Today, I review, link to, and excerpt from The Cribsiders‘ #120: Muscular Dystrophy – From Diagnosis to Hope for a Cure.*
*Ledingham L, Flanigan K, Masur S, Chiu C, Berk J. “#120: Muscular Dystrophy – From Diagnosis to Hopes for a Cure ”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ September 11, 2024.
All that follows is from the above resource.
Summary:
Join us for a fantastic conversation with an expert in the field of neuromuscular disorders, Dr. Kevin Flanigan. Dr. Flanigan is the director of the Center for Gene Therapy at Nationwide Children’s Hospitals, which developed the first FDA-approved gene therapy to treat Duchenne Muscular Dystrophy. He teaches us when to include muscular dystrophy in the differential, how BiPAP extends the lives of patients with Duchenne, and what the latest gene replacement therapies have to offer.
Muscular Dystrophy Pearls
- Have a low threshold to check a CK. If your patient has a speech delay, a motor delay, or elevated transaminases, grab a CK!
- Female genetic carriers of muscular dystrophy can exhibit symptoms similar to those of affected males; make sure not to neglect evaluation of the females in this X-linked disease.
- Regardless of genetic test results, look at the patient in front of you to treat and prognosticate effectively.
- Multidisciplinary teams are key to coordination and provision of excellent care for patients with muscular dystrophies.
- Although muscular dystrophy is currently a significantly limiting disease, research is rapidly advancing and there is hope that this may become a curable illness.
Muscular Dystrophy Notes
What is dystrophin?
Dystrophin is a critical protein in the muscle fiber membrane that works to stabilize the membrane. The gene encoding dystrophin is found on the X chromosome and is the largest known human gene, which makes it very susceptible to function-limiting mutations. Without it, the stress of repeated contracting and lengthening results in tears in the muscle membrane (that are actually visible under an electron microscope!) that causes CK to leak out and calcium to leak in. The excess calcium activates proteases that destroy the muscle fiber, leading to fibrosis and fatty replacement of the muscle tissue.
While some deterioration occurs in all individuals and everyone has regeneration capacity of muscle cells, the destruction far exceeds regeneration in muscular dystorphy.
When should I suspect muscular dystrophy?
- Proximal limb weakness
- Gower’s maneuver*: when a patient has to use their hands and arms to “walk” up their legs from a squatting position due to lack of hip and thigh muscle strength
- History of motor delay or not able to keep up with peers when running around
- Toe walking
- A family history of muscular dystrophy
- A slowly progressive, insidious disease course
*from neurosigns.org.
Women can have symptoms too!
Carrier females (females with one copy of the mutation) can have a disease phenotype ranging from mild to as severe as the affected boys. This variability in presentation is thought to be due to skewed X inactivation. Signs and symptoms may include exertional myalgias, cramping, muscle aches, mild elevations in CK, and cardiomyopathy.
What else is on the differential?
Congenital conditions: usually have a slowly progressive course and a family history of similar symptoms
- Duchenne muscular dystrophy (DMD): absent dystrophin; most common as dystrophin is a very large gene with potential for a lot of de novo mutations
- Becker muscular dystrophy (BMD): partially functioning dystrophin; describes any dystrophinopathy that is not Duchenne
- Congenital muscular dystrophy: symptoms present at birth or within the first year
- Limb girdle muscular dystrophy: weakness of the hips and shoulders
Acquired conditions
- Inflammatory myopathies: polymyositis, juvenile dermatomyositis, inclusion body myositis
- Myasthenia gravis
How do I diagnose muscular dystrophy?
- CHECK A CREATINE KINASE (CK)
If it’s elevated, it’s DMD until proven otherwise… if it’s not elevated, it’s most likely not DMD.
*CK has an activity dependent range. So if your muscular dystrophy patient has been sitting on the couch for the past week, it likely won’t be as impressively elevated as if the patient runs around all the time.
**AST and ALT can come from either liver OR muscle cells. So if you have elevated transaminases, check a CK (think muscle) and GGT (think liver) to determine the source of AST and ALT before performing an unnecessary liver biopsy!
2. If CK is elevated, order genetic testing (panel for muscular dystrophies).
Make sure to correlate clinically: if a genetic report comes back with a mutation predicting DMD, but the child in front of you is running up and down the hall at age 10, it’s not DMD
Do you ever need a muscle biopsy in these patients?
