nerve reconstruction and other therapies.

Cerebral palsy describes a variety of conditions in which brain damage or malfunction leads to muscle weakness and movement disorders. Causes include bleeding in the brain, infections, trauma and genetic variations.

Combined, these conditions are the most common causes of childhood paralysis, occurring once in every 200 births. While the conditions differ in origin, both lead to similar muscle contractures that limit how well the limbs can move, and alter how the skeleton grows, leading to bone deformities and joint dislocations.

Discovery focused on muscle growth disruption

Cornwall, co-author Douglas Millay, PhD, Division of Molecular Cardiovascular Biology, and colleagues developed and studied a mouse model that mimics brachial plexus injury. They found that contractures occurred because paralyzed muscles lacked the ability to grow normally in length when deprived of critical signaling input from normal nerve fibers during early muscle development.

They further learned that healthy longitudinal muscle growth depends primarily on a balance between the synthesis and breakdown of muscle proteins. Previously, scientists had assumed muscle growth to depend primarily on the activity of stem cells, which the authors found to not be required for specifically longitudinal muscle growth.

Using that information, the team tested the drug bortezomib, a chemotherapy agent known to inhibit protein breakdown, as a possible way to re-balance muscle growth at the cellular level. The drug made a dramatic impact, but also required a second medication to reduce toxicity that proved fatal to some mice early in the study.

The beneficial effects of the drug were strongest when administered soon after birth. It remains unclear how much older children might benefit from this approach, and it's unlikely that fully grown adults could be helped this way.

Given the potential toxicity of this medication, it also remains unclear whether bortezomib, currently FDA approved for cancer treatment in adults, will be considered safe enough to test in human children in clinical trials. But the early success still points the way for researchers to develop a more refined drug that eventually could transform childhood paralysis care.

"This discovery provides, for the first time, a proof of concept that something we have always considered to be a purely mechanical consequence of limb immobility is actually a biological problem with a medical, rather than physical, solution," Cornwall says.
-end-
Funding sources for this work include the National Institutes of Health (NIH) (R01AR068286, R01AG059605); the Pew Charitable Trusts; a Career Development Grant from the Orthopaedic Research and Education Foundation; the Cincinnati Children's Division of Orthopaedic Surgery; and the Junior Cooperative Society.

Cincinnati Children's Hospital Medical Center

Related Cerebral Palsy Articles from Brightsurf:

Study confirms genetic link in cerebral palsy
An international research team including the University of Adelaide has found further evidence that rare gene mutations can cause cerebral palsy, findings which could lead to earlier diagnosis and new treatments for this devastating movement disorder.

Cerebral palsy also has genetic underpinnings
Scientists have identified mutations in single genes that can be responsible for at least some cases of cerebral palsy, according to a new study led by researchers at Washington University School of Medicine in St.

About 14% of cerebral palsy cases may be tied to brain wiring genes
In an article published in Nature Genetics, NIH funded researchers confirm that about 14% of all cases of cerebral palsy, a disabling brain disorder for which there are no cures, may be linked to a patient's genes and suggest that many of those genes control how brain circuits become wired during early development.

How rehabilitation impacts research and care of patients with cerebral palsy
Cerebral palsy (CP) is one of the most common developmental movement disorders in children.

The risk of cerebral palsy linked to IVF has more than halved in the past two decades
Fifteen years ago a large population study from Denmark found a significantly increased risk of cerebral palsy in infants born as a result of assisted reproduction.

Orthotics breakthrough helps children with Cerebral Palsy walk and play
Children with Cerebral Palsy have more energy to play and be physically active for longer thanks to specially designed orthotics.

How a network of hospitals reduced average age at cerebral palsy diagnosis to 9.5 months
Five hospital systems in the United States have become the first in the world to successfully implement, in clinical practice, international CP diagnosis guidelines that were released in 2017.

Adults with cerebral palsy about twice as likely to develop non-communicable diseases
Adults with cerebral palsy are about twice as likely to develop cardiovascular disease and chronic respiratory disease compared to adults without cerebral palsy, according to a new study led by RCSI (Royal College of Surgeons in Ireland) and Brunel University London.

New insights: Improving function, independence and quality of life of individuals with cerebral palsy
Cerebral palsy (CP) is one of the most common movement disorders in children.

Adults with cerebral palsy at increased risk for mental health conditions
A new study finds that adults with cerebral palsy are at an increased risk of experiencing a mental health disorder compared to adults without the condition.

Read More: Cerebral Palsy News and Cerebral Palsy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.