Diagnosing and Managing Duchenne Muscular Dystrophy: Tips for Practicing Clinicians
Diagnosing DMD
“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.6
Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.6 In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.
In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).6
The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.
If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).6 Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.4
The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.
Targeting Inflammation in DMD
Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.10
The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.11
In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.12 A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.13
“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.
The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.14
Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