Although controversial, muscle biopsies are helpful in situations like these when the genetic report does not match the patient in front of you. The mutation does not always predict the degree of dystrophin dysfunction, so a muscle biopsy can help predict whether the patient will be walking until he’s 12 or 25 (which makes a big difference in the life of the patient).
3. If you haven’t already, refer to a center specializing in muscular dystrophies for ongoing care!
Your patient is diagnosed with DMD… What’s next?
Plan for a long first visit to discuss the diagnosis. This is a life changing diagnosis for the family. Take the time, have empathy, and do not try to cover everything all at once.
Referrals: DMD affects many organ systems. Not all of these referrals have to happen at once, however. Multidisciplinary clinics that offer families the opportunity to see multiple specialties in a single day improve patient care and experience, particularly as the patient ages and becomes more dependent.
- Genetic counseling: immediately after diagnosis. They can help understand mom’s risk and can inform future family planning
- Cardiology: all affected boys should have cardiac imaging by age 5 (either an echo or cardiac MRI)
- Pulmonology: Patients with DMD develop restrictive respiratory weakness
- Orthopedics: to perform scoliosis surgery to improve restrictive breathing
- Endocrinology: to help manage long term effects of steroid use
- Psychiatry and psychology: to manage the psychological effects of diagnosis, as well as evaluate for cognitive dysfunction. There is a form of dystrophin in the brain such that many patients with DMD have mild to moderate cognitive dysfunction, anxiety, or behavioral concerns and should have early testing to ensure they get appropriate support in school
- Physical and occupational therapy
What is the treatment for DMD?
Steroids are the mainstay of treatment and can add an ambulation time of 1 – 3 years. Side effects include weight gain, osteoporosis, and diabetes.
Expert opinion: The most effective steroid regimen varies between providers. Historically, physicians have favored a daily steroid dosing regimen. More recently, research has supported an intermittent dosing schedule (e.g. dosing every Saturday and Sunday) that provides the same benefits but reduces possible side effects.
Most patients are started on ACE inhibitors by age 8 and 9 to theoretically slow development of cardiomyopathy, although this has not been proven in the literature. Some patients may require a beta-blocker for sinus tachycardia that worsens with loss of ambulation.
All patients should undergo early and frequent screening for nighttime hypoventilation (ask about morning headaches, interrupted sleep, poor sleep quality, etc) and use nocturnal noninvasive ventilatory support at the first signs of hypoventilation. NIPPV has been shown to improve survival in DMD.
I hear gene therapy is a hot topic these days. How does this relate to DMD?
GENE therapy is different from GENETIC therapy.
Genetic therapy works to modify existing genes to enhance the capabilities of the corresponding protein. In DMD, genetic therapy consists of exon-skipping therapies that help make some functional dystrophin. Genetic therapies have been available for years.
Gene therapy works to correct genetic defects to prevent or cure genetic diseases. The first gene therapy for DMD received FDA approval in 2023. It works by introducing a shortened, functional form of dystrophin that is linked to adenovirus. Because the gene is linked to an adenovirus, individuals with adeno-associated viral antibodies are not eligible for treatment. Adenovirus also preferentially infects hepatocytes, which means that there is a high risk of liver toxicity associated with this therapy. Ongoing research is directed to modifying the viral capsid to direct delivery to specific cells.
Other Stuff
Citations
Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, Cripe L, Herron AR, Kennedy A, Kinnett K, Naprawa J, Noritz G, Poysky J, Street N, Trout CJ, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7. Epub 2018 Feb 2. PMID: 29398641; PMCID: PMC5902408.
D’Ambrosio ES, Mendell JR. Evolving Therapeutic Options for the Treatment of Duchenne Muscular Dystrophy. Neurotherapeutics. 2023 Oct;20(6):1669-1681. doi: 10.1007/s13311-023-01423-y. Epub 2023 Sep 6. PMID: 37673849.
Brian Faux; Muscular Dystrophy. Quick References 2023; 10.1542/aap.ppcqr.396198
Waldrop MA, Flanigan KM. Update in Duchenne and Becker muscular dystrophy. Curr Opin Neurol. 2019 Oct;32(5):722-727. doi: 10.1097/WCO.0000000000000739. PMID: 31343429.
Wein N, Alfano L, Flanigan KM. Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008. Epub 2015 Apr 20. PMID: 26022172.
